Charlottes’s BHD Story: Kidney Cancer

Charlotte lives in Denmark and was diagnosed with BHD after multiple lung collapses in the family.  Kidney screening revealed a mass on her kidney resulting in surgery which didn’t go as expected. Watch Charlotte’s inspiration interview as she discusses how it felt to find a mass on her kidney, the treatment she underwent and how she strongly believes that in most cases BHD does not affect your quality of life.  

The transcript is available here. We also want to thank Charlotte for her help with the Danish translation of the transcript available here.

Who should be referred for genetic testing for inherited kidney cancer syndromes?

It is well known that mutations in certain genes can contribute to the development of kidney cancer. The Cancer Genome Atlas and studies investigating germline mutations in adult cancers identified mutations in 6 – 16% (i.e. 6 – 16  out of 100 people) of kidney cancer cases and there are now 15 genes associated with hereditary kidney cancer syndromes (including folliculin, the gene mutated in Birt-Hogg-Dubé Syndrome, BHD). Therefore, identification of individuals who require genetic risk assessment is important to ensure they receive the most appropriate care. However, clinical guidelines on genetic risk assessment are lacking. Clear guidelines are required to aid clinicians to decide who requires further evaluation, how genetic counselling and testing should be performed, and which genes should be considered. This has particular relevance in the US where differing insurance policies on coverage for genetic testing can result in barriers in to access care. To address this a panel of experts, including Professor Gennady Bratslavsky (the invited speaker at our most recent Meet the Expert event), discussed several questions regarding genetic risk assessment for hereditary kidney cancer to develop consensus clinical guidelines (Please note this paper isn’t open access).

A series of questions were curated by a steering committee and grouped into 5 different categories:

  1. Who should undergo genetic risk assessment?
  2. When should genetic risk assessment be performed?
  3. What testing should be performed?
  4. How should germline risk assessment be conducted?
  5. Testing in cases of isolated extrarenal lesions associated with known syndromes.

The questions were reviewed by the expert panel which included urologists, medical oncologists, genetic counsellors, clinical geneticists, and patient advocates. Uniform consensus was defined as ≥85% agreement.

1. Who should undergo genetic risk assessment?

Uniform consensus on who should undergo genetic risk assessment was reached for the following conditions:

  • Individuals with or without kidney tumours with a personal or family history of classic manifestations associated with hereditary kidney cancer (e.g. spontaneous pneumothorax).
  • Individuals with a 1st degree relative with a documented germline mutation (or 2nd degree relative if 1st degree is not available – see family tree diagram below ).
  • Individuals with kidney cancer who also have a 1st or 2nd degree relative with kidney cancer.
  • Individuals with kidney cancer that shows a specific histology (such as hybrid oncocytoma tumours – common in BHD).
  • Individuals with bilateral or multifocal kidney tumours (also common in BHD).

A consensus could not be agreed regarding a cut-off age for genetic risk assessment (i.e. whether age alone was a sufficient criterion to recommend genetic risk assessment in an individual with a kidney tumour).

2. When should genetic risk assessment be performed?

Uniform consensus on when genetic risk assessment should be performed was reached for the following condition:

  • Individuals with a renal lesion less than 3 cm and a strong suspicion for a hereditary cancer syndrome.

It was also agreed that a skin biopsy is not necessary to guide genetic risk assessment in individuals with a kidney tumour and skin lesions resembling those associated with a hereditary cancer syndrome. Other questions, including whether histologic diagnosis (i.e. confirming the type of kidney cancer) is required before genetic risk assessment was more contentious and the panel did not reach a consensus.

3. What testing should be performed?

A uniform consensus was agreed that multi-gene testing should be considered for individuals with more than 1 risk factor for a hereditary kidney cancer syndrome. It was generally agreed (although a uniform consensus was not reached) that individuals with a suspicion for a particular syndrome with a defined gene should be considered for single gene testing.

