A special case study of Birt–Hogg–Dubé syndrome

A special case study of Birt–Hogg–Dubé syndrome | 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Cite Share Download PDF Case Report A special case study of Birt–Hogg–Dubé syndrome Yan Zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6548870/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Birt-Hogg-Dubé (BHD) syndrome, an autosomal dominantly inherited disorder, manifests primary through triad clinical features: pulmonary cysts, pneumothorax, fibrofolliculomas, and renal tumors. While respiratory symptoms like spontaneous pneumothorax often constitute initial clinical presentations, but the majority of patients remain clinically asymptomatic. The molecular basis of this condition stems from germline mutations in the folliculin (FLCN) gene (chromosomal locus 17p11.2). Genetic analyses have identified heterogeneous FLCN mutations spanning the entire coding region, including frameshift insertions/deletions and pathogenic nonsense variants. More than 600 BHDS families have been reported so far. BHD syndrome research is less frequent in Chinese patients than in European and American patients. This article delineates a novel Chinese BHDS case with molecular confirmation, supplemented by a systematic review of existing literature to address current knowledge gaps. Birt-Hogg-Dubé syndrome FLCN pulmonary cysts Figures Figure 1 Figure 2 Figure 3 Figure 4 Case report In mid-2019, a previously healthy 29-year-old woman presented to the emergency department with acute-onset spontaneous pneumothorax (SP) persisting for 48 hours. The episode occurred without identifiable predisposing factors, as confirmed through comprehensive medical history review and environmental exposure assessment. Actually, spontaneous pneumothorax has a occurred 3 times in the past month, and the patients were dealt with closed thoracic drainage. Besides, the patient informed that her mother and her sister has pulmonary bulla. And her sister has history of spontaneous pneumothorax. High-resolution computed tomography (HRCT) scan showed right pneumothorax with 50% lung compression, multiple cystic pulmonary sacs in both lungs, right pulmonary bulla, which was suggestive of BHDS (Fig. 1 ). Based on the above speculation, the patient take Pulmonary function tests and enhanced abdominal CT, which were normal. We noticed that multiple, white, slightly elevated pimples located in her upper arm, neck(Fig. 2 ). Skin biopsy of the upper arm showed that the epidermis was normal in microscopic examination, with a few mononuclear cells infiltrating around small vessels in the superficial dermis, and collagen in the dermal fibrous tissue(Fig. 3 ). Germline sequencing analysis identified a clinically validated pathogenic variant in the FLCN locus, specifically a splice-site frameshift deletion [c.1177-5_1177-3delCTC] (Fig. 4 ), an important basis for diagnosis.. Unfortunately, we don't know the source of the mutation for no providing her parent samples. Discussion Birt-Hogg-Dubé syndrome (BHDS) was initially characterized in the late 20th century[1]. Current evidence reveals significant epidemiological knowledge gaps, particularly regarding disease prevalence in East Asian populations. Contrastingly, western registry data demonstrate high penetrance of pathognomonic cutaneous manifestations, with fibrofolliculomas affecting >80% of confirmed cases in North American and European cohorts. Population-based registries estimate renal pathology prevalence in BHDS cohorts at 15-35%[2]. Notably, multinational comparative studies demonstrate significant interethnic variation, with East Asian populations exhibiting lower incidence rates [3]. A seminal Chinese study (Ding et al., 2023) involving 8 multigenerational pedigrees (n=40 genetically confirmed cases) demonstrated striking phenotypic divergence: pathognomonic dermatological features manifested in 20% penetrance (8/40), while renal manifestations showed complete absence - contrasting sharply with Western epidemiological benchmarks [4]. Lung manifestations The main pulmonary manifestation of BHD is basilar and peripheral bullous changes and parenchymal cysts. Multiple pulmonary cysts occur in approximately 67–90% of BHDS patients [5]. Pulmonary cysts are bilateral, middle and lower basal lung zones in location, irregular in shape, varying in size and thin-walled (Figure 1)[9]. Basal location and large size of the cysts are associated with an increased risk of SP[5,6,10]. Spontaneous pneumothorax (SP) in BHDS predominantly manifests during adulthood (median onset age 38 years), with exceptional pediatric presentations documented - including a 7-year-old male case exhibiting characteristic pneumothorax and genetic