Prevalence of Birt-Hogg-Dube Syndrome and Kidney Cancer Surveillance in Tasmania, Australia

Prevalence of Birt-Hogg-Dube Syndrome and Kidney Cancer Surveillance in Tasmania, Australia | 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 Research Article Prevalence of Birt-Hogg-Dube Syndrome and Kidney Cancer Surveillance in Tasmania, Australia Denisse Garza, Michael Millward, Laura Cuthbertson, Jo Burke, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3835636/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 Syndrome (BHD) is a rare autosomal dominant condition characterised by a predisposition to benign skin lesions, pulmonary cysts, spontaneous pneumothorax and kidney cancer. An audit of the Tasmanian Clinical Genetics Service database was conducted to identify individuals with molecularly confirmed BHD. To ensure Tasmanians with BHD would be able to meet contemporary national screening guidelines, individuals diagnosed with BHD seen by the Tasmanian Clinical Genetics Service between 2010 and 2021 were invited to complete a survey regarding screening practices. We identified 37 individuals (23 women and 14 males, mean age 62 years old) with molecularly confirmed BHD, giving an estimated population prevalence in 2021 of 7 per 100,000. The majority (80%) lived in inner-regional locations with up to a one-hour travel time to medical imaging facilities. Of those identified, 14 (37%) completed the screening survey, with 8 (57%) reporting at least one screening test for kidney cancer since diagnosis; only 4 (28%) met current guidelines on screening frequency. Our findings showed that Tasmania had an unexpectedly high population prevalence of BHD yet screening for kidney cancer was suboptimal. This is the first study that demonstrates BHD is more prevalent in Tasmania compared to the global average and highlights the need for improved access and education on cancer surveillance. Birt–Hogg Dubé Syndrome BHD FLCN gene kidney cancer screening Figures Figure 1 Introduction Birt-Hogg-Dube syndrome (BHD) is a rare autosomal dominant condition caused by heterozygous pathogenic variants in the folliculin (FLCN) gene and characterised by a predisposition to benign skin lesions, pulmonary cysts that may be associated with pneumothorax, and kidney cancer [ 1 – 3 ]. By applying the Bayes theorem of conditional probability to epidemiological data on spontaneous pneumothorax, the worldwide prevalence of BHD has been estimated to be 2 in 1,000,000 [ 4 ]. The most common observable feature of BHD is benign, white domed skin lesions known as fibrofolliculomas, seen in 85% of patients by the age of 25 [ 3 ]. Other cutaneous manifestations (acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts) have also been observed [ 3 , 5 , 6 ]. Pulmonary cysts are also common and are present in up to 85% of patients by the age of 30 [ 3 ]. These cysts increase the risk of a pneumothorax by 50-fold over background risk, and are often located in the basal regions, as opposed to a sporadic primary pneumothorax, where the pulmonary cysts are typically found in the apical zones [ 7 , 8 ]. The third major feature associated with BHD is a predisposition to bilateral and multifocal kidney tumours, with a lifetime risk of around 19% and average age of onset being 50 years of age [ 3 , 9 ]. Unlike other inherited kidney cancers, patients with BDH develop kidney tumours with multiple histology. The most common kidney tumour in BHD is the hybrid oncocytic tumour with both chromophobe and renal oncocytoma features [ 10 ]. Other forms of kidney tumours, listed in decreasing order of frequency, include chromophobe renal cell carcinoma (RCC), clear cell RCC, renal oncocytoma, and papillary RCC [ 11 ]. Renal angiomyolipomas have also been described in one patient with somatic TSC1/2 loss [ 12 ]. Clinical diagnostic guidelines for BHD have been published by the European Birt-Hogg-Dubé consortium who proposed that patients need to fulfill one major criteria, or two minor criteria for a BHD diagnosis [ 1 ]: Major criteria Five or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically A heterozygous pathogenic germline variant in FLCN [ 1 ] Minor criteria Multiple lung cysts Bilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax Early-onset kidney cancer (age < 50 years) Multifocal or bilateral kidney cancer Kidney cancer of mixed chromophobe and oncocytic histology First-degree relative with BHD Given the increased risk of malignancy, individuals with BHD are encouraged to undertake lifetime kidney imaging surveillance for the early detection and treatment of kidney cancers [ 1 , 3 , 11 , 13 ]. The Tasmanian Clinical Genetics Service (TCGS) and Nephrology services in Tasmania adopted diagnostic and screening guidelines proposed by contemporary Australian guidelines [ 14 ]. Prior to 2019, national screening guidelines recommended a baseline MRI at age 30 followed by three-yearly screening, with ultrasound considered a reasonable alternative to MRI. After 2019 national screening guidelines were updated to a baseline MRI at 20 years, followed by three-yearly MRI or two-yearly high-resolution ultrasound. In Tasmania, ultrasound investigations are relatively easy to obtain with a referral from a General Practitioner and are performed in many regional centres. However, access to MRI is more limited, requiring a specialist referral, and scanning available only in Hobart for the early part of this study. MRI only became available in Launceston in May 2014. The aim of this study was to examine current screening practices of patients with BHD in Tasmania, and to determine how these are impacted by the recent changes in national kidney cancer screening guidelines. A secondary aim to assess the overall prevalence of BHD in Tasmania was established after initial data suggested that Tasmania may harbour a higher prevalence of BHD compared to other populations. Methods Study Design A clinical audit was conducted of the TCGS database to ascertain individuals found to have BHD due to a pathogenic FLNC variant detected between 2010 and 2021. Identified individuals were contacted by letter to notify them of updated screening recommendations and to invite them to participate in this study (See Online Resource 1). Enclosed with this letter was a consent form to participate in the survey, the survey itself with a re-identifiable code, and a reply-paid envelope. Non-responders were contacted via phone a month after the letter was sent to ensure receipt of the letter and with a verbal invitation to take part in this study. The survey included a mix of yes/no and opened-ended questions, asking participants to provide information regarding their age, age at diagnosis, highest