Two genetically confirmed Japanese cases of Birt Hogg Dube syndrome presenting with pneumothorax including early onset bilateral renal tumors in one case

Two genetically confirmed Japanese cases of Birt Hogg Dube syndrome presenting with pneumothorax including early onset bilateral renal tumors in one case | 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 Two genetically confirmed Japanese cases of Birt Hogg Dube syndrome presenting with pneumothorax including early onset bilateral renal tumors in one case Eitetsu Koh, Yasuo Sekine, Tadao Nakazawa This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7957154/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: Birt Hogg Dube (BHD) syndrome is an autosomal dominant disorder caused by pathogenic variants in FLCN . It characteristically features multiple pulmonary cysts and spontaneous pneumothorax, renal tumors, and cutaneous fibrofolliculomas, with renal tumors most often diagnosed in middle age [1–3] . Case presentation: We report two genetically confirmed Japanese patients with contrasting BHD phenotypes. Case 1 was a 25-year-old woman with recurrent bilateral pneumothorax and basally predominant subpleural cysts; sequencing identified an FLCN splice variant (c.1062+1G>A). Abdominal imaging showed no renal lesions, and she remains under surveillance. Case 2 was a 29-year-old man with right pneumothorax, multiple facial papules consistent with fibrofolliculomas, and bilateral renal tumors; genetic testing detected the recurrent frameshift variant FLCN c.1285dupC (exon 11). He underwent bilateral nephron-sparing surgery, and pathology revealed hybrid oncocytic/chromophobe tumors. Conclusions: These cases illustrate the phenotypic spectrum of BHD in young adults and support early FLCN testing in recurrent pneumothorax to enable risk-adapted renal surveillance and timely nephron-sparing management [1–3,6] . Only one patient developed early-onset bilateral renal tumors (Case 2). Figures Figure 1 Figure 2 Introduction Birt Hogg Dube (BHD) syndrome is a rare autosomal dominant disorder due to pathogenic variants in FLCN on chromosome 17p11.2 and is classically associated with pulmonary cysts and spontaneous pneumothorax, renal tumors, and cutaneous fibrofolliculomas [ 1 , 2 ]. Clinical expression is heterogeneous; many patients manifest only a subset of features for years [ 1 ]. Renal tumors most often arise in middle age and include chromophobe renal cell carcinoma, oncocytoma, or hybrid oncocytic/chromophobe histology; they are frequently multifocal and bilateral, favoring nephron-sparing strategies when intervention is indicated [ 1 – 3 ]. On chest CT, BHD-related cysts show a characteristic pattern— subpleural and basally predominant, often elliptical/multilocular —helping distinguish BHD from primary spontaneous pneumothorax due to apical blebs [ 4 ]. In Japanese cohorts, several FLCN variants recur, notably c.1285dupC (exon 11) [ 5 ]. Cohort data quantify risks of pneumothorax and renal neoplasia and underscore the need for structured, lifelong surveillance once the diagnosis is established [ 1 – 3 , 6 ]. We present two genetically confirmed Japanese patients—a young woman with isolated pulmonary disease and a young man with the full triad including bilateral renal tumors in his twenties—to highlight imaging cues that should prompt FLCN testing and to emphasize implications for early renal surveillance. Materials and Methods Patient selection and consent. Two patients who presented with recurrent primary spontaneous pneumothorax to our institution between 2020 and 2024 were retrospectively reviewed. Both were evaluated for BHD on clinical and radiologic grounds and underwent confirmatory genetic testing. Written informed consent for participation and publication (including images) was obtained from both patients. Ethics approval for this case report was waived by the Ethics Review Committee of Tokyo Women’s Medical University Yachiyo Medical Center. Clinical data and imaging. Demographics, clinical history, dermatologic findings, and operative/pathology reports were abstracted. Chest CT was reviewed for number, size, and distribution of cysts, with attention to subpleural and basilar predominance [4] . Abdominal CT/MRI was