confirmation of BHDS [7-8]. Key Differential diagnoses for BHD syndrome encompass three categories: (1) cystic pulmonary pathologies including Langerhans cell histiocytosis (LCH) and lymphangioleiomyomatosis (LAM); (2) genetic disorders such as Marfan syndrome; (3) acquired pulmonary conditions like chronic obstructive pulmonary disease/emphysema complex, all associated with elevated spontaneous pneumothorax incidence..The structural characteristics and spatial patterns of pulmonary cysts, combined with clinical manifestations, serve as key discriminators in diagnosing BHD syndrome. Moreover, we have no found that BHDS may contribute to the development of COPD[11-12].Lung function is rarely affected in BHDS. Skin manifestations Cutaneous injury is the other vital manifestation of BHDS and occurs in nearly 58–90% of the patients[13,14]. Pathognomonic cutaneous manifestations of the syndrome predominantly present as multiple hypopigmented papules (2-4 mm diameter) exhibiting three cardinal features: dome-shaped architecture, subtle elevation, and smooth surface topography (Figure 2). These fibrofolliculomas represent the most prevalent diagnostic hallmark, as established in dermatopathological consensus criteria [1,5]. Skin biopsies demonstrating fibrofolliculomas provide histopathological confirmation of BHD. These cutaneous manifestations, characterized by multiple 2-4 mm pale yellow/white dome-shaped papules, represent benign lesions requiring no therapeutic intervention beyond cosmetic management. Kidney manifestations Patients with BHDS maybe at greater risk of renal cell tumors (RCC)than normal [6] Additionally, the incidence of renal tumors in BHDS is higher and higher with the increase with age [15]. RCC typically develop in middle-aged patients (mean age 50.7), but it have been reported in patients as young as 20 years of age.[16]. The most common histologic tumor in BHD patients is hybrid oncolytic tumor (50%) with histological features of chromophobe RCC and renal oncocytoma. An additional 33% are chRCC, with both having low malignant potential[17-18].Early discovery of renal tumor can effectively enable us to additional diagnosis and management. Renal tumor could be identified by ultrasonography, abdominal CT or MR imaging and subsequently verified by biopsy[19].More specifically, similar screening within BHDS needs to be made available[20]. Diagnosis The diagnosis of most BHDS patients with rare syndrome, the clinical picture is variable, are often delayed for years. Due to BHDS the possibility of developing RCC, early diagnosis and treatment of BHDS is crucial to interdict metastatic disease. The European researcher has proposed a set of criteria for the diagnosis of BHDS [21]. The diagnostic criteria for BHDS as follows: (1) Cutaneous criteria≥2 clinical fibrofolliculomas/trichodiscomas ≥1 histopathologically confirmed fibrofolliculoma; (2)Pulmonary criteria: Bilateral basilar lung cysts (HRCT-confirmed), Early-onset spontaneous pneumothorax (<40 years); (3)Familial pneumothorax/cyst history; (4)Renal criteria: Bilateral chromophobe/mixed oncocytic tumors, Early-onset renal neoplasia (<50 years), Familial renal cancer history (5)Combinatorial criteria: Co-occurrence of ≥2 domain manifestations in proband/kindred. A diagnosis of BHD is established: diagnostic genetic test positive for a germline FLCN mutation. Once the doctor determines 'Probable BHDS', additional investigation is needed. Treatment Patients with BHDS have a wide range of clinical features. These patients may have lesions in more than one organ system concurrently, while others have purely dermatological symptoms or isolated respiratory involvement. Most of these lesions are chronic and are not life-threatening, requiring only observation and symptomatic treatment. Diagnosis of renal tumors while on surveillance, however, warrants urgent intervention. Among the numerous clinical manifestations of BHDS, renal lesions are most important and have the greatest impact on patient prognosis. Nephron-sparing surgery is now the most accepted first-line treatment modality. In the situation where both kidneys have tumors that need to be operated on, one may initiate treatment with a less invasive and non-radical nature on one side, followed by an operation on the other kidney three months later, depending on renal function recovery [22]. Similarly, in the event of a large and acute pneumothorax which is a clinical emergency, one should administer immediate treatment. Closed thoracic drainage is a very frequently used treatment modality. In those patients with recurrent pneumothoraxes that significantly affect their quality of life, surgical pleurodesis may present an acceptable option. With regard to additional