Is there a Beneficial Role for Loss of FLCN in the Liver?

Birt-Hogg-Dubé Syndrome (BHD) is caused by mutations in the gene folliculin (FLCN). We have previously covered some of the roles FLCN plays within our cells that contributes to the manifestations seen in BHD (link to blogs). Most of the research done on FLCN has been focused on the role of FLCN in the kidneys or lungs as these are the tissues most relevant to BHD. However, FLCN is expressed in the majority of our tissues and so it may be important to understand the role FLCN plays in other parts of the body. A recent study by Paquette et al., has uncovered a surprising role for FLCN in the liver in the context of fatty liver disease progression.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and is associated with obesity, type 2 diabetes and dyslipidemia (unhealthy levels of fat in the blood e.g. high cholesterol). Around one third of patients will progress to non-alcoholic steatohepatitis (NASH), which is characterised by liver damage, persistent inflammation fibrosis (scarring) due to accumulation of lipids (fats) in the liver. Around one third of NASH cases will lead to liver cirrhosis and liver failure. There are no approved drugs to treat NASH or to slow its progression.

How does FLCN play a role in fatty liver disease?

As it is accumulation of lipids in the liver that drives damage, regulation of lipid levels is crucial to maintain a healthy liver. FLCN is a known regulator of a protein called AMPK (AMP-activated protein kinase), a master regulator of cellular energy metabolism. Importantly, AMPK controls the switch from the generation of fatty acids to their breakdown. Loss of FLCN leads to a chronic activation of AMPK, which could be beneficial in the context of fatty liver disease. To study the role of FLCN in the role of liver fibrosis progression, the authors of the study generated a mouse model that lacked FLCN specifically in the liver and examined fatty acid accumulation and liver damage.

Firstly, they fed a high-fat diet to the mice lacking FLCN in the liver, or control mice and found that the control mice gained significantly more weight. When they looked at the livers of these mice, they could also see a reduction in fat droplets in the mice lacking liver FLCN compared to control. 

Secondly, they fed the same mice a specific diet that results in the onset of NASH-like symptoms such as liver fibrosis. Unlike the high fat diet in the first experiment, this diet-induced model of fibrosis does not lead to weight gain. Again, they saw significant reduction in fat accumulation in the livers lacking FLCN compared to control. They also saw reduced markers of liver fibrosis and inflammation in the absence of FLCN in the liver, demonstrating that a loss of FLCN protects against liver damage in this context. 


This is the first time a protective role for FLCN has been demonstrated in the liver. The authors of the study also saw no harmful effect of FLCN deletion in the liver which means there is potential for FLCN to be targeted therapeutically for fatty liver disease. It may be possible to develop a drug that is able to inhibit FLCN in the liver and could represent a new treatment route for NASH and even obesity. However, extreme care would have to be taken so that the loss of FLCN is specific to the liver, and would not be able to result in any of the manifestations seen in BHD.

What does this mean for individuals with BHD?
This was not addressed in the current study and so it is currently unclear if there are any consequences for individuals with BHD. It would be extremely interesting to look at samples of the liver in BHD patients or to examine the prevalence of fatty liver diseases within the BHD community. However, it is important to remember that these studies were conducted in mice lacking FLCN in only the liver, and were fed particular diets to induce a model of liver fibrosis and disease and as such may not be reflective of what happens in an individual with BHD.

Day of Giving

Today is the Day of Giving, a day when people come together to support a cause or community. We are developing a BHD patient registry which is a centralised database that collects information about people with BHD. They are particularly useful in the context of rare diseases as they help researchers and clinicians to build a more complete picture of the condition.

View our infographic to find out more. The infographic includes information about our September meeting which has now taken place however there are still ways you can get involved and support the development of the registry.  

Ways to help:

1. Select Myrovlytis Trust on Amazon Smile. We have joined forces with Amazon Smile. Select Myrovlytis Trust as your charity and for each purchase, you make through Amazon Smile, Amazon will donate 0.5% to us.

2. Make a donation through PayPal. Select your charity as the Myrovlytis Trust or use our charity number 1122073 and donate.

3. Sign up for our newsletter to keep up to date with the progress of the registry and associated volunteering opportunities.

4. Share a fundraising idea with us and we can work together to make it a reality. Email us at contact@bhdsyndrome.org

5. Share your time and expertise. Do you have a skill in design, translation or other? We would love to know and will get in contact with volunteering opportunities that match your skill. Email us at contact@bhdsyndrome.org

6. Share our Twitter and Facebook posts with #GivingTuesday

We want to send out a massive thank you to the BHD community for all your support since the relaunch of BHD Foundation this year.