4. How should germline risk assessment be conducted?

Uniform consensus on how genetic risk assessment should be conducted was reached for the following conditions:

  • Genetic testing should not be performed without prior genetic counselling.
  • Genetic counselling may be offered by a clinician with expertise in hereditary kidney cancer syndromes.
  • A telehealth consultation with a licensed counsellor is also sufficient before genetic testing.

Some of the panel agreed that a standardised video covering the essentials of pre-test genetic counselling was sufficient, however many were concerned about the lack of opportunity for discussion with a qualified provider.

5. Testing in cases of isolated extrarenal lesions associated with known syndromes

This category covered whether genetic risk assessment should be considered for individuals with no kidney lesions or a family history of kidney cancer but have other manifestations outside of the kidney associated with known hereditary kidney cancer syndromes. It was agreed that genetic testing should be offered in the following cases:

  • A single pheochromocytoma or paraganglioma (adrenal gland tumours).
  • A single endolymphatic sac tumour (a tumour in the ear strongly associated with Von Hippel-Lindau syndrome).
  • Uveal melanoma (cancer of the eye).
  • A single fumarate hydratase-deficient uterine fibroid (associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC)).

Regarding BHD, a consensus was not reached on individuals with a history of spontaneous pneumothorax or skin fibrofolliculomas.


Genetic testing is an important factor in assuring an individual receives appropriate care and management. For example, in BHD individuals should monitor their kidneys regularly and if the need for surgery arises, preserving as much of the kidney as possible is essential.  It was noted that there are several barriers to initiating genetic testing including a lack of confidence of clinicians to discuss the risks and benefits and interpretation and explanation of genetic testing results. Consensus guidelines on genetic risk assessment may aid clinicians to overcome the barriers of initiating genetic testing. As such, the findings here represent the first consensus guidelines for genetic risk assessment in hereditary kidney cancer. However, it should be noted that all panel members were from North America and therefore these findings may not necessarily be applicable worldwide. Additionally, the statements here are relatively broad given there are no previous consensus statements that can be further refined. Therefore, it is vital that follow up meetings are held to further refine and update these guidelines, particularly where there was a lack of consensus.

At the BHD Foundation, we think this is a really important step towards implementing standardised guidelines for the diagnosis and management of BHD. We are happy to further advise on genetic counselling and testing and to help locate specialists in your area. Please do email us with all your BHD related queries.

What are the Different Types of Kidney Cancer?

A recent study estimated that there were 431,000 new cases of renal cell carcinoma (RCC – kidney cancer) and an estimated 179,000 deaths in 2020 worldwide. In non-metastatic settings (i.e., where the cancer is localised in the kidney and has not spread beyond) more than 90% of patients survive at least 5 years. However, in patients with metastatic RCC (where the cancer has spread to other parts of the body) the outcome is poorer.

RCC can be categorised into 2 main groups – clear cell RCC, which accounts for 75-80% of all cases, and non-clear cell RCC (nccRCC), which can be further subdivided into smaller groups based on the differences in histology, for example cell shape and cellular alterations. Around 5% of nccRCC cases have a genetic disposition and, like in Birt-Hogg-Dubé syndrome (BHD), these tumours are commonly multiple and bilateral and have an earlier age of onset compared to nccRCC not associated with a genetic condition. In general, kidney cancer associated with BHD is normally slow growing and rarely metastasises. This blog post will focus on the features and treatment of nccRCC. However, it does not discuss oncocytoma or hybrid RCC, 2 of the most common types of BHD-associated kidney cancer.

Types of nccRCC

  • Papillary RCC – the most frequent type of nccRCC and 2nd most common type of kidney cancer. Several genetic mutations are associated with papillary nccRCC, but this type is not normally associated with BHD.
  • Chromophobe RCC – the next most frequent type of nccRCC and one of the most common types associated with BHD. Chromophobe RCC is also associated with a number of other rare genetic syndromes including tuberous sclerosis and Cowden syndrome.
  • Other types of nccRCC include collecting duct RCC, MiT family translocation RCC and renal medullary carcinoma. None of these have been previously associated with BHD and are all very rare, aggressive forms with poor prognoses.