considerations, the typical skin lesions of BHDS do not usually cause severe clinical symptoms and, as such, do not necessitate therapeutic intervention. A high percentage of patients seek treatment solely for cosmetic purposes, which can be successfully addressed by a number of techniques such as electrocoagulation, laser treatment, and curettage. Besides these procedural treatments, targeted pharmacological therapy appears to be another promising option for the treatment of BHDS, acting through mTOR pathway suppression. Sirolimus (rapamycin) is currently known to be the leading clinical agent used in this regard. Some researchers have conducted trials of 0.1% topical sirolimus to treat fibrofolliculomas in BHDS, but they have had no conclusive evidence of its effectiveness [23], necessitating additional studies and confirmation of its true therapeutic effect. Conclusion The patient in our case was diagnosed only when the fourth pneumothorax. Four years of follow-up, there is no new bulla in the lungs for this patient, no lump in the kidneys, and daily life is in good condition. However, it is difficult to make an early diagnosis for the diverse manifestations of BHDS, which requires multiple disciplines. Clinical doctors should improve their knowledge about this disease, particularly those working in the departments of respiratory medicine, thoracic surgery, dermatology and urology, and raise their vigilance. For patients suspected of BHDS, multidisciplinary consultation with radiology and pathology should be conducted to improve multidisciplinary collaboration, increase the rate of diagnosis and avoid misdiagnosis and missed diagnosis. Targeted therapy should be given for different types of lesions. To some extent, this disease is chronic and psychological counseling and disease education should be given to improve patient compliance with long-term follow-up treatment. Molecular targeted treatment of BHDS is still in clinical research verification and will hopefully be the mainstream treatment method in this field in the future. Declarations Competing interests ： The author declares no competing interests. Ethics approval and consent to participate ： Institutional ethical committee approval was obtained. Consent for publication ： Consent was obtained from the patients before publication. Funding ： This study was funded by the Zhejiang Province Medical and Health Science and Technology Project (Nos:2025KY1200). Date availability: No datasets were generated or analysed during the current study. Authors contributions: Yan Zhu contributed to study design, the collection of information about the case and written. Acknowledgements ： No References Birt AR，Hogg GR，Dubé WJ．Hereditary multiple fibrofollicu Lomas with trichiliocosm’s and acrochordons[J]，Arch Dermatol，1977，113(12)：1674—1677．DOI：10.1001/archderm．11 3.12.1674． James WD, Berger T, Elston D. Andrews’ diseases of the skin: clinical dermatology: Elsevier Health Sciences; 2015. Yang CY, Wang HC, Chen JS, Yu CJ. Isolated familial pneumoth- orax in a Taiwanese family with Birt Hogg-Dube syndrome. J Postgrad Med. 2013; 59: 321–323. doi:10.4103/0022-3859. 123169 PMID: 24346394. Ding Y, Zhu C, Zou W, Ma D, Min H, Chen B, et al. FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. Am J Med Genet A. 2015; 167A: 1125–1133. doi: 10.1002/ajmg.a.36979 PMID: 25807935. Skolnik K, Tsai WH, Dornan K, et al. Birt-Hogg-Dubé syndro- me: a large single family cohort. Respir Res. 2016;17:22. 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: Publ Am Assoc Cancer Res, Cosponsored by Am Soc Prev Oncol. 2002;11 (4):393–400. Toro JR, Wei MH, Glenn GM, et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45 (6):321–331. 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. Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology. 2014;65(1):100–110. Tomassetti S, Carloni A, Chilosi M, et al. Pulmonary features of Birt-Hogg-Dubé syndrome: cystic lesions and pulmonary histiocytoma. Respir Med. 2011;105 (5):768–774. Fabre A, Borie R, Debray MP, et al. Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dubé syndrome from those of tobacco-related spontaneous pneumothorax. Histopathology. 2014;64(5):741–749. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 2015;192(1):17–29. Benusiglio PR, Giraud S, Deveaux S, et al. Renal cell tumor characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicenter study. Orphanet J Rare Dis. 2014;9:163. 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. 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. Furuya M, Yao M, Tanaka R, et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. Clin Genet. 