education completed, kidney cancer history and surgical management, kidney cancer screening practices, whether they have seen a Nephrologist since their diagnosis and whether they would like to be referred to one. Demographic information and details of the variant identified in the individual were collected from the TCGS database. Socioeconomic status (SES) was derived for all individuals via their postcode using the Index of Relative Socio-economic Advantage and Disadvantage from 2016 Socio-economic Indexes for Area [ 15 ]. Geographic classification was derived from the Australian Standard Geographical Classification (ASGC) based on residential postcode. The ASGC measures remoteness based on the distance of geographic locations from the nearest population centre. The five remoteness classes include Major Cities, Inner Regional, Outer Regional, Remote and Very Remote [ 16 ] All data and re-identifiable codes were stored in a password protected file on a secure server. Paper copies of each survey were kept for the duration of the study and stored in locked cabinets within TCGS offices. Data obtained for this study was analysed using descriptive analytics, to describe trends and relationships within the data set. Results Participants We identified 37 individuals with molecularly confirmed BHD. A completed survey was received from 38% (n = 14/37) of these individuals after follow-up. Of the 62% (n = 23) who did not respond, 78% (n = 18) were unable to be contacted via phone, 8% (n = 2) were deceased, 4% (n = 1) had moved overseas, and 8% (n = 2) stated they did not wish to participate. See Fig. 1 for participant breakdown. Demographics The search of the TCGS database revealed 37 individuals with molecularly confirmed BHD across five Tasmanian families. Our audit revealed four different pathogenic germline variants in the FLCN gene within five known BHD families. Those who responded to the survey had similar demographics to the overall cohort, averaging 63.1 years of age and comprised of nine females and five males. Most participants lived in low SES postcodes and were from inner-regional locations. See Table 1 for a full breakdown of participant demographics. Table 1 Demographic data regarding the individuals in Tasmania identified as having molecularly confirmed BHD and survey respondents. All Tasmanian’s with BHD (n = 37) Survey respondents (n = 14) SES High 3% (1) 7% (1) Medium 24% (9) 7% (1) Low 68% (25) 86% (12) Unknown 5% (2) 0% (0) ASGC Inner-regional area 76% (28) 93% (13) Outer-regional area 19% (7) 7% (1) Unknown 5% (2) 0% (0) Age (years) 20–49 30% (11) 14% (2) 50–69 38% (14) 57% (8) 70+ 27% (10) 29% (4) Unknown 5% (2) 0% (0) Age (mean ± SD) 61.8 years ± 17 63.1 ± 12 years Gender Female 60.5% (23) 64.3% (9) Male 36.8% (14) 35.7% (5) Years since diagnosis 0–3 35% (13) 0% (5) 4–5 22% (8) 36% (3) 6–7 43% (16) 14% (6) Average 4.3 years 4.6 years Abbreviations: SES = socioeconomic status (based on postcode), ASGC = Australian Standard Geographical Classification (based on postcode). SD Standard deviation Kidney cancer 21% (n = 3) of participants reported a kidney cancer diagnosis. These individuals were the only ones who reported having kidney surgery. Screening Participants were asked to complete a table detailing the kidney cancer screening they have had since their diagnosis of BHD. 64% (n = 9) participants, either partially or fully, completed this table. Respondents to this question included five females and four males. 89% (n = 8) of those who responded to this question reported at least some kidney cancer screening. 78% individuals (n = 7) reported having ultrasounds of the kidneys. 57% individuals (n = 4) reported having kidney ultrasounds at least two yearly, two participants did not give a frequency, and one commented “once” but did not specify whether this meant one ultrasound ever or once a year. 33% individuals (n = 3) reported having a CT scan, and only one participant reported having had a kidney MRI. Renal Specialist Participants were asked whether they had been referred to a Nephrologist since their BHD diagnosis. 21% (n = 3) of respondents reported having seen a Nephrologist since their diagnosis of BHD. Of the 79% (n = 11) of respondents who either reported having not seen a Nephrologist since their diagnosis or who did not respond to this question, 64% (n = 7) asked to be referred to a Nephrologist, which was subsequently arranged by the study team. Combining the number of respondents who reported they have seen a Nephrologist since their diagnosis with the number of respondents who requested to be seen by a Nephrologist though this survey, a total of 71% (n = 10) of respondents have now seen a Nephrologist since their diagnosis of BHD. Discussion There are two important findings from this study: i) a low rate of adherence to kidney cancer screening and ii) there may be a high prevalence of BHD in Tasmania. Our study revealed that individuals with BHD in Tasmania are not meeting current guidelines for kidney cancer screening. Interestingly, only 57% of survey respondents are having some form of cancer screening. The purposes of screening for BHD is to facilitate early detection of kidney malignancies enabling early interventions such as nephron sparing surgery. Nephron sparing surgery is an effective therapy for patients that allows preservation of kidney function [ 17 ]. Therefore, imaging expertise is critical irrespective of modality. In rural/regional locations, access to medical imaging services can be limited compared to metropolitan areas, resulting in inequitable access for patients within those areas [ 18 ]. Studies have observed significant variation in the health-service utilisation of individuals depending on their geographical location in Australia, with individuals living in socioeconomically disadvantaged areas and areas outside major metropolitan centres to have the most adverse health-behaviours profiles [ 19 , 20 ]. Additionally, individuals from low SES have been shown to attend family clinics less frequently, assumedly in part due to increased costs associated in regional or rural areas [ 21 ]. Whilst we did not observe differences in screening practices between males or females, most of our respondents are from inner regional areas, which according to ASGC, inner Regional Australia are areas where geographic distance imposes some restriction on accessibility to a range of goods, services and opportunities [ 16 ]. Those in outer regional Australia experience a moderate restriction to goods and services [ 16 ]. This could explain why 43% of respondents in Tasmania are not undergoing kidney cancer screening and why only 21% of respondents reported having seen a Nephrologist