BHD Toolkit: Getting your Diagnosis

We know that receiving a diagnosis for a rare condition can sometimes be a confusing and overwhelming process. Following on from our first BHD Toolkit, we spoke to Dr Derek Lim, Consultant Clinical Geneticist at Birmingham Women’s and Children’s Hospital, UK to help understand what happens at an appointment with a clinical geneticist. Although this pathway is specific to the UK, we hope this provides a general idea of what to expect when you see a clinical geneticist.

How do you get an appointment with a clinical geneticist?

Dr Lim described the three main routes by which individuals are referred to his monthly BHD genetics clinic.

  1. Individuals who have already had a positive diagnostic genetic test for BHD and are referred to discuss the diagnosis, management, surveillance and genetic counselling.
  2. Individuals who are referred to him for a possible diagnosis of BHD (i.e. they have not yet had a genetic test).
  3. Individuals who have a family member who has been diagnosed with BHD.

What happens during your appointment?

What happens during the appointment will depend on whether an individual has already had a genetic test for BHD.

If this is the case (i.e. route number 1), then the genetic test result is explained to them along with an explanation of BHD including the different manifestations and recommended management and surveillance strategies. Dr Lim explained he would also take a thorough family history, examine individuals for skin bumps and refer them for a CT scan of their lungs if they have not already had one and arrange a scan of the kidneys.

If an individual has not had a genetic test for folliculin (FLCN) and are being referred for a possible BHD diagnosis (i.e. route number 2), then Dr Lim provides an explanation of BHD and offers a skin examination to check for skin bumps. If there is sufficient evidence to suspect BHD, a genetic test to look for FLCN variants will be offered. In this instance, the results are often relayed to the individual in a letter as BHD and the management of the condition have already been explained. There is, however, less opportunity to offer further explanation of the sequencing result itself but a follow-up consultation can be arranged if required.

If an individual has been referred to the clinic because a family member has been diagnosed with BHD (i.e. route number 3), a genetic test for the specific variant identified in the family is offered in the following cases: If there are clinical signs of BHD (e.g. skin bumps, or history of pneumothorax/lung cysts or kidney tumours) – this is called a “diagnostic test” or, if there are no clinical signs  a “pre-symptomatic test” is offered. Sometimes it may be appropriate to test another family member first (e.g. a parent of the individual being seen in clinic).

Why is it important to know the specific FLCN variants?

There are several reasons why knowing the specific variant an affected individual has is important. Firstly, from a clinical perspective, the test required for other family members is simpler and cheaper than having to test for variants in the entire FLCN gene, or potentially panel of genes. Dr Lim likened this to finding a spelling mistake in a book. It is a much easier task to find the spelling mistake once you have been able to narrow down the page, paragraph and line the spelling mistake is in. Secondly, knowing the specific variant is also useful to predict the effect of the mutation on the function of the FLCN protein. In turn, this allows the prediction of whether the FLCN variant will be pathogenic, in other words, how likely it is to develop any symptoms associated with BHD. Finally, it is useful for scientists to know what different variants exist so that research can be done to identify if there are any correlations between genotype (the genetic code) and phenotype (the symptoms of BHD), e.g. whether having a particular FLCN variant increases the risk of developing kidney cancer.

What are some of the common questions asked during an appointment?

During appointments where an individual is discussing their diagnosis, a lot of information can be given in a short space of time, and it may be difficult to think of questions that might be relevant.  We asked Dr Lim the most common questions he is asked in his clinic and here are his top 3:

  1. When should my children be tested?
    In the UK, monitoring of the kidneys (preferably a MRI scan) begins at 18 years of age and so appointments to discuss genetic testing are usually made between the ages of 16 and 18.
  2. How often do I need lung scans?
    In the UK, regular monitoring of the lungs isn’t recommended due to repeated radiation exposure through CT imaging. A CT scan is recommended at diagnosis if the individual has not already had one. Importantly, individuals are made aware of the symptoms of a pneumothorax and what to do if an individual experiences one.
  3. Will I get skin bumps and what are the available treatments?
    Although skin bumps are the most common manifestation of BHD, it is not guaranteed an individual will develop them Some individuals may only have a few whereas others may have hundreds. There are treatments available, however they do not prevent the formation of new skin bumps. You can find a list of possible treatments here.