2016; 90(5):403–412. Benusiglio PR, Giraud S, Deveaux S, et al. Renal cell tumor characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis. 2014;9:163. Giunchi F, Fiorentino M, Vagnoni V, et al. Renal oncocytosis: a clinicopathological and cytogenetic study of 42 tumors occurring in 11 patients. Pathology. 2016;48 (1):41–46. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol.2015; 67(5):913–924. Menko FH, van Steensel MA, Giraud S, et al. Birt-HoggDubé syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199–1206. Molecular Genetics and Clinical Features of Birt-Hogg-Dubé-Syndrome,Laura S. Schmidt, W. Marston Linehan.2015 October ; 12(10): 558–569. doi:10.1038/nrurol.2015.206. Gong K,Zhang N,Xu W.Hereditary Renal Carcinoma-in Basic and Clinical Practice[M].BeiJing: People’s Medical Publishing House.2021. Gijezen LM, Vernooij M, Martens H, et al. Topical rapamycin as a treatment for fibrofolliculomas in Birt‑Hogg‑Dubé syndrome: a double‑blind placebo‑controlled randomized split‑face trial[J]. PLoS One, 2014, 9(6): e99071. DOI: 10.1371/journal. pone.0099071. Additional Declarations No competing interests reported. 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The episode occurred without identifiable predisposing factors, as confirmed through comprehensive medical history review and environmental exposure assessment. Actually, spontaneous pneumothorax has a occurred 3 times in the past month, and the patients were dealt with closed thoracic drainage. Besides, the patient informed that her mother and her sister has pulmonary bulla. And her sister has history of spontaneous pneumothorax. High-resolution computed tomography (HRCT) scan showed right pneumothorax with 50% lung compression, multiple cystic pulmonary sacs in both lungs, right pulmonary bulla, which was suggestive of BHDS (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Based on the above speculation, the patient take Pulmonary function tests and enhanced abdominal CT, which were normal. We noticed that multiple, white, slightly elevated pimples located in her upper arm, neck(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Skin biopsy of the upper arm showed that the epidermis was normal in microscopic examination, with a few mononuclear cells infiltrating around small vessels in the superficial dermis, and collagen in the dermal fibrous tissue(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Germline sequencing analysis identified a clinically validated pathogenic variant in the FLCN locus, specifically a splice-site frameshift deletion [c.1177-5_1177-3delCTC] (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), an important basis for diagnosis.. Unfortunately, we don't know the source of the mutation for no providing her parent samples.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBirt-Hogg-Dub\u0026eacute;\u0026nbsp;syndrome (BHDS) was initially characterized in the late 20th century[1]. Current evidence reveals significant epidemiological knowledge gaps, particularly regarding disease prevalence in East Asian populations. Contrastingly, western registry data demonstrate high penetrance of pathognomonic cutaneous manifestations, with fibrofolliculomas affecting \u0026gt;80% of confirmed cases in North American and European cohorts. Population-based registries estimate renal pathology prevalence in BHDS cohorts at 15-35%[2]. Notably, multinational comparative studies demonstrate significant interethnic variation, with East Asian populations exhibiting lower incidence rates [3]. A seminal Chinese study (Ding et al., 2023) involving 8 multigenerational pedigrees (n=40 genetically confirmed cases) demonstrated striking phenotypic divergence: pathognomonic dermatological features manifested in 20% penetrance (8/40), while renal manifestations showed complete absence - contrasting sharply with Western epidemiological benchmarks [4].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLung manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main pulmonary manifestation of BHD is basilar and peripheral bullous changes and parenchymal cysts.\u003c/p\u003e\n\u003cp\u003eMultiple pulmonary cysts occur in approximately 67\u0026ndash;90% of BHDS patients [5]. Pulmonary cysts are bilateral, middle and lower basal lung zones in location, irregular in shape, varying in size and thin-walled (Figure 1)[9]. Basal location and large size of the cysts are associated with an increased risk of SP[5,6,10].