since their diagnosis of BHD. The most common mode of screening reported by our respondents were ultrasounds, possibly because ultrasound imaging is inexpensive, non-invasive, and easier to access in Tasmania [ 22 ]. Ultrasound imagining has a sensitivity of 82% and specificity of 98% [ 22 ]. However, ultrasound detection rates are limited to renal lesion size of > 3 cm. This means that tumours < 3 cm are not always detected, leading to false negatives. False positives can also occur, and may be correlated to radiologist experience [ 23 ]. False negatives and false positives can have significant psychosocial impact on individuals, suggesting another reason why ultrasound screening may not be considered gold standard for BHD [ 24 ]. In contrast, sensitivity and specificity for MRI at 1.5T is around 86% and 94%, respectively [ 25 ]. MRI can detect small renal masses, helps with histology differentiation, allows restaging of disease, and may elucidate treatment response [ 26 , 27 ]. In general, MRI is considered gold standard for the diagnosis of kidney cancer, compared to ultrasound or other imaging, such as CT [ 25 ]. Despite these benefits, only one participant from our study reported having had an MRI, supporting the anecdotal evidence that MRI might be more difficult to access within Tasmania. Literature describes a lack of trust in healthcare and lack of education as other reasons for low engagement from patients [ 28 ]. This could suggest why nearly a third of those who completed the survey did not ask to be referred to a Nephrologist or why most patients diagnosed with BHD did not complete the survey. A specialist kidney genetics clinic is an opportunity for patients to access specialist services, provides education, and can help establish trust with healthcare providers. In turn, this has the potential to significantly improve screening practices. Additionally, low penetrance of malignancy in BHD, particularly as exemplified from the figures derived in this study (19%), could mean that some individuals may perceive the cancer risk as low and are less likely to participate in risk reducing behaviours [ 29 ].An unexpected finding in our study was the identification of the high BHD prevalence in Tasmania. The current population of Tasmania is approximately 560,000 [ 30 ] making the observed prevalence of BHD in Tasmania 0.0068% or approximately seven per 100,000. Given the estimated worldwide prevalence of BHD of two per 1,000,000, the observed prevalence of BHD in Tasmania is approximately 15 times higher. Furthermore, other Tasmanian based studies have shown that only 12% of patients with other forms of genetic kidney disease are known to the TCGS [ 31 ]. Therefore, our estimate of BHD prevalence in Tasmania is likely to be an underestimate; the TCGS is unlikely to know all individuals living with BHD in Tasmania. There are at least two possible explanations for this observation. Founder effect is one possibility. Tasmania is a small island state which has experienced limited immigration since convict transportation ceased in 1853. It is estimated that 65% of Tasmania’s residents are descendants of approximately 10,000 "founding couples" from the mid-19th century. Founder effects resulting in high incidences of both Huntington disease and Multiple Endocrine Neoplasia type 1 have been documented in Tasmania [ 32 , 33 ]. However, there was no evidence of a founder effect in our study to explain the higher prevalence of BHD in Tasmania, given that four different FLCN variants were identified through our audit. Our audit of the TCGS database identified 37 individuals with BHD belonging to 5 different families. Each of those families contained one index case, meaning that on average 6.4 additional asymptomatic mutation positive family members were identified by predictive genetic testing for each index case diagnosed with BHD. We are not aware of any published data documenting the number of predictive tests performed per proband for BHD by other genetics services, but it is possible that cascade predictive testing for this low penetrance cancer predisposition syndrome identifies more mutation-positive relatives per index case in Tasmania than elsewhere, resulting in a higher estimated prevalence for BHD. This could come about because predictive genetic testing is more easily accessed in Tasmania than elsewhere. Both genetic counselling appointments and predictive genetic testing are available free of charge in all Australian states to Australian residents, which removes a financial barrier to access. This may prevent uptake of predictive testing in other populations where BHD epidemiological data has previously been collected. Furthermore, predictive genetic testing may be more pro-actively offered by the TCGS than is the case in other areas. Historically, genetic counsellors at TCGS expended considerable effort to notify at-risk relatives of the availability of predictive genetic testing following the diagnosis of a hereditary cancer syndrome in a proband [ 34 ]. Whilst similar protocols for the notification of at-risk relatives may be used in other Australian clinical genetics services and around the world, the centralization of genetic services in Tasmania into a single State-wide Genetics Service may result in an additional advantage by providing consistency and familiarity for family members, who are all cared for by the same genetic counsellors. Study Limitations Due to the small number of participants in this study, we are unable to examine the data for statistical significance between those identified in the audit and the population who returned the survey. However, there was very little difference in average age, or in average years since diagnosis between the clinical audit population and those who returned the survey. We also did not observe differences in gender. Therefore, we feel the population who returned the survey are reasonably representative of the population from the clinical audit. Conclusion Tasmania had an unexpectedly high population prevalence of BHD yet screening for kidney cancer is suboptimal. Given BHD is a comparatively common disorder in Tasmania, a lack of screening could contribute significantly to morbidity and mortality of individuals with this condition in Tasmania. We found no evidence of a founder effect in Tasmania, and it is possible that earlier prevalence estimates of BHD were low due to poor ascertainment. Our results suggest that improved access to cancer surveillance is needed. To help combat the deficit in screening and disconnect between individuals diagnosed with BHD and Nephrologists, the TCGS and Renal services at RHH have developed a joint multidisciplinary clinic. The