reviewed for presence, size, and laterality of renal tumors [1–3] . Genetic testing. Genomic DNA was extracted from peripheral blood. Direct sequencing of FLCN was performed using standard methods. Variants were reported in HGVS nomenclature [5] . Case Presentations Case 1. A 25-year-old woman presented with recurrent chest pain. She had a history of right-sided spontaneous pneumothorax at age 21 treated by video-assisted thoracoscopic surgery. Four years later, she developed left-sided pneumothorax and was admitted to our hospital. Chest CT at recurrence demonstrated multiple subpleural, basally predominant cysts without a substantial interval increase in cyst burden relative to the earlier event [4] . She was a non-smoker with no personal or family history of renal tumors, cutaneous papules, or spontaneous pneumothorax. Dermatologic examination was unremarkable. Genetic analysis identified an FLCN splice donor variant ( c.1062+1G>A ) [5] . No renal tumors were detected on abdominal imaging. She remains under surveillance without further pneumothorax or renal lesions to date. Case 2. A 29-year-old man was referred for persistent air leak despite chest drainage for right spontaneous pneumothorax. Chest CT revealed numerous subpleural cysts with basilar predominance [4] . Dermatologic examination showed multiple facial papules compatible with fibrofolliculomas. Abdominal imaging demonstrated bilateral renal tumors [1–3,6] . He was a non-smoker with no contributory family history. Genetic testing detected a frameshift variant, FLCN c.1285dupC (exon 11) [5] . He underwent bilateral partial nephrectomies ; pathology confirmed hybrid oncocytic/chromophobe tumors [1–3] . He remains under multidisciplinary follow-up with no evidence of recurrence or metastasis. Discussion These cases bracket the early-adult spectrum of BHD. Case 1 shows isolated thoracic disease with recurrent bilateral pneumothorax and an FLCN splice-site variant (c.1062 + 1G > A). Case 2 demonstrates syndromic involvement with fibrofolliculomas, bilateral renal tumors in the third decade, and the recurrent Japanese variant c.1285dupC [ 1 , 5 ]. Absence of family history or extrathoracic findings does not exclude BHD; in young adults with recurrent pneumothorax, the basally predominant, subpleural cyst pattern on CT should prompt targeted FLCN testing [ 1 , 4 , 5 ]. Although renal tumors typically present in middle age, clinically significant bilateral tumors can occur in the twenties, supporting early surveillance once a pathogenic FLCN variant is confirmed and nephron-sparing management when intervention is required [ 1 – 3 , 6 ]. Practical implications. For young adults with recurrent pneumothorax, we recommend: (1) reviewing CT for the BHD pattern (subpleural/basal-predominant, often elliptical/multilocular) [ 4 ]; (2) eliciting personal/family history of pneumothorax, fibrofolliculomas, or renal tumors while recognizing that history may be negative [ 1 , 2 ]; (3) proceeding to FLCN sequencing when imaging is suggestive [ 1 , 5 ]; and (4) arranging multidisciplinary follow-up with renal surveillance when a pathogenic variant is identified [ 1 – 3 , 6 ]. When renal tumors are detected, nephron-sparing strategies should be prioritized given the propensity for multifocality/bilaterality and lifelong risk [ 1 – 3 ]. Limitations. This is a small case series with limited follow-up; precise risk estimation is beyond scope [ 1 – 3 , 6 ]. Conclusions Young adults with recurrent pneumothorax and basally predominant subpleural cysts should be evaluated for BHD with FLCN testing. A confirmed diagnosis justifies early renal surveillance and, when needed, nephron-sparing intervention —even in the third decade—within a multidisciplinary framework [1–3,6] . Only one of our two patients developed early-onset bilateral renal tumors. Declarations Ethical Approval and accordance This case report was conducted in accordance with the Declaration of Helsinki and relevant institutional guidelines and regulations. Ethics approval was waived by the Ethics Review Committee of Tokyo Women’s Medical University Yachiyo Medical Center. Written informed consent for participation and for publication of clinical details and images was obtained from both