\u003c/p\u003e\n\u003cp\u003eSpontaneous pneumothorax (SP) in BHDS predominantly manifests during adulthood (median onset age 38 years), with exceptional pediatric presentations documented - including a 7-year-old male case exhibiting characteristic pneumothorax and genetic confirmation of BHDS [7-8]. Key Differential diagnoses for BHD syndrome encompass three categories: (1) cystic pulmonary pathologies including Langerhans cell histiocytosis (LCH) and lymphangioleiomyomatosis (LAM); (2) genetic disorders such as Marfan syndrome; (3) acquired pulmonary conditions like chronic obstructive pulmonary disease/emphysema complex, all associated with elevated spontaneous pneumothorax incidence..The structural characteristics and spatial patterns of pulmonary cysts, combined with clinical manifestations, serve as key discriminators in diagnosing BHD syndrome. Moreover, we have no found that BHDS may contribute to the development of COPD[11-12].Lung function is rarely affected in BHDS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSkin manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCutaneous injury is the other vital manifestation of BHDS and occurs in nearly 58\u0026ndash;90% of the patients[13,14]. Pathognomonic cutaneous manifestations of the syndrome predominantly present as multiple hypopigmented papules (2-4 mm diameter) exhibiting three cardinal features: dome-shaped architecture, subtle elevation, and smooth surface topography (Figure 2). These fibrofolliculomas represent the most prevalent diagnostic hallmark, as established in dermatopathological consensus criteria [1,5]. Skin biopsies demonstrating fibrofolliculomas provide histopathological confirmation of BHD. These cutaneous manifestations, characterized by multiple 2-4 mm pale yellow/white dome-shaped papules, represent benign lesions requiring no therapeutic intervention beyond cosmetic management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKidney manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with BHDS maybe at greater risk of renal cell tumors (RCC)than normal [6] Additionally, the incidence of renal tumors in BHDS is higher and higher with the increase with age [15]. RCC typically develop in middle-aged patients (mean age 50.7), but it have been reported in patients as young as 20 years of age.[16].\u003c/p\u003e\n\u003cp\u003eThe most common histologic tumor in BHD patients is hybrid oncolytic tumor (50%) with histological features of chromophobe RCC and renal oncocytoma. An additional 33% are chRCC, with both having low malignant potential[17-18].Early discovery of renal tumor can effectively enable us to additional diagnosis and management. Renal tumor could be identified by ultrasonography, abdominal CT or MR imaging and subsequently verified by biopsy[19].More specifically, similar screening within BHDS needs to be made available[20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnosis of most \u0026nbsp;BHDS patients with rare syndrome, the clinical picture is variable, are often delayed for years. Due to BHDS the possibility of developing RCC, early diagnosis and treatment of BHDS is crucial to interdict metastatic disease.\u003c/p\u003e\n\u003cp\u003eThe European researcher has proposed a set of criteria for the diagnosis of BHDS [21]. The diagnostic criteria for BHDS as follows: (1) Cutaneous criteria\u0026ge;2 clinical fibrofolliculomas/trichodiscomas\u003c/p\u003e\n\u003cp\u003e\u0026ge;1 histopathologically confirmed fibrofolliculoma; (2)Pulmonary criteria: Bilateral basilar lung cysts (HRCT-confirmed), Early-onset spontaneous pneumothorax (\u0026lt;40 years); (3)Familial pneumothorax/cyst history; (4)Renal criteria: Bilateral chromophobe/mixed oncocytic tumors, Early-onset renal neoplasia (\u0026lt;50 years), Familial renal cancer history (5)Combinatorial criteria: Co-occurrence of \u0026ge;2 domain manifestations in proband/kindred. A diagnosis of BHD is established: diagnostic genetic test positive for a germline FLCN mutation. Once the doctor determines \u0026apos;Probable BHDS\u0026apos;, additional investigation is needed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients with BHDS have a wide range of clinical features. These patients may have lesions in more than one organ system concurrently, while others have purely dermatological symptoms or isolated respiratory involvement. Most of these lesions are chronic and are not life-threatening, requiring only observation and symptomatic treatment. Diagnosis of renal tumors while on surveillance, however, warrants urgent intervention. Among the numerous clinical manifestations of BHDS, renal lesions are most important and have the greatest impact on patient prognosis. Nephron-sparing surgery is now the most accepted first-line treatment modality.\u003c/p\u003e\n\u003cp\u003eIn the situation where both kidneys have tumors that need to be operated on, one may initiate treatment with a less invasive and non-radical nature on one side, followed by an operation on the other kidney three months later, depending on renal function recovery [22]. Similarly, in the event of a large and acute pneumothorax which is a clinical emergency, one should administer immediate treatment.