Although the treatments for advanced clear cell RCC have significantly evolved, little progress has been made in metastatic nccRCC due to the low incidence rates and the clinical and molecular diversity of this cancer, resulting in limited numbers of therapies available. Over the past decade, researchers have produced the cancer genome atlas, an in-depth molecular understanding of key cancer-causing alterations in different cancers. Importantly, this includes some types of RCC including clear cell, chromophobe and papillary and has revealed specific spectrums of molecular features for each type to improve the therapeutic management.

A recent paper by Marchetti et al., describes the most important signalling pathways involved in different nccRCC subtypes and includes an overview of ongoing/recently published clinical trials involving nccRCC patients (1).

nccRCC signalling pathways

There are 3 main pathways that are important in driving tumourigenesis (cancer formation) in nccRCC.

1. VEGF axis pathway

This pathway is involved in angiogenesis (the formation of new blood vessels). This is an important pathway in driving the growth of tumours which need a good network of blood vessels to provide oxygen and essential nutrients. There are several existing anticancer drugs that target this pathway to slow the growth of tumours.

2. Mesenchymal-Epithelial Transition (MET) pathway

This pathway is associated with tumour growth, metastasis and malignant cell infiltration (spread of the cancer). This pathway is particularly important in papillary RCC in which the MET gene is often mutated. A number of MET-directed inhibitory cancer drugs have been developed and some, such as cabozantinib target both the MET and VEGF pathways.

3. mTOR pathway

We have recently discussed the mTOR pathway and its role in BHD-related kidney cancer. Although there are several mTOR inhibitors available which are used in other clinical settings, they have not shown to be effective in the setting of BHD.


Generally, RCCs are characterised by a dysfunctional immune cell infiltrate leading to immune suppression in the tumour microenvironment allowing growth of the tumour. This makes it targetable by immunotherapy drugs that work against the major proteins that mediate the immune suppressive environment in the tumour microenvironment. These major proteins are called PD-1, PD-L1 and CTLA-4.

Although the use of immunotherapies in clear cell RCC was assessed in 2015, it has only recently been studied in the context of nccRCC and there are now several recently published and ongoing clinical trials (see our clinical trials page for more information on how clinical trials work).

  • The recent KEYNOTE-427 phase II clinical trial looked at the efficacy and safety of the immunotherapy pembrolizumab (a PD-1 inhibitor) as a monotherapy in advanced nccRCC (types papillary, chromophobe and unclassified). The study showed promising clinical activity however the response rates were higher for papillary and unclassified RCC than chromophobe.
  • Another phase II clinical trial tested nivolumab (another PD-1 inhibitor) in combination with cabozantinib in 2 cohorts of patients. The first had papillary, MiT family translocation or unclassified RCC and the second had chromophobe RCC. Like the KEYNOTE-427 trial, this showed promising clinical efficacy in the first cohort but there was no response in the second cohort of chromophobe RCC patients.
  • Several other trials assessing immunotherapies or combination immunotherapies are underway and are showing promising preliminary results.

The International Kidney Cancer Coalition have a very user-friendly clinical trials search tool that gives up-to-date information on current clinical trials.

Various novel strategies for the treatment of nccRCC are also emerging and are under investigation (2). These include combination therapy of the PD-1 inhibitor camrelizumab and cytokine-induced killer cells. These are immune cells that can recognise and specifically kill cancer cells. The field of individualised DNA plasmid cancer vaccines is also progressing and are used to induce an anti-tumour immune response.


nccRCC is very diverse and complex but we are constantly improving our knowledge and understanding of these cancers and therefore increasing the number of therapeutic options. However, there is still lots of research to be done including the identification of biomarkers for the prediction of progression and response to treatment for nccRCC. Recruitment of sufficient numbers of patients to clinical trials for nccRCC is still an issue due to the rarity and diversity of this group of cancers. Innovation in clinical trial design will be key to the success of future clinical trials in this context.