purpose of this clinic is to help organise kidney cancer screening and improve access to MRI for individuals newly diagnosed with BHD, as well as to educate patients on ongoing screening and accessibility. Further research to understand the impacts of this multidisciplinary clinic on screening practices within BHD patients should be considered. Declarations Authors’ contribution All authors contributed to the study conception and design. Material preparation was performed by Jo Burke, with input from Mathew Jose. Data collection was performed by Michael Millward and data analysis performed by Denisse Garza. The first draft of the manuscript was written by Denisse Garza and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Competing Interests The authors declare no conflict of interest. Funding This study was funded by the Royal Hobart Hospital Research Foundation Incubator Grant. Consent to participate This was a low-risk study, and implied consent was obtained from all participants included in the study. Ethics Declaration This study has been approved by the Tasmania Health and Medical Human Research Ethics Committee (Study H0018485). References Menko, F.H., et al., Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol, 2009. 10 (12): p. 1199-206. 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Campbell, N., A.B. Rosenkrantz, and I. Pedrosa, MRI phenotype in renal cancer: is it clinically relevant? Top Magn Reson Imaging, 2014. 23 (2): p. 95-115. Krajewski, K.M. and I. Pedrosa, Imaging Advances in the Management of Kidney Cancer. J Clin Oncol, 2018. 36 (36): p. Jco2018791236. Young, B., et al., Factors influencing the decision to attend screening for cancer in the UK: a meta-ethnography of qualitative research. Journal of Public Health, 2017. 40 (2): p. 315-339. Weinstein, N.D., Optimistic Biases About Personal Risks. Science, 1989. 246 (4935): p. 1232-1233. Snapshot of Tasmania . 2022; Available from: https://www.abs.gov.au/articles/snapshot-tas-2021. Brailsford, G., et al., Genetic kidney disease in Southern Tasmania. Kidney international reports, 2020. 5 (4): p. 534. Pridmore, S.A., The prevalence of Huntington's disease in Tasmania. Medical Journal of Australia, 1990. 153 (3): p. 133-134. Wilkinson, S., M. Young, and J.J. Shepherd, THE PREVALENCE OF MEN-I IN TASMANIA. Australian and New Zealand Journal of Surgery, 1996. 66 (3): p. 141-143. Forrest, L.E., et al., Increased genetic counseling support improves communication of genetic information in families. Genet Med, 2008. 10 (3): p. 167-72. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3835636","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265495175,"identity":"eed5f188-0cbe-43f8-ac47-3129c775d08e","order_by":0,"name":"Denisse Garza","email":"","orcid":"","institution":"Tasmanian Clinical Genetics Service, Royal Hobart Hospital","correspondingAuthor":false,"prefix":"","firstName":"Denisse","middleName":"","lastName":"Garza","suffix":""},{"id":265495176,"identity":"bd80b0d2-ec90-4021-94e6-bc8bf0cb2b7a","order_by":1,"name":"Michael Millward","email":"","orcid":"","institution":"Tasmanian Clinical Genetics Service, Royal Hobart Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Millward","suffix":""},{"id":265495177,"identity":"b647d89e-1804-4475-a749-a5deac1b825c","order_by":2,"name":"Laura Cuthbertson","email":"","orcid":"","institution":"Nephrology Unit, Royal Hobart Hospital","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Cuthbertson","suffix":""},{"id":265495178,"identity":"816255d4-b9e7-44b0-878f-2d5660ce0470","order_by":3,"name":"Jo Burke","email":"","orcid":"","institution":"Tasmanian Clinical Genetics Service, Royal Hobart Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jo","middleName":"","lastName":"Burke","suffix":""},{"id":265495179,"identity":"a88c36c2-3782-485f-bc7c-c6539238bf0a","order_by":4,"name":"Matthew Jose","email":"","orcid":"","institution":"Nephrology Unit, Royal Hobart Hospital","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Jose","suffix":""},{"id":265495180,"identity":"3cea5155-be11-4397-a388-46361849e1f7","order_by":5,"name":"Mathew Wallis","email":"data:image/png;base64,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","orcid":"","institution":"Tasmanian Clinical Genetics Service, Royal Hobart Hospital","correspondingAuthor":true,"prefix":"","firstName":"Mathew","middleName":"","lastName":"Wallis","suffix":""}],"badges":[],"createdAt":"2024-01-04 23:59:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3835636/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3835636/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49326399,"identity":"bd9e89df-8ec1-4fd4-9d6b-ee6f13326cef","added_by":"auto","created_at":"2024-01-08 17:31:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30500,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant breakdown\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3835636/v1/548ac1c1068efb650f33cff2.png"},{"id":61996554,"identity":"f753a7e3-4034-4eaa-9053-1e91815041a2","added_by":"auto","created_at":"2024-08-08 04:39:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":408992,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3835636/v1/f304d99f-64f4-4399-8a90-98b956069ab8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prevalence of Birt-Hogg-Dube Syndrome and Kidney Cancer Surveillance in Tasmania, Australia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBirt-Hogg-Dube syndrome (BHD) is a rare autosomal dominant condition caused by heterozygous pathogenic variants in the folliculin (FLCN) gene and characterised by a predisposition to benign skin lesions, pulmonary cysts that may be associated with pneumothorax, and kidney cancer [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. By applying the Bayes theorem of conditional probability to epidemiological data on spontaneous pneumothorax, the worldwide prevalence of BHD has been estimated to be 2 in 1,000,000 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most common observable feature of BHD is benign, white domed skin lesions known as fibrofolliculomas, seen in 85% of patients by the age of 25 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Other cutaneous manifestations (acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts) have also been observed [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePulmonary cysts are also common and are present in up to 85% of patients by the age of 30 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These cysts increase the risk of a pneumothorax by 50-fold over background risk, and are often located in the basal regions, as opposed to a sporadic primary pneumothorax, where the pulmonary cysts are typically found in the