\u003c/p\u003e\n\u003cp\u003eClosed thoracic drainage is a very frequently used treatment modality. In those patients with recurrent pneumothoraxes that significantly affect their quality of life, surgical pleurodesis may present an acceptable option. With regard to additional considerations, the typical skin lesions of BHDS do not usually cause severe clinical symptoms and, as such, do not necessitate therapeutic intervention. A high percentage of patients seek treatment solely for cosmetic purposes, which can be successfully addressed by a number of techniques such as electrocoagulation, laser treatment, and curettage. Besides these procedural treatments, targeted pharmacological therapy appears to be another promising option for the treatment of BHDS, acting through mTOR pathway suppression. Sirolimus (rapamycin) is currently known to be the leading clinical agent used in this regard. Some researchers have conducted trials of 0.1% topical sirolimus to treat fibrofolliculomas in BHDS, but they have had no conclusive evidence of its effectiveness [23], necessitating additional studies and confirmation of its true therapeutic effect.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe patient in our case was diagnosed only when the fourth pneumothorax. Four years of follow-up, there is no new bulla in the lungs for this patient, no lump in the kidneys, and daily life is in good condition. However, it is difficult to make an early diagnosis for the diverse manifestations of BHDS, which requires multiple disciplines. Clinical doctors should improve their knowledge about this disease, particularly those working in the departments of respiratory medicine, thoracic surgery, dermatology and urology, and raise their vigilance. For patients suspected of BHDS, multidisciplinary consultation with radiology and pathology should be conducted to improve multidisciplinary collaboration, increase the rate of diagnosis and avoid misdiagnosis and missed diagnosis. Targeted therapy should be given for different types of lesions. To some extent, this disease is chronic and psychological counseling and disease education should be given to improve patient compliance with long-term follow-up treatment. Molecular targeted treatment of BHDS is still in clinical research verification and will hopefully be the mainstream treatment method in this field in the future.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThe author declares no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eInstitutional ethical committee approval was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eConsent was obtained from the patients before publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThis study was funded by the Zhejiang Province Medical and Health Science and Technology Project (Nos:2025KY1200).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDate availability:\u003c/strong\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u0026nbsp;\u003c/strong\u003eYan Zhu contributed to study design, the collection of information about the case and written.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e No\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBirt AR，Hogg GR，Dub\u0026eacute; WJ．Hereditary multiple fibrofollicu Lomas with trichiliocosm\u0026rsquo;s and acrochordons[J]，Arch Dermatol，1977，113(12)：1674\u0026mdash;1677．DOI：10.1001/archderm．11 3.12.1674．\u003c/li\u003e\n\u003cli\u003eJames WD, Berger T, Elston D. Andrews\u0026rsquo; diseases of the skin: clinical dermatology: Elsevier Health Sciences; 2015.\u003c/li\u003e\n\u003cli\u003eYang CY, Wang HC, Chen JS, Yu CJ. Isolated familial pneumoth- orax in a Taiwanese family with Birt Hogg-Dube syndrome. J Postgrad Med. 2013; 59: 321\u0026ndash;323. doi:10.4103/0022-3859. 123169 PMID: 24346394.\u003c/li\u003e\n\u003cli\u003eDing Y, Zhu C, Zou W, Ma D, Min H, Chen B, et al. FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. Am J Med Genet A. 2015; 167A: 1125\u0026ndash;1133. doi: 10.1002/ajmg.a.36979 PMID: 25807935.\u003c/li\u003e\n\u003cli\u003eSkolnik K, Tsai WH, Dornan K, et al. Birt-Hogg-Dub\u0026eacute; syndro- me: a large single family cohort. Respir Res. 2016;17:22.\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. Cancer Epidemiol, Biomarkers Prev: Publ Am Assoc Cancer Res, Cosponsored by Am Soc Prev Oncol. 2002;11 (4):393\u0026ndash;400.\u003c/li\u003e\n\u003cli\u003eToro JR, Wei MH, Glenn GM, et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dub\u0026eacute; syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45 (6):321\u0026ndash;331.\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. Br J Cancer. 2011;105(12):1912-1919.