patients. Clinical trial number: Not applicable. Availability of data and materials: De-identified data are available from the corresponding author on reasonable request. Competing interests: The authors declare no competing interests. Funding: No specific funding was received for this work. Authors’ contributions: EK collected clinical data and drafted the manuscript; YS provided surgical management and critical revision; TN performed pathologic evaluation and critical revision. All authors approved the final version. References Menko FH, van Steensel MAM, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199–1206. doi:10.1016/S1470-2045(09)70188-3. Toro JR, Glenn G, Duray P, et al. Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135(10):1195–1202. doi:10.1001/archderm.135.10.1195. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11(4):393–400. PMID: 11948100（※ご希望ならQCのPMIDに合わせて11927500→11948100を採用可）. Furuya M, Nakatani Y. Birt-Hogg-Dubé syndrome: clinicopathological features of the lung. J Clin Pathol. 2013;66(3):178–186. doi:10.1136/jclinpath-2012-201200. Kunogi M, Kurihara M, Ikegami TS, et al. Clinical and genetic spectrum of Birt-Hogg-Dubé syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010;47(4):281–287. doi:10.1136/jmg.2009.070565. Houweling AC, Gijezen LM, Jonker MA, et al. Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer. 2011;105(12):1912–1919. doi:10.1038/bjc.2011.463. Additional Declarations No competing interests reported. Supplementary Files ResearchSquare.docx Take.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 15 Dec, 2025 Reviews received at journal 12 Dec, 2025 Reviews received at journal 11 Dec, 2025 Reviewers agreed at journal 10 Dec, 2025 Reviewers agreed at journal 09 Dec, 2025 Reviewers invited by journal 07 Dec, 2025 Editor invited by journal 02 Dec, 2025 Editor assigned by journal 01 Dec, 2025 Submission checks completed at journal 27 Nov, 2025 First submitted to journal 27 Nov, 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. We do this by developing innovative software and high quality services for the global research community. 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class=\"CitationRef\"\u003e2\u003c/span\u003e]. Clinical expression is heterogeneous; many patients manifest only a subset of features for years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Renal tumors most often arise in middle age and include chromophobe renal cell carcinoma, oncocytoma, or hybrid oncocytic/chromophobe histology; they are frequently multifocal and bilateral, favoring nephron-sparing strategies when intervention is indicated [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. On chest CT, BHD-related cysts show a characteristic pattern\u0026mdash;\u003cb\u003esubpleural and basally predominant, often elliptical/multilocular\u003c/b\u003e\u0026mdash;helping distinguish BHD from primary spontaneous pneumothorax due to apical blebs [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In Japanese cohorts, several \u003cb\u003eFLCN\u003c/b\u003e variants recur, notably \u003cb\u003ec.1285dupC (exon 11)\u003c/b\u003e [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Cohort data quantify risks of pneumothorax and renal neoplasia and underscore the need for \u003cb\u003estructured, lifelong surveillance\u003c/b\u003e once the diagnosis is established [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe present two genetically confirmed Japanese patients\u0026mdash;a young woman with isolated pulmonary disease and a young man with the full triad including bilateral renal tumors in his twenties\u0026mdash;to highlight imaging cues that should prompt \u003cb\u003eFLCN\u003c/b\u003e testing and to emphasize implications for early renal surveillance.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003ePatient selection and consent.\u003c/strong\u003e Two patients who presented with recurrent primary spontaneous pneumothorax to our institution between 2020 and 2024 were retrospectively reviewed. Both were evaluated for BHD on clinical and radiologic grounds and underwent confirmatory genetic testing. Written informed consent for participation and publication (including images) was obtained from both patients. Ethics approval for this case report was\u0026nbsp;\u003cstrong\u003ewaived\u003c/strong\u003e by the Ethics Review Committee of Tokyo Women’s Medical University Yachiyo Medical Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical data and imaging.