apical zones [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe third major feature associated with BHD is a predisposition to bilateral and multifocal kidney tumours, with a lifetime risk of around 19% and average age of onset being 50 years of age [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Unlike other inherited kidney cancers, patients with BDH develop kidney tumours with multiple histology. The most common kidney tumour in BHD is the hybrid oncocytic tumour with both chromophobe and renal oncocytoma features [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Other forms of kidney tumours, listed in decreasing order of frequency, include chromophobe renal cell carcinoma (RCC), clear cell RCC, renal oncocytoma, and papillary RCC [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Renal angiomyolipomas have also been described in one patient with somatic TSC1/2 loss [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical diagnostic guidelines for BHD have been published by the European Birt-Hogg-Dub\u0026eacute; consortium who proposed that patients need to fulfill one major criteria, or two minor criteria for a BHD diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]:\u003c/p\u003e \u003cp\u003eMajor criteria\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFive or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eA heterozygous pathogenic germline variant in \u003cem\u003eFLCN\u003c/em\u003e [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eMinor criteria\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMultiple lung cysts\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eBilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEarly-onset kidney cancer (age\u0026thinsp;\u0026lt;\u0026thinsp;50 years)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMultifocal or bilateral kidney cancer\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eKidney cancer of mixed chromophobe and oncocytic histology\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFirst-degree relative with BHD\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eGiven the increased risk of malignancy, individuals with BHD are encouraged to undertake lifetime kidney imaging surveillance for the early detection and treatment of kidney cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Tasmanian Clinical Genetics Service (TCGS) and Nephrology services in Tasmania adopted diagnostic and screening guidelines proposed by contemporary Australian guidelines [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Prior to 2019, national screening guidelines recommended a baseline MRI at age 30 followed by three-yearly screening, with ultrasound considered a reasonable alternative to MRI. After 2019 national screening guidelines were updated to a baseline MRI at 20 years, followed by three-yearly MRI or two-yearly high-resolution ultrasound.\u003c/p\u003e \u003cp\u003eIn Tasmania, ultrasound investigations are relatively easy to obtain with a referral from a General Practitioner and are performed in many regional centres. However, access to MRI is more limited, requiring a specialist referral, and scanning available only in Hobart for the early part of this study. MRI only became available in Launceston in May 2014.\u003c/p\u003e \u003cp\u003e The aim of this study was to examine current screening practices of patients with BHD in Tasmania, and to determine how these are impacted by the recent changes in national kidney cancer screening guidelines. A secondary aim to assess the overall prevalence of BHD in Tasmania was established after initial data suggested that Tasmania may harbour a higher prevalence of BHD compared to other populations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Design\u003c/p\u003e \u003cp\u003eA clinical audit was conducted of the TCGS database to ascertain individuals found to have BHD due to a pathogenic \u003cem\u003eFLNC\u003c/em\u003e variant detected between 2010 and 2021.\u003c/p\u003e \u003cp\u003eIdentified individuals were contacted by letter to notify them of updated screening recommendations and to invite them to participate in this study (See Online Resource 1). Enclosed with this letter was a consent form to participate in the survey, the survey itself with a re-identifiable code, and a reply-paid envelope. Non-responders were contacted via phone a month after the letter was sent to ensure receipt of the letter and with a verbal invitation to take part in this study.\u003c/p\u003e \u003cp\u003eThe survey included a mix of yes/no and opened-ended questions, asking participants to provide information regarding their age, age at diagnosis, highest education completed, kidney cancer history and surgical management, kidney cancer screening practices, whether they have seen a Nephrologist since their diagnosis and whether they would like to be referred to one. Demographic information and details of the variant identified in the individual were collected from the TCGS database. Socioeconomic status (SES) was derived for all individuals via their postcode using the Index of Relative Socio-economic Advantage and Disadvantage from 2016 Socio-economic Indexes for Area [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Geographic classification was derived from the Australian Standard Geographical Classification (ASGC) based on residential postcode. The ASGC measures remoteness based on the distance of geographic locations from the nearest population centre. The five remoteness classes include Major Cities, Inner Regional, Outer Regional, Remote and Very Remote [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAll data and re-identifiable codes were stored in a password protected file on a secure server. Paper copies of each survey were kept for the duration of the study and stored in locked cabinets within TCGS offices.\u003c/p\u003e \u003cp\u003eData obtained for this study was analysed using descriptive analytics, to describe trends and relationships within the data set.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eParticipants\u003c/p\u003e \u003cp\u003eWe identified 37 individuals with molecularly confirmed BHD. A completed survey was received from 38% (n\u0026thinsp;=\u0026thinsp;14/37) of these individuals after follow-up. Of the 62% (n\u0026thinsp;=\u0026thinsp;23) who did not respond, 78% (n\u0026thinsp;=\u0026thinsp;18) were unable to be contacted via phone, 8% (n\u0026thinsp;=\u0026thinsp;2) were deceased, 4% (n\u0026thinsp;=\u0026thinsp;1) had moved overseas, and 8% (n\u0026thinsp;=\u0026thinsp;2) stated they did not wish to participate. See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for participant breakdown.