\u003c/li\u003e\n\u003cli\u003eCharacterization of pulmonary cysts in Birt-Hogg-Dub\u0026eacute; syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology. 2014;65(1):100\u0026ndash;110.\u003c/li\u003e\n\u003cli\u003eTomassetti S, Carloni A, Chilosi M, et al. Pulmonary features of Birt-Hogg-Dub\u0026eacute; syndrome: cystic lesions and pulmonary histiocytoma. Respir Med. 2011;105 (5):768\u0026ndash;774.\u003c/li\u003e\n\u003cli\u003eFabre A, Borie R, Debray MP, et al. Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dub\u0026eacute; syndrome from those of tobacco-related spontaneous pneumothorax. Histopathology. 2014;64(5):741\u0026ndash;749.\u003c/li\u003e\n\u003cli\u003eGupta N, Vassallo R, Wikenheiser-Brokamp KA, et al. Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 2015;192(1):17\u0026ndash;29.\u003c/li\u003e\n\u003cli\u003eBenusiglio PR, Giraud S, Deveaux S, et al. Renal cell tumor characteristics in patients with the Birt-Hogg-Dub\u0026eacute; cancer susceptibility syndrome: a retrospective, multicenter study. Orphanet J Rare Dis. 2014;9:163.\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. Br J Cancer. 2011;105(12):1912-1919.\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. Br J Cancer. 2011;105(12):1912-1919.\u003c/li\u003e\n\u003cli\u003eFuruya M, Yao M, Tanaka R, et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dub\u0026eacute; syndrome. Clin Genet. 2016; 90(5):403\u0026ndash;412.\u003c/li\u003e\n\u003cli\u003eBenusiglio PR, Giraud S, Deveaux S, et al. Renal cell tumor characteristics in patients with the Birt-Hogg-Dub\u0026eacute; cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis. 2014;9:163.\u003c/li\u003e\n\u003cli\u003eGiunchi F, Fiorentino M, Vagnoni V, et al. Renal oncocytosis: a clinicopathological and cytogenetic study of 42 tumors occurring in 11 patients. Pathology. 2016;48 (1):41\u0026ndash;46.\u003c/li\u003e\n\u003cli\u003eLjungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol.2015; 67(5):913\u0026ndash;924.\u003c/li\u003e\n\u003cli\u003eMenko FH, van Steensel MA, Giraud S, et al. Birt-HoggDub\u0026eacute; syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199\u0026ndash;1206.\u003c/li\u003e\n\u003cli\u003eMolecular Genetics and Clinical Features of Birt-Hogg-Dub\u0026eacute;-Syndrome,Laura S. Schmidt, W. Marston Linehan.2015 October ; 12(10): 558\u0026ndash;569. doi:10.1038/nrurol.2015.206.\u003c/li\u003e\n\u003cli\u003eGong K,Zhang N,Xu W.Hereditary Renal Carcinoma-in Basic and Clinical Practice[M].BeiJing: People\u0026rsquo;s Medical Publishing House.2021.\u003c/li\u003e\n\u003cli\u003eGijezen LM, Vernooij M, Martens H, et al. Topical rapamycin as a treatment for fibrofolliculomas in Birt‑Hogg‑Dub\u0026eacute; syndrome: a double‑blind placebo‑controlled randomized split‑face trial[J]. PLoS One, 2014, 9(6): e99071. DOI: 10.1371/journal. pone.0099071.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Birt-Hogg-Dubé syndrome, FLCN, pulmonary cysts","lastPublishedDoi":"10.21203/rs.3.rs-6548870/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6548870/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBirt-Hogg-Dub\u0026eacute; (BHD) syndrome, an autosomal dominantly inherited disorder, manifests primary through triad clinical features: pulmonary cysts, pneumothorax, fibrofolliculomas, and renal tumors. While respiratory symptoms like spontaneous pneumothorax often constitute initial clinical presentations, but the majority of patients remain clinically asymptomatic. The molecular basis of this condition stems from germline mutations in the folliculin (FLCN) gene (chromosomal locus 17p11.2).\u003c/p\u003e \u003cp\u003eGenetic analyses have identified heterogeneous FLCN mutations spanning the entire coding region, including frameshift insertions/deletions and pathogenic nonsense variants. More than 600 BHDS families have been reported so far. BHD syndrome research is less frequent in Chinese patients than in European and American patients. This article delineates a novel Chinese BHDS case with molecular confirmation, supplemented by a systematic review of existing literature to address current knowledge gaps.\u003c/p\u003e","manuscriptTitle":"A special case study of Birt–Hogg–Dubé syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 07:12:37","doi":"10.21203/rs.3.rs-6548870/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"76e17196-1d56-45c1-81f3-393b53437b7a","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-24T16:39:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-03 07:12:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6548870","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6548870","identity":"rs-6548870","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}