\u003c/strong\u003e Demographics, clinical history, dermatologic findings, and operative/pathology reports were abstracted. Chest CT was reviewed for number, size, and distribution of cysts, with attention to \u003cstrong\u003esubpleural\u003c/strong\u003e and \u003cstrong\u003ebasilar\u003c/strong\u003e predominance \u003cstrong\u003e[4]\u003c/strong\u003e. Abdominal CT/MRI was reviewed for presence, size, and laterality of renal tumors\u0026nbsp;\u003cstrong\u003e[1–3]\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic testing.\u003c/strong\u003e Genomic DNA was extracted from peripheral blood. Direct sequencing of \u003cstrong\u003eFLCN\u003c/strong\u003e was performed using standard methods. Variants were reported in HGVS nomenclature \u003cstrong\u003e[5]\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Case Presentations","content":"\u003cp\u003e\u003cstrong\u003eCase 1.\u003c/strong\u003e A 25-year-old woman presented with recurrent chest pain. She had a history of right-sided spontaneous pneumothorax at age 21 treated by video-assisted thoracoscopic surgery. Four years later, she developed left-sided pneumothorax and was admitted to our hospital. Chest CT at recurrence demonstrated \u003cstrong\u003emultiple subpleural, basally predominant cysts\u003c/strong\u003e without a substantial interval increase in cyst burden relative to the earlier event \u003cstrong\u003e[4]\u003c/strong\u003e. She was a non-smoker with no personal or family history of renal tumors, cutaneous papules, or spontaneous pneumothorax. Dermatologic examination was unremarkable. Genetic analysis identified an \u003cstrong\u003eFLCN\u003c/strong\u003e splice donor variant (\u003cstrong\u003ec.1062+1G\u0026gt;A\u003c/strong\u003e) \u003cstrong\u003e[5]\u003c/strong\u003e. No renal tumors were detected on abdominal imaging. She remains under surveillance without further pneumothorax or renal lesions to date.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2.\u003c/strong\u003e A 29-year-old man was referred for persistent air leak despite chest drainage for right spontaneous pneumothorax. Chest CT revealed numerous subpleural cysts with basilar predominance \u003cstrong\u003e[4]\u003c/strong\u003e. Dermatologic examination showed \u003cstrong\u003emultiple facial papules\u003c/strong\u003e compatible with fibrofolliculomas. Abdominal imaging demonstrated \u003cstrong\u003ebilateral renal tumors\u003c/strong\u003e \u003cstrong\u003e[1–3,6]\u003c/strong\u003e. He was a non-smoker with no contributory family history. Genetic testing detected a frameshift variant, \u003cstrong\u003eFLCN c.1285dupC (exon 11)\u003c/strong\u003e \u003cstrong\u003e[5]\u003c/strong\u003e. He underwent \u003cstrong\u003ebilateral partial nephrectomies\u003c/strong\u003e; pathology confirmed \u003cstrong\u003ehybrid oncocytic/chromophobe tumors\u003c/strong\u003e \u003cstrong\u003e[1–3]\u003c/strong\u003e. He remains under multidisciplinary follow-up with no evidence of recurrence or metastasis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThese cases bracket the early-adult spectrum of BHD. \u003cb\u003eCase\u003c/b\u003e \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e\u003cb\u003e1\u003c/b\u003e\u003c/span\u003e shows isolated thoracic disease with recurrent bilateral pneumothorax and an \u003cb\u003eFLCN\u003c/b\u003e splice-site variant (c.1062\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A). \u003cb\u003eCase\u003c/b\u003e \u003cspan refid=\"FPar2\" class=\"InternalRef\"\u003e\u003cb\u003e2\u003c/b\u003e\u003c/span\u003e demonstrates syndromic involvement with fibrofolliculomas, bilateral renal tumors in the third decade, and the recurrent Japanese variant \u003cb\u003ec.1285dupC\u003c/b\u003e [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Absence of family history or extrathoracic findings does not exclude BHD; in young adults with recurrent pneumothorax, the \u003cb\u003ebasally predominant, subpleural cyst pattern on CT\u003c/b\u003e should prompt targeted \u003cb\u003eFLCN\u003c/b\u003e testing [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although renal tumors typically present in middle age, clinically significant \u003cb\u003ebilateral\u003c/b\u003e tumors can occur in the twenties, supporting \u003cb\u003eearly surveillance\u003c/b\u003e once a pathogenic \u003cb\u003eFLCN\u003c/b\u003e variant is confirmed and \u003cb\u003enephron-sparing management\u003c/b\u003e when intervention is required [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003ePractical implications.