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003cp\u003eThe search of the TCGS database revealed 37 individuals with molecularly confirmed BHD across five Tasmanian families. Our audit revealed four different pathogenic germline variants in the \u003cem\u003eFLCN\u003c/em\u003e gene within five known BHD families.\u003c/p\u003e \u003cp\u003eThose who responded to the survey had similar demographics to the overall cohort, averaging 63.1 years of age and comprised of nine females and five males. Most participants lived in low SES postcodes and were from inner-regional locations. See Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for a full breakdown of participant demographics.\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\u003eDemographic data regarding the individuals in Tasmania identified as having molecularly confirmed BHD and survey respondents.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Tasmanian\u0026rsquo;s with BHD (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvey respondents (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSES\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3% (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7% (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24% (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7% (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68% (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86% (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5% (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eASGC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInner-regional area\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76% (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93% (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOuter-regional area\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19% (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7% (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5% (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30% (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14% (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38% (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57% (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27% (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29% (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5% (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.8 years\u0026thinsp;\u0026plusmn;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.5% (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.3% (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.8% (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.7% (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYears since diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35% (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0% (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22% (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36% (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43% (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14% (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.6 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: SES\u0026thinsp;=\u0026thinsp;socioeconomic status (based on postcode), ASGC\u0026thinsp;=\u0026thinsp;Australian Standard Geographical Classification (based on postcode). SD Standard deviation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eKidney cancer\u003c/p\u003e \u003cp\u003e21% (n\u0026thinsp;=\u0026thinsp;3) of participants reported a kidney cancer diagnosis. These individuals were the only ones who reported having kidney surgery.\u003c/p\u003e \u003cp\u003eScreening\u003c/p\u003e \u003cp\u003eParticipants were asked to complete a table detailing the kidney cancer screening they have had since their diagnosis of BHD. 64% (n\u0026thinsp;=\u0026thinsp;9) participants, either partially or fully, completed this table. Respondents to this question included five females and four males. 89% (n\u0026thinsp;=\u0026thinsp;8) of those who responded to this question reported at least some kidney cancer screening. 78% individuals (n\u0026thinsp;=\u0026thinsp;7) reported having ultrasounds of the kidneys. 57% individuals (n\u0026thinsp;=\u0026thinsp;4) reported having kidney ultrasounds at least two yearly, two participants did not give a frequency, and one commented \u0026ldquo;once\u0026rdquo; but did not specify whether this meant one ultrasound ever or once a year. 33% individuals (n\u0026thinsp;=\u0026thinsp;3) reported having a CT scan, and only one participant reported having had a kidney MRI.\u003c/p\u003e \u003cp\u003eRenal Specialist\u003c/p\u003e \u003cp\u003eParticipants were asked whether they had been referred to a Nephrologist since their BHD diagnosis. 21% (n\u0026thinsp;=\u0026thinsp;3) of respondents reported having seen a Nephrologist since their diagnosis of BHD. Of the 79% (n\u0026thinsp;=\u0026thinsp;11) of respondents who either reported having not seen a Nephrologist since their diagnosis or who did not respond to this question, 64% (n\u0026thinsp;=\u0026thinsp;7) asked to be referred to a Nephrologist, which was subsequently arranged by the study team.\u003c/p\u003e \u003cp\u003eCombining the number of respondents who reported they have seen a Nephrologist since their diagnosis with the number of respondents who requested to be seen by a Nephrologist though this survey, a total of 71% (n\u0026thinsp;=\u0026thinsp;10) of respondents have now seen a Nephrologist since their diagnosis of BHD.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere are two important findings from this study: i) a low rate of adherence to kidney cancer screening and ii) there may be a high prevalence of BHD in Tasmania.\u003c/p\u003e \u003cp\u003e Our study revealed that individuals with BHD in Tasmania are not meeting current guidelines for kidney cancer screening. Interestingly, only 57% of survey respondents are having some form of cancer screening. The purposes of screening for BHD is to facilitate early detection of kidney malignancies enabling early interventions such as nephron sparing surgery. Nephron sparing surgery is an effective therapy for patients that allows preservation of kidney function [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, imaging expertise is critical irrespective of modality.