One of the most striking observations from this review was the lack of response to immunotherapies in chromophobe RCC. As this is one of the most common types of kidney cancer in BHD patients, it is particularly important to us as a charity that further work can be performed to understand why this is the case. This knowledge is greatly needed to open up the therapeutic potential of these immunotherapy drugs which made huge advances in the treatment of other cancers.


1.        Marchetti A, Rosellini M, Mollica V, Rizzo A, Tassinari E, Nuvola G, et al. Molecular Sciences The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory? 2021 [cited 2021 Sep 10]; Available from:

2.        M S, F M, G A, V M, A C, A L-B, et al. Designing novel immunocombinations in metastatic renal cell carcinoma. Immunotherapy [Internet]. 2020 Dec 1 [cited 2021 Sep 10];12(17):1257–68. Available from:

A New Role for Folliculin in Cancer Prevention

We are excited to be sharing with you a recently published paper by Woodford et al., exploring the reason why the loss of folliculin (FLCN), the gene mutated in Birt-Hogg-Dubé syndrome (BHD), drives tumour development.

Cancer cells have characteristics that allow them to grow and replicate uncontrollably. One of these is the deregulation of cellular metabolism, in other words, cancer cells can change how they get their energy. To produce energy cells normally break up glucose to produce pyruvate which then interacts with oxygen and releases carbon dioxide (CO2). If there is limited or no oxygen pyruvate is converted to lactate instead. However, cancer cells will rapidly take up glucose and convert pyruvate into lactate, even in the presence of oxygen, which is beneficial for the cancer cell. This shift in cellular metabolism is known as the Warburg effect and is driven by Lactate Dehydrogenase A (LDHA), the enzyme which converts pyruvate into lactate. Interestingly, loss of FLCN has previously been shown to increase LDHA activity. Woodford et al., examined this relationship further and investigated whether LDHA could be targeted to treat Kidney cancer.

Several different experiments were undertaken to characterise the relationship between FLCN and LDHA. Detailed examination of the FLCN protein in a kidney cell line showed that FLCN interacted with 114 different proteins including LDHA and that high FLCN expression reduced LDHA activity. To determine how FLCN reduced LDHA activity the relationship between LDHA and its cofactor (a small molecule needed for LDHA activity) was examined. High levels of FLCN reduced the binding between LDHA and its cofactor likely through alteration of LDHA’s structure thereby reducing the activity of LDHA. Taken together these results demonstrate a new role for folliculin as a binding partner and inhibitor of LDHA.  

Next Woodford et al., examined the significance of this finding in cancer cells. 13 cell lines, including a kidney cell line, showed a metabolic shift and hyperactivity of LDHA. 11 of these cell lines also showed a dissociation between FLCN and LDHA suggesting that the inhibitory effects of FLCN are lost in many cancer cell lines.

The creation of targeted therapies against LDHA has always been an appealing area of investigation for cancer treatments, however creating a target that is specific to LDHA has been challenging because there are other similar proteins. The discovery of FLCN as an inhibitor of LDHA creates a new opportunity for such therapies. Firstly, Woodford et al, showed that FLCN binds specifically to LDHA and none of its similar proteins. They then identified the specific region of the FLCN protein which binds to LDHA.  They produced a series of peptides (a chain of amino acids which is the building blocks of proteins) derived from FLCN to target LDHA based on their findings of how FLCN binds to LDHA. These peptides were tested in normal kidney cells in vitro and those that were taken up by the cells and reduced LDHA activity were selected for further tests. They then examined the response to the peptides in a kidney cancer cell line. One of the peptides named FLCN-10 was able to bind to LHDA and this resulted in cancer cell death. Next tissue samples from a kidney cancer of a BHD patient were treated with FLCN-10. FLCN effectively reduced LDHA activity in the kidney cancer cells.  

Altogether Woodford et al., have demonstrated a new role of FLCN as an inhibitor of LDHA. It binds to LDHA and regulates its activity. Therefore, in BHD, loss of FLCN results in LDHA hyperactivity resulting in the Warburg effect which is beneficial for cancer cells.  An understanding of this interaction between FLCN and LDHA meant Woodford et al., were able to create a folliculin derived peptide which bound to LDHA and inhibited its activity. This discovery could pave the way for a new LDHA targeted cancer treatment not only for BHD patients but other cancer patients as well.