We are extremely thankful to Dr Lim for providing us with his insight into what happens during a clinical genetics appointment. If you have any further questions about genetic testing for BHD please get in touch with us by email and we will be happy to help. Our next toolkit will delve deeper into the actual sequencing results to help you understand what they mean!

Lenke’s BHD Story: Pregnancy

Lenke was diagnosed with BHD after a collapsed lung during her pregnancy. In this interview, she discusses her pregnancy, genetic testing, her decision not to have IVF and her yearly BHD dates with her mum at the clinic.

You can watch the interview below.

A transcript of the interview is available here. You can read the transcript in Dutch here.

Why does BHD cause lung cysts?

Birt-Hogg-Dubé syndrome is caused by a mutation in the gene folliculin (FLCN). Unravelling the functions of FLCN has been a focus of research into BHD, because if we can determine how FLCN mutations cause the characteristics of BHD we can potentially reverse them or even prevent them from happening. Lung cysts are a common feature of BHD with cysts being present in up to 80% of patients. An exciting study by Ikue Tai-Nagara and colleagues discovered a new function of folliculin and hypothesised that when lost it may result in lung cyst formation (1).

The body contains different systems, working in harmony to keep us functioning including the cardiovascular and lymphatic systems. The cardiovascular system transports blood throughout the body whereas the lymphatic system collects excess fluid, clears waste, and transports immune cells. The vessels of these two systems are very similar and both are lined with a layer of cells known as endothelial cells. However, throughout the body, the lymphatic and blood vessels are mostly separated. Imagine they are two different train tracks, structurally similar but carrying different cargo.

The research team investigated what would happen if FLCN was knocked out (removed) in endothelial cells. They studied mouse models at different developmental stages and found that knocking out FLCN in mice that were still developing resulted in enlarged and blood-filled lymphatic vessels. Examining both the lymphatic vessels and blood vessels under a microscope they observed that the lymphatic vessels were developing offshoots towards veins (the blood vessels that transport blood from the organs to the heart) and the veins were developing offshoots towards the lymphatic vessels. It appeared that there was an attraction between the two systems that had not previously been present. Additionally, the lymphatic endothelial cells were dividing rapidly which was the likely cause for the enlargement of the lymphatic vessels.

Next, the researchers investigated why knocking out FLCN caused a change in the relationship between the lymphatic vessels and veins and one key gene stood out. PROX1 controls the development of lymphatic endothelial cells. In mice where FLCN was knocked out not only was PROX1 expressed in the lymphatic endothelial cells (where it should be) but it was also inappropriately expressed in the endothelial cells of the veins. The significance of this expression was highlighted when PROX1 was deleted from the endothelial cells and the characteristics of the vessels normalised.

Next, they needed to connect how knocking out FLCN caused PROX1 expression to increase. They focused on TFE3, which is well documented as being regulated by FLCN (find out more in our recent blog post). Firstly they found that TFE3 was highly expressed in the endothelial cells of the FLCN knockout mice. They then looked at human endothelial cells and found that knocking down FLCN increased PROX1 and that this could be reversed by also knocking down TFE3. They also showed that TFE3 bound and regulated the PROX1 gene. Therefore, when FLCN was knocked down and could no longer regulate TFE3, PROX1 increased resulting in changes to the lymphatic vessels and veins.

So, what has all this got to do with the lungs? The final experiment involved looking at lung samples from three BHD patients. The samples were compared with normal lung specimens and non-BHD cyst-filled lungs. Significantly, only the BHD lung specimens showed evidence of lymphatic vessels filled with blood, inappropriate PROX1 expression and increased TFE3 expression. This suggests that the structural changes in the lungs such as cysts could be linked with the disruption of the lymphatic and cardiovascular systems.

Altogether this research demonstrates a new role of folliculin as a gatekeeper of the lymphatic and cardiovascular system. New research is on the horizon looking further into how lung cysts form and how these pathways can be targeted therapeutically to improve the lung symptoms associated with BHD.

References

1.      Tai-Nagara I, Hasumi Y, Kusumoto D, Hasumi H, Okabe K, Ando T, et al. Blood and lymphatic systems are segregated by the FLCN tumor suppressor. Nat Commun [Internet]. 2020 Dec 1 [cited 2021 Oct 27];11(1). Available from: /pmc/articles/PMC7725783/

2021 BHD Symposium Report

October saw the first ever virtual BHD Symposium, and we were delighted to welcome speakers, chairs and 293 attendees from across the globe for two days of research updates and discussion. In this report we highlight the current research conducted into BHD and look to the future for what this means for those who have been diagnosed with the condition.