\u003c/p\u003e \u003cp\u003eIn rural/regional locations, access to medical imaging services can be limited compared to metropolitan areas, resulting in inequitable access for patients within those areas [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Studies have observed significant variation in the health-service utilisation of individuals depending on their geographical location in Australia, with individuals living in socioeconomically disadvantaged areas and areas outside major metropolitan centres to have the most adverse health-behaviours profiles [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, individuals from low SES have been shown to attend family clinics less frequently, assumedly in part due to increased costs associated in regional or rural areas [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhilst we did not observe differences in screening practices between males or females, most of our respondents are from inner regional areas, which according to ASGC, inner Regional Australia are areas where geographic distance imposes some restriction on accessibility to a range of goods, services and opportunities [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Those in outer regional Australia experience a moderate restriction to goods and services [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This could explain why 43% of respondents in Tasmania are not undergoing kidney cancer screening and why only 21% of respondents reported having seen a Nephrologist since their diagnosis of BHD.\u003c/p\u003e \u003cp\u003eThe most common mode of screening reported by our respondents were ultrasounds, possibly because ultrasound imaging is inexpensive, non-invasive, and easier to access in Tasmania [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Ultrasound imagining has a sensitivity of 82% and specificity of 98% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, ultrasound detection rates are limited to renal lesion size of \u0026gt;\u0026thinsp;3 cm. This means that tumours\u0026thinsp;\u0026lt;\u0026thinsp;3 cm are not always detected, leading to false negatives. False positives can also occur, and may be correlated to radiologist experience [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. False negatives and false positives can have significant psychosocial impact on individuals, suggesting another reason why ultrasound screening may not be considered gold standard for BHD [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast, sensitivity and specificity for MRI at 1.5T is around 86% and 94%, respectively [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. MRI can detect small renal masses, helps with histology differentiation, allows restaging of disease, and may elucidate treatment response [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In general, MRI is considered gold standard for the diagnosis of kidney cancer, compared to ultrasound or other imaging, such as CT [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Despite these benefits, only one participant from our study reported having had an MRI, supporting the anecdotal evidence that MRI might be more difficult to access within Tasmania.\u003c/p\u003e \u003cp\u003eLiterature describes a lack of trust in healthcare and lack of education as other reasons for low engagement from patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This could suggest why nearly a third of those who completed the survey did not ask to be referred to a Nephrologist or why most patients diagnosed with BHD did not complete the survey. A specialist kidney genetics clinic is an opportunity for patients to access specialist services, provides education, and can help establish trust with healthcare providers. In turn, this has the potential to significantly improve screening practices. Additionally, low penetrance of malignancy in BHD, particularly as exemplified from the figures derived in this study (19%), could mean that some individuals may perceive the cancer risk as low and are less likely to participate in risk reducing behaviours [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].An unexpected finding in our study was the identification of the high BHD prevalence in Tasmania. The current population of Tasmania is approximately 560,000 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] making the observed prevalence of BHD in Tasmania 0.0068% or approximately seven per 100,000. Given the estimated worldwide prevalence of BHD of two per 1,000,000, the observed prevalence of BHD in Tasmania is approximately 15 times higher. Furthermore, other Tasmanian based studies have shown that only 12% of patients with other forms of genetic kidney disease are known to the TCGS [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Therefore, our estimate of BHD prevalence in Tasmania is likely to be an underestimate; the TCGS is unlikely to know all individuals living with BHD in Tasmania.\u003c/p\u003e \u003cp\u003eThere are at least two possible explanations for this observation. Founder effect is one possibility. Tasmania is a small island state which has experienced limited immigration since convict transportation ceased in 1853. It is estimated that 65% of Tasmania\u0026rsquo;s residents are descendants of approximately 10,000 \"founding couples\" from the mid-19th century. Founder effects resulting in high incidences of both Huntington disease and Multiple Endocrine Neoplasia type 1 have been documented in Tasmania [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, there was no evidence of a founder effect in our study to explain the higher prevalence of BHD in Tasmania, given that four different \u003cem\u003eFLCN\u003c/em\u003e variants were identified through our audit.\u003c/p\u003e \u003cp\u003eOur audit of the TCGS database identified 37 individuals with BHD belonging to 5 different families. Each of those families contained one index case, meaning that on average 6.4 additional asymptomatic mutation positive family members were identified by predictive genetic testing for each index case diagnosed with BHD. We are not aware of any published data documenting the number of predictive tests performed per proband for BHD by other genetics services, but it is possible that cascade predictive testing for this low penetrance cancer predisposition syndrome identifies more mutation-positive relatives per index case in Tasmania than elsewhere, resulting in a higher estimated prevalence for BHD. This could come about because predictive genetic testing is more easily accessed in Tasmania than elsewhere. Both genetic counselling appointments and predictive genetic testing are available free of charge in all Australian states to Australian residents, which removes a financial barrier to access. This may prevent uptake of predictive testing in other populations where BHD epidemiological data has previously been collected.