We are sorry that the paper is currently not freely available. Please message us if you have any further questions at


1. Woodford MR, Baker-Williams AJ, Sager RA , Backe SJ , Blanden AR, Hashmi F, et al. The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect. Nat Struct Mol Biol [Internet]. 2021 Aug 1 [cited 2021 Sep 3];28(8):662–70. Available from:

Is Birt-Hogg-Dubé Syndrome linked with colon cancer?

Is Birt-Hogg-Dubé Syndrome (BHD) linked with colon cancer? This is a question we often receive at the BHD Foundation and does not have a simple answer. Colon cancer is one of the most common cancers in the western world and is thought to be largely linked to environmental factors such as diet and age. However specific genetic mutations increase the risk of developing colon cancer and it is yet to be proven whether folliculin (the gene mutated in BHD) is one of them. There are reports of BHD patients developing colon cancer, but current research is not conclusive on whether these cases are linked to BHD or it is just a coincidence. Investigating this link is important as it will help to inform colon cancer screening in the BHD community.

A recent paper by Sattler et al., analysed the frequency of colon cancer in 256 BHD patients compared to 519 non BHD patients(1). We spoke to the lead researcher and BHD expert Professor Steinlein about this paper and delved into why researchers may be getting different results and what needs to be done to provide further evidence on the link between colon cancer and BHD.

What inspired your research looking into the risk of colon cancer in BHD?

Elke Sattler, Dermatology, and I (Human Genetics) started Germany’s only interdisciplinary BHD outpatient clinic more than 10 years ago and, together with Zulfiya Syunyaeva (Pulmonology) we have by now collected nearly 100 mostly multiplex families. Our patients, finding information about possible associations between colorectal cancer and BHD on Google, are often asking about their risk for this tumor type. Furthermore, we always perform extensive pedigree analysis in our BHD families and observed a higher than expected rate of early onset colon cancer. Some months ago we therefore decided to systematically analyse our data.

What did you discover?

We first looked at the frequency of colorectal cancer and found it to be significantly more frequent in BHD patients than in controls. However, the difference between both groups was small, meaning we found only a moderate increase in risk. Such small differences are statistically not very robust and not all previously published studies reported the same effect. Much more important is our observation that in BHD families in which colorectal cancer occurred, it often occurred either at an unusually early age (i. e. before the age 50 years) or affected several family members. This is a pattern well known from HNPCC (hereditary non-polyposis colon cancer or Lynch syndrome), the most common hereditary colorectal cancer syndrome.

There is an ongoing discussion about whether there is a link between colon cancer and BHD and whether BHD patients should get screening. What are the challenges faced by researchers to answer these questions and how can we overcome them? 

The biggest challenge will be the availability of a large number of clinically well characterized BHD families. During the last decade several of such samples have been collected by different research groups but sample sizes still need to be increased. There is also the possibility, that cancer risks differ between ethnic or regional backgrounds. It therefore most likely will take several more years to collect enough large BHD samples from different populations before the BHD research community will be able to give a final answer to the question about a possible association between colorectal cancer and BHD.

What message would you give to BHD patients who are concerned about developing colon cancer?

We are counselling our patients that after age 50 years the colon cancer risk is likely to be comparable to the age-related risk for this cancer type in the general population. However, there might be a small but significant risk for early onset colorectal cancer. We are therefore suggesting to start coloscopy at age 40 (or ten years before the first family member developed colorectal cancer in patients where there is a family history of colon cancer).

Are you working on any other BHD research projects currently and can you tell us a bit about them?

BHD is our main research focus and we are steadily increasing our sample of families. Most of our current research projects are focused on clinical aspects, especially possible associations between BHD and different cancer types but we are also in the planning stage for functional studies.