\u003c/b\u003e For young adults with recurrent pneumothorax, we recommend: (1) reviewing CT for the BHD pattern (subpleural/basal-predominant, often elliptical/multilocular) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]; (2) eliciting personal/family history of pneumothorax, fibrofolliculomas, or renal tumors while recognizing that history may be negative [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]; (3) proceeding to \u003cb\u003eFLCN\u003c/b\u003e sequencing when imaging is suggestive [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]; and (4) arranging multidisciplinary follow-up with \u003cb\u003erenal surveillance\u003c/b\u003e when a pathogenic variant is identified [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. When renal tumors are detected, \u003cb\u003enephron-sparing strategies\u003c/b\u003e should be prioritized given the propensity for multifocality/bilaterality and lifelong risk [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations.\u003c/b\u003e This is a small case series with limited follow-up; precise risk estimation is beyond scope [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eYoung adults with recurrent pneumothorax and basally predominant subpleural cysts should be evaluated for BHD with \u003cstrong\u003eFLCN\u003c/strong\u003e testing. A confirmed diagnosis justifies \u003cstrong\u003eearly renal surveillance\u003c/strong\u003e and, when needed, \u003cstrong\u003enephron-sparing intervention\u003c/strong\u003e—even in the third decade—within a multidisciplinary framework \u003cstrong\u003e[1–3,6]\u003c/strong\u003e. Only one of our two patients developed early-onset bilateral renal tumors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and accordance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was conducted \u003cstrong\u003ein accordance with the Declaration of Helsinki\u003c/strong\u003e and relevant institutional guidelines and regulations. \u003cstrong\u003eEthics approval was waived by the Ethics Review Committee of Tokyo Women\u0026rsquo;s Medical University Yachiyo Medical Center.\u003c/strong\u003e Written informed consent for participation and for publication of clinical details and images was obtained from both patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e Not applicable.\u003cbr\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e De-identified data are available from the corresponding author on reasonable request.\u003cbr\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare no competing interests.\u003cbr\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No specific funding was received for this work.\u003cbr\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e EK collected clinical data and drafted the manuscript; YS provided surgical management and critical revision; TN performed pathologic evaluation and critical revision. All authors approved the final version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMenko FH, van Steensel MAM, Giraud S, et al. Birt-Hogg-Dub\u0026eacute; syndrome: diagnosis and management. \u003cem\u003eLancet Oncol.\u003c/em\u003e 2009;10(12):1199\u0026ndash;1206. doi:10.1016/S1470-2045(09)70188-3.\u003c/li\u003e\n \u003cli\u003eToro JR, Glenn G, Duray P, et al. Birt-Hogg-Dub\u0026eacute; syndrome: a novel marker of kidney neoplasia. \u003cem\u003eArch Dermatol.\u003c/em\u003e 1999;135(10):1195\u0026ndash;1202. doi:10.1001/archderm.135.10.1195.\u003c/li\u003e\n \u003cli\u003eZbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dub\u0026eacute; syndrome. \u003cem\u003eCancer Epidemiol Biomarkers Prev.\u003c/em\u003e 2002;11(4):393\u0026ndash;400. PMID: 11948100（※ご希望ならQCのPMIDに合わせて11927500\u0026rarr;11948100を採用可）.