BHD Diagnosis and Management 

Raising awareness of BHD was a prominent theme throughout the symposium. There were discussions about involving the media, creating accessible resources and the patient panel together emphasised the importance of healthcare professionals recognising and diagnosing BHD. It was wonderful to see active research carried out on how to support doctors to identify the symptoms and investigate the possibility of BHD. One study found that 1 in 7 pneumothoraces were familial and BHD was the most common known cause (1). It was suggested that people who have a spontaneous pneumothorax could have CT scans to look for BHD. As BHD associated pneumothoraces tend to first occur in 20/30s this also means if BHD is diagnosed from the CT scan, kidney screening can start early. Currently kidney cancer screening is recommended for all BHD patients from the age of 20, and research has so far not identified any folliculin (FLCN) variants that predispose to a specific BHD symptom (2). Avgi Andreou, one of our early career talk winners, is investigating pathogenic variants in cancer susceptibility genes in kidney cancer and we can’t wait to blog about her research when it’s published. It’s inspiring to see a new generation of researchers dedicated to improving outcomes for those diagnosed with BHD.

It was also interesting to hear how BHD presents differently in different populations and the challenges of identifying whether this is due to lack of awareness or difference in genetics. Lung symptoms appear to be the most common presentation of BHD in Asian patients whereas the skin symptoms appear to be less common compared with Caucasian patients.  Additionally, a pilot study investigated the genetics of 15 Indian BHD families. One particularly interesting aspect was four of these families, although presenting clinically with BHD, had no identifiable pathogenic mutation. At the BHD Foundation we often get asked whether you can have BHD without a folliculin variant, and the answer appears to be yes; there may be other genes involved that we do not know about. This is why the BHD Foundation is investigating the creation of clear diagnostic guidelines in the presence and absence of FLCN mutations.

Several talks discussed the management of the symptoms of BHD. A novel technique to prevent recurrent pneumothoraces, called total pleural covering was described. Pleurodesis is the most common treatment to prevent recurrent pneumothorax (3). Surgeons irritate the lining of the lung causing it to stick to the chest. Total pleural covering on the other hand involves a mesh network to keep the lung inflated. It will be interesting to see what techniques are adopted by surgeons over the next few years. It was also exciting to hear ongoing research into fibrofolliculomas and kidney cancer. Research into the structure and formation of fibrofolliculomas has the potential to lead to new topical treatments. Additionally the identification of drugs to treat kidney cancers could prevent the need for recurrent surgeries. Lastly in Germany BHD patients are also offered colon cancer screening from the age of 40. A recent paper found that there may be an increased risk of early onset colon cancer in the BHD population (4). Further research into this is required and it is one of the many questions we hope our registry, that we are setting up will be able to answer.

Understanding Folliculin

There were several talks focusing on trying to understand what FLCN is doing inside cells that contributes to the manifestations seen in BHD. This knowledge is important so that it can guide the development of new therapies to treat the symptoms of BHD. Many talks centred around the kidneys and the role FLCN as a tumour suppressor i.e., the lack of FLCN contributes to tumour growth and therefore kidney cancer development. One of the major pathways studied in the context of FLCN and BHD is the mTOR signalling pathway and the transcription factors TFEB and TFE3 (5,6). Loss of FLCN leads to constitutive activation of TFEB and TFE3 which drive tumour progression; further understanding of this pathway was the focus of several talks.

However, FLCN is also involved in many cellular pathways, on which other speakers presented data demonstrating other roles for FLCN in cancer development (7). Iris Glykofridis, one of our early career talk winners described her work showing that a lack of FLCN has the potential to alter immune responses (8). This is important as the immune system can inhibit tumour growth and as such, the immune system is often modulated in cancer. The role of FLCN in epidermal growth factor receptor (EGFR) signalling was also discussed. EGFR is often overexpressed in cancers and results in a number of so-called ‘hallmarks of cancer’ such as increased cell growth. Loss of FLCN led to an increase in EGFR signalling and could therefore contribute to cancer progression (9). Another important change that cancer cells undergo to favour their growth is alteration of metabolism to increase the amount of available energy (known as the Warburg effect). Data presented at the BHD symposium demonstrated that a loss of FLCN increased a key enzyme important in the switch to this altered metabolism and suggested that inhibition of this enzyme could inhibit tumour progression (10).  