Altogether this study suggests that although there is not a significant increase in colon cancer, BHD patients may be at increased risk of developing colon cancer at a younger age. Because of this discovery Professor Steinlein advises caution and suggests that BHD patients start colon cancer screening from the age of 40 (10 years earlier than screening for the general population).

It must be noted that due to the variation in results investigating the link between colon cancer and BHD, recommendations may vary in different areas. We recommend discussing any queries regarding colon screening with your BHD doctor. If you would like assistance identifying a BHD specialist please contact us at or search our interactive map.

The BHD Foundation sincerely thanks Professor Steinlein for discussing her paper with us and the BHD community. The research paper is not currently freely available. Please contact us at if you have any questions regarding this research.  


1.          Sattler EC, Syunyaeva Z, Reithmair M, Dempke W, Steinlein OK. Colorectal cancer risk in families with Birt-Hogg-Dubé syndrome increased. Eur J Cancer. 2021 Jul 1;151:168–74.

Register Now for the BHD Symposium Patient Sessions!

The BHD Foundation is excited to announce that the tickets for the BHD symposium patient-focused sessions are now available. Tickets are free and are aimed at BHD patients and their families and friends.  

There will be two unique sessions exploring the future of BHD.  Please register for each event separately and note you are welcome to attend both sessions or just one (they both work well as standalone sessions).  

Thursday 21st October 7:00pm – 8:10pm (British Summer Time)

The Future of BHD Session 1 

In this session, you will have the opportunity to explore the exciting and innovative research being done into BHD and what this means for the future. BHD experts from around the world will be sharing their work and answering your questions, so together we can look towards a future of curing BHD.  

Register for The Future of BHD session 1 here.

Friday 22nd October 7:00pm – 8:10pm (British Summer Time)

The Future of BHD Session 2

On day two we will have a panel of BHD patients who will be sharing their personal BHD stories and discussing the challenges BHD patients face and how to support those who are newly diagnosed. You will also have the opportunity to ask the Team at the BHD Foundation about the work we do and how together we can raise awareness of BHD.

Register for The Future of BHD session 2 here.

If you have any questions about the event or would like to volunteer to be part of the patient panel please email us at

We are looking forwards to seeing you all there!

Are there pathogenic variants of FLCN that do not cause kidney cancer, thus avoiding a requirement for lifelong surveillance?

Guest Blog by Richard Thrift

Birt-Hogg-Dubé Syndrome (BHD) is an inherited autosomal dominant disorder caused by mutations in the folliculin (FLCN) gene. About 200 pathogenic variants in FLCN have been identified to date. The three classic symptoms of BHD are spontaneous pneumothoraces, characteristic skin lesions associated with hair follicles (the most common of which are fibrofolliculomas), and kidney cancer (also known as renal cell carcinoma, RCC). Not all BHD patients have all symptoms. In particular, only about 1 in 3 patients develop RCC. It has been suggested, based on very limited data, that some FLCN variants may not give rise to RCC. If it were possible to identify variants that do not increase the risk of RCC, expensive and uncomfortable imaging (typically CT or MRI every three year) could be avoidable for people with those variants.

Matsumoto et al. undertook an extensive literature search to try to identify pneumothorax only pathogenic variants(POPVs) (1) . They found 158 articles, which described 1059 individuals from 575 families. 194 unique pathogenic FLCN variants were identified, with patient details provided in most reports. Patients were evenly split between East Asia (Japan, South Korea, China and Taiwan) (33.3%), North America (32.7%), and Europe (31.7%). They broke down the data to make several interesting observations.

Of the documented patients, 91.9% were shown to have pulmonary cysts. The prevalence of pneumothorax, characteristic skin lesions, and RCC in BHDS were 50.9%, 47.9%, and 22.5% respectively. The median age at first pneumothorax was 34 years (range 10–78 years). The median age at which skin changes were first noted was 38 years (range 20–65 years). The median age at first diagnosis of RCC was 47 years (range 14–83 years).