\u003c/li\u003e\n \u003cli\u003eFuruya M, Nakatani Y. Birt-Hogg-Dub\u0026eacute; syndrome: clinicopathological features of the lung. \u003cem\u003eJ Clin Pathol.\u003c/em\u003e 2013;66(3):178\u0026ndash;186. doi:10.1136/jclinpath-2012-201200.\u003c/li\u003e\n \u003cli\u003eKunogi M, Kurihara M, Ikegami TS, et al. Clinical and genetic spectrum of Birt-Hogg-Dub\u0026eacute; syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. \u003cem\u003eJ Med Genet.\u003c/em\u003e 2010;47(4):281\u0026ndash;287. doi:10.1136/jmg.2009.070565.\u003c/li\u003e\n \u003cli\u003eHouweling AC, Gijezen LM, Jonker MA, et al. Renal cancer and pneumothorax risk in Birt-Hogg-Dub\u0026eacute; syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. \u003cem\u003eBr J Cancer.\u003c/em\u003e 2011;105(12):1912\u0026ndash;1919. doi:10.1038/bjc.2011.463.\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":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7957154/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7957154/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Birt Hogg Dube (BHD) syndrome is an autosomal dominant disorder caused by pathogenic variants in \u003cstrong\u003eFLCN\u003c/strong\u003e. It characteristically features multiple pulmonary cysts and spontaneous pneumothorax, renal tumors, and cutaneous fibrofolliculomas, with renal tumors most often diagnosed in middle age \u003cstrong\u003e[1–3]\u003c/strong\u003e.\u003cbr\u003e\n \u003cstrong\u003eCase presentation:\u003c/strong\u003e We report two genetically confirmed Japanese patients with contrasting BHD phenotypes. \u003cstrong\u003eCase 1\u003c/strong\u003e was a 25-year-old woman with recurrent bilateral pneumothorax and basally predominant subpleural cysts; sequencing identified an \u003cstrong\u003eFLCN\u003c/strong\u003e splice variant (c.1062+1G\u0026gt;A). Abdominal imaging showed no renal lesions, and she remains under surveillance. \u003cstrong\u003eCase 2\u003c/strong\u003ewas a 29-year-old man with right pneumothorax, multiple facial papules consistent with fibrofolliculomas, and bilateral renal tumors; genetic testing detected the recurrent frameshift variant \u003cstrong\u003eFLCN\u003c/strong\u003e c.1285dupC (exon 11). He underwent bilateral nephron-sparing surgery, and pathology revealed hybrid oncocytic/chromophobe tumors.\u003cbr\u003e\n \u003cstrong\u003eConclusions:\u003c/strong\u003e These cases illustrate the phenotypic spectrum of BHD in young adults and support early \u003cstrong\u003eFLCN\u003c/strong\u003e testing in recurrent pneumothorax to enable risk-adapted renal surveillance and timely nephron-sparing management \u003cstrong\u003e[1–3,6]\u003c/strong\u003e. Only one patient developed early-onset bilateral renal tumors (Case 2).\u003c/p\u003e","manuscriptTitle":"Two genetically confirmed Japanese cases of Birt Hogg Dube syndrome presenting with pneumothorax including early onset bilateral renal tumors in one case","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-15 21:12:18","doi":"10.21203/rs.3.rs-7957154/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-15T10:01:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-12T14:50:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-11T22:51:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308062552849404632277066059990665644577","date":"2025-12-10T15:15:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34102655327488637058459177006041971776","date":"2025-12-09T14:00:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-07T13:38:06+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-02T12:09:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-01T13:36:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-27T09:39:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Medicine","date":"2025-11-27T09:07:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5240848c-fbba-43b7-ab0d-9a6fa8aa8ef2","owner":[],"postedDate":"December 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T08:40:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-15 21:12:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7957154","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7957154","identity":"rs-7957154","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}