\u003c/p\u003e \u003cp\u003eFurthermore, predictive genetic testing may be more pro-actively offered by the TCGS than is the case in other areas. Historically, genetic counsellors at TCGS expended considerable effort to notify at-risk relatives of the availability of predictive genetic testing following the diagnosis of a hereditary cancer syndrome in a proband [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Whilst similar protocols for the notification of at-risk relatives may be used in other Australian clinical genetics services and around the world, the centralization of genetic services in Tasmania into a single State-wide Genetics Service may result in an additional advantage by providing consistency and familiarity for family members, who are all cared for by the same genetic counsellors.\u003c/p\u003e\n\u003ch3\u003eStudy Limitations\u003c/h3\u003e\n\u003cp\u003eDue to the small number of participants in this study, we are unable to examine the data for statistical significance between those identified in the audit and the population who returned the survey. However, there was very little difference in average age, or in average years since diagnosis between the clinical audit population and those who returned the survey. We also did not observe differences in gender. Therefore, we feel the population who returned the survey are reasonably representative of the population from the clinical audit.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTasmania had an unexpectedly high population prevalence of BHD yet screening for kidney cancer is suboptimal. Given BHD is a comparatively common disorder in Tasmania, a lack of screening could contribute significantly to morbidity and mortality of individuals with this condition in Tasmania. We found no evidence of a founder effect in Tasmania, and it is possible that earlier prevalence estimates of BHD were low due to poor ascertainment. Our results suggest that improved access to cancer surveillance is needed.\u003c/p\u003e \u003cp\u003eTo help combat the deficit in screening and disconnect between individuals diagnosed with BHD and Nephrologists, the TCGS and Renal services at RHH have developed a joint multidisciplinary clinic. The purpose of this clinic is to help organise kidney cancer screening and improve access to MRI for individuals newly diagnosed with BHD, as well as to educate patients on ongoing screening and accessibility. Further research to understand the impacts of this multidisciplinary clinic on screening practices within BHD patients should be considered.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthors\u0026rsquo; contribution\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation was performed by Jo Burke, with input from Mathew Jose. Data collection was performed by Michael Millward and data analysis performed by Denisse Garza. The first draft of the manuscript was written by Denisse Garza and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Royal Hobart Hospital Research Foundation Incubator Grant.\u003c/p\u003e\n\u003cp\u003eConsent to participate\u003c/p\u003e\n\u003cp\u003eThis was a low-risk study, and implied consent was obtained from all participants included in the study.\u003c/p\u003e\n\u003cp\u003eEthics Declaration\u003c/p\u003e\n\u003cp\u003eThis study has been approved by the Tasmania Health and Medical Human Research Ethics Committee (Study H0018485).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMenko, F.H., et al., \u003cem\u003eBirt-Hogg-Dub\u0026eacute; syndrome: diagnosis and management.\u003c/em\u003e Lancet Oncol, 2009. \u003cstrong\u003e10\u003c/strong\u003e(12): p. 1199-206.\u003c/li\u003e\n\u003cli\u003eNickerson, M.L., et al., \u003cem\u003eMutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dub\u0026eacute; syndrome.\u003c/em\u003e Cancer Cell, 2002. \u003cstrong\u003e2\u003c/strong\u003e(2): p. 157-64.\u003c/li\u003e\n\u003cli\u003eSchmidt, L.S. and W.M. 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Reithmair, and O.K. 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Young, and J.J. Shepherd, \u003cem\u003eTHE PREVALENCE OF MEN-I IN TASMANIA.\u003c/em\u003e Australian and New Zealand Journal of Surgery, 1996. \u003cstrong\u003e66\u003c/strong\u003e(3): p. 141-143.\u003c/li\u003e\n\u003cli\u003eForrest, L.E., et al., \u003cem\u003eIncreased genetic counseling support improves communication of genetic information in families.\u003c/em\u003e Genet Med, 2008. \u003cstrong\u003e10\u003c/strong\u003e(3): p. 167-72.\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, BHD, FLCN gene, kidney cancer screening","lastPublishedDoi":"10.21203/rs.3.rs-3835636/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3835636/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBirt-Hogg Dub\u0026eacute; Syndrome (BHD) is a rare autosomal dominant condition characterised by a predisposition to benign skin lesions, pulmonary cysts, spontaneous pneumothorax and kidney cancer. An audit of the Tasmanian Clinical Genetics Service database was conducted to identify individuals with molecularly confirmed BHD. To ensure Tasmanians with BHD would be able to meet contemporary national screening guidelines, individuals diagnosed with BHD seen by the Tasmanian Clinical Genetics Service between 2010 and 2021 were invited to complete a survey regarding screening practices. We identified 37 individuals (23 women and 14 males, mean age 62 years old) with molecularly confirmed BHD, giving an estimated population prevalence in 2021 of 7 per 100,000. The majority (80%) lived in inner-regional locations with up to a one-hour travel time to medical imaging facilities. Of those identified, 14 (37%) completed the screening survey, with 8 (57%) reporting at least one screening test for kidney cancer since diagnosis; only 4 (28%) met current guidelines on screening frequency. Our findings showed that Tasmania had an unexpectedly high population prevalence of BHD yet screening for kidney cancer was suboptimal. This is the first study that demonstrates BHD is more prevalent in Tasmania compared to the global average and highlights the need for improved access and education on cancer surveillance.\u003c/p\u003e","manuscriptTitle":"Prevalence of Birt-Hogg-Dube Syndrome and Kidney Cancer Surveillance in Tasmania, Australia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-08 17:31:53","doi":"10.21203/rs.3.rs-3835636/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":"2125e3f4-8c85-43e6-b58c-18dd27f216eb","owner":[],"postedDate":"January 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-08T04:31:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-08 17:31:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3835636","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3835636","identity":"rs-3835636","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}