In previous reports there appeared to be a higher percentage of pneumothorax and fewer dermatological findings and RCCs among patients from East Asia. The current study bears this out and provides a more detailed overview. The prevalence of pneumothorax in East Asians was 74%, vs 45% in Europe and 35% in North America. It’s not clear whether this might be explained by genetic and physiological or environmental differences, but there does seem to be some sampling bias due to differences in diagnostic pathways. Pneumothorax recurred in 2 out of 3 patients (geographic differences were not mentioned).

It typically took 6 years for patients to be diagnosed with BHD following a pneumothorax, compared with 0 years for diagnoses following RCC or skin changes. Lack of awareness by clinicians can delay life-saving screening for RCC.

Out of 991 patients identified, only one had RCC below age 20 (at 14 years of age), while 14 had a pneumothorax before age 20. This bears on the minimum age at which genetic testing should be performed. Ethical considerations are discussed by Borry et al, (2); generally, testing is discouraged before the age at which diagnosis might influence management of the condition.

Matsumoto et al. discuss some of the unavoidable limitations and potential biases of a study based on a review of the literature. FLCN variants were analyzed according to the type of mutation, because different mutations behave differently. 68% were nonsense and frameshift variants, 16% were intronic variants, 6% were missense variants/in-frame deletions, 7% were large deletions/duplications, and 4% were variants affecting transcription initiation. The class of large deletions is significant because these variants are not readily identified by DNA sequencing. These are identifiable by copy number analysis, a technique that has only become common in recent years. Patients with large deletion variants who were tested more than a few years ago have often been told they were negative for BHD.

Ideally, there would be enough data to pinpoint which variants are associated with RCC and which are not. But BHD is a rare disease, and there simply aren’t enough documented patients. Many variants have only been documented a few times; not enough to say “this variant, although known to have caused pneumothoraces, will never give rise to RCC.” So, in order to get a little traction, we can try to focus on the variants that seem least likely to cause major problems.

For most of these classes of variants, it is thought that the mutation either causes the variant protein to be destabilized and rapidly degraded, or causes much less protein to be made because the mRNA is either rapidly degraded or just not functional. Missense variants, small in-frame deletions, and a small percentage of nonsense / frameshift variants (those near the last exon) are the only ones with much hope of making a normal amount of (possibly only slightly defective) protein. It is assumed that in general, inadequate amounts of protein being made will absolutely prevent normal function of FLCN, while normal amounts of (slightly defective) protein might have selective effects on function, perhaps leading to a milder condition that does not progress to RCC.

Of the 194 pathogenic FLCN variants (after eliminating variants known to be associated with RCC), 76 appeared, given the limited data, to be POPV. The authors looked for differences between POPVs and non-POPVS by assessing variant type, location within the gene, age of patients, and number of patients with that variant. There were no statistical differences in type or distribution. Almost 90% of POPVs were found in only three or fewer individuals; clearly there is a decent chance that for many of these variants, RCCs will be found if more patients are tested. There was a tendency for patients with POPVs to be younger than those with non-POPVs; if these patients are observed for a longer time, RCCs may develop in them.

Given the above, of the 76 apparent POPVs, it seems unlikely that the majority of these variants are only linked to pneumothorax. However, it cannot yet be ruled out that some of these may be genuine POPVs. The ability to follow BHD patients with these variants over time and assess whether they develop further BHD-associated manifestations would be greatly beneficial in furthering our understanding of whether certain variants are linked to particular manifestations.

Based on this conclusion, the authors recommend lifelong monitoring for RCC (by CT or MRI) of all BHD patients, since pneumothorax-only FLCN variants are likely to be rare.


1) Matsumoto K, Lim D, Pharoah PD, Maher ER, Marciniak SJ. A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours. Eur J Hum Genet (2021). Online ahead of print. 2) Borry P, Evers-Kiebooms G, Cornel M, et al. Genetic testing in asymptomatic minors. Eur J Hum Genet 17, 711–719 (2009).

2) Borry P, Evers-Kiebooms G, Cornel M, et al. Genetic testing in asymptomatic minors. Eur J Hum Genet 17, 711–719 (2009).

Exploring a molecular link between Birt-Hogg-Dubé Syndrome and Tuberous Sclerosis.

Tuberous Sclerosis (TSC) is an autosomal disorder caused by mutations in the genes TSC1 or TSC2. It is characterised by the development of tumours that affect several organs including the brain, heart, kidney, lung and skin. Most TSC-associated tumours are benign however malignant tumours do occur, particularly in the kidneys. As such, TSC and Birt-Hogg-Dubé Syndrome (BHD) share some similar features as well as manifestations that are unique to each condition. Like folliculin (FLCN), which is mutated in BHD, TSC1 and TSC2 also regulate the activity of mTOR signalling. We recently published a blog that reviewed the function of FLCN in regulating mTOR signalling. The authors of the review highlighted work which demonstrated that in kidney tumours derived from BHD patients, the loss of FLCN led to hyperactivation of mTOR. Similarly, in TSC, loss of either TSC1 or TSC2 leads to hyperactivation of mTOR which is believed to be the main driver of tumourigenesis.

A recent paper by Alesi et al., investigated the role that TSC1 and TSC2 play in the regulation of lysosome biogenesis and mTOR signalling (1). Lysosomes are organelles responsible for degradation and recycling of cellular waste. Studying lysosomes is important in this context as they have been increasingly shown to be a driver of tumourigenesis. The activity of mTORC1 (a key player in the mTOR signalling pathway) tightly regulates the transcription factors TFEB and TFE3, master regulators of lysosome gene expression, biogenesis and autophagy. In theory, hyperactivation of mTOR signalling should result in prevention of TFEB translocating to the nucleus where it is active. However, there is conflicting evidence of this in the literature in the context of TSC. This present study shows that despite high mTORC1 activity, the localisation of TFEB is predominantly nuclear. Of interest, this has also been shown for a mouse model of BHD-associated kidney cancer in a paper by Napolitano et al., indicating that TFEB may be a driver of tumourigenesis in both TSC and BHD. This is the opposite of what you would expect and so it is important to understand why this happens.

The authors made use of multiple different models to examine TFEB activity in cells lacking TSC2. In a mouse model of TSC which develops kidney cysts they found a 3-fold increase in the number of lysosomes in the tumours compared to adjacent healthy tissue, indicating an increase in TFEB activity in tumours. They also demonstrated an increase of TFEB with a predominantly nuclear localisation in cells lacking TSC2 in vitro. They confirmed that the nuclear TFEB was active in these cells and that this activity led to an increase in cell proliferation, which is required for tumourigenesis.

As FLCN has been shown to be important for TFEB regulation, Alesi et al., next looked at a combined effect of FLCN and TSC2. They depleted TSC2 and FLCN either alone or in combination in vitro and as expected, saw a significant increase in TFEB nuclear localisation and activity when either TSC2 or FLCN were depleted alone. This effect was further enhanced when both TSC2 and FLCN were depleted. The ability of FLCN to regulate TFEB activity is mediated by the proteins RAGC and RAGD which activate mTORC1. The authors demonstrated an increase in the expression of RAGC and RAGD in TSC2 deficient cells, as well as in FLCN-deficient cells and cells lacking both TSC2 and FLCN. They suggested that this could represent an additional mechanism for sustained mTORC1 activity in TSC2 and/or FLCN-depleted cells. The authors stated that the combined loss of TSC2 and FLCN resulting in an even stronger nuclear localisation and thus activity of TFEB implies that there is a pathogenic link between TSC and BHD and that TFEB may represent a therapeutic target for both these rare conditions.

At the BHD Foundation and Myrovlytis Trust we found this paper exciting. The rarity and complexity of conditions such as BHD and TSC present many research challenges. Identification of common pathways that may be targeted therapeutically against multiple conditions is an extremely attractive approach. Further research needs to be performed to investigate if TFEB can be a therapeutic target for alleviating kidney disease in both TSC and BHD.


1.        Alesi N, Akl EW, Khabibullin D, Liu HJ, Nidhiry AS, Garner ER, et al. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nat Commun. 2021;12(1).