Although kidney cancer is the most serious manifestation of BHD from a clinical perspective and thus warrants a lot of research, it was fantastic to see research presented that focused on the role FLCN plays in the development of lung cysts (11). This research was centred around the FLCN – TFE3 signalling axis, although outside of the role of FLCN as a tumour suppressor. This highlights the complexity of the molecular biology of FLCN and the need to fully understand the many roles FLCN plays and how this contributes to BHD pathogenesis.

The BHD Voice

As well as hearing from the researchers It was wonderful to hear from those living with BHD. They discussed the challenges they faced to reach a diagnosis and the resources that could be useful for them. The BHD Foundation are working on a number of projects that we hope to bring to the BHD community in the near future, including a BHD patient registry, virtual coffee mornings and a global BHD day.

We asked you what you thought and this is what you said:

The BHD Symposium reinforced the importance of unifying the BHD community and working together to raise awareness and hopefully one day find a cure for BHD. We are looking forward to hosting the next BHD Symposiumhopefully both in person and virtually and can’t wait to see you there.

References

1.        Grimes HL, Holden S, Babar J, Karia S, Wetscherek MT, Barker A, et al. Combining clinical, radiological and genetic approaches to pneumothorax management. Thorax [Internet]. 2021 Jun 18 [cited 2021 Oct 27]; Available from: https://thorax.bmj.com/content/early/2021/06/17/thoraxjnl-2021-217210

2.        Are there pathogenic variants of FLCN that do not cause kidney cancer, thus avoiding a requirement for lifelong surveillance? – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/news-blog/are-there-pathogenic-variants-of-flcn-that-do-not-cause-kidney-cancer-thus-avoiding-a-requirement-for-lifelong-surveillance/

3.        Mizobuchi T, Kurihara M, Ebana H, Yamanaka S, Kataoka H, Okamoto S, et al. A total pleural covering of absorbable cellulose mesh prevents pneumothorax recurrence in patients with Birt-Hogg-Dubé syndrome. Orphanet J Rare Dis [Internet]. 2018 May 15 [cited 2021 Oct 27];13(1). Available from: https://pubmed.ncbi.nlm.nih.gov/29764481/

4.        Is Birt-Hogg-Dubé Syndrome linked with colon cancer? – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/news-blog/is-birt-hogg-dube-syndrome-linked-with-colon-cancer/

5.        Folliculin: A Regulator of mTOR Signaling – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/news-blog/folliculin-a-regulator-mtor-signaling/

6.        Exploring a molecular link between Birt-Hogg-Dubé Syndrome and Tuberous Sclerosis. – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/news-blog/exploring-a-molecular-link-between-birt-hogg-dube-syndrome-and-tuberous-sclerosis/https://bhdsyndrome.org/forum/news-blog/exploring-a-molecular-link-between-birt-hogg-dube-syndrome-and-tuberous-sclerosis/

7.        Folliculin: Functions Independent of mTOR and AMPK – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/news-blog/folliculin-functions-independent-of-mtor-and-ampk/

8.        Disruption of Folliculin Induces the Activation of Interferon Response Genes in a Human Renal Cell Model – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/bhd-blog-archives/disruption-of-folliculin-induces-the-activation-of-interferon-response-genes-in-a-human-renal-cell-model/

9.        Laviolette LA, Mermoud J, Calvo IA, Olson N, Boukhali M, Steinlein OK, et al. Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein. Nat Commun 2017 81 [Internet]. 2017 Jun 28 [cited 2021 Oct 27];8(1):1–14. Available from: https://www.nature.com/articles/ncomms15866

10.      A New Role for Folliculin in Cancer Prevention – Birt-Hogg-Dubé Syndrome [Internet]. [cited 2021 Oct 27]. Available from: https://bhdsyndrome.org/forum/uncategorized/a-new-role-for-folliculin-in-cancer-prevention/

11.      Tai-Nagara I, Hasumi Y, Kusumoto D, Hasumi H, Okabe K, Ando T, et al. Blood and lymphatic systems are segregated by the FLCN tumor suppressor. Nat Commun [Internet]. 2020 Dec 1 [cited 2021 Oct 27];11(1). Available from: /pmc/articles/PMC7725783/

RAREsummit21 Conference Report

The Myrovlytis Trust and BHD Foundation attended RAREsummit21 on 7th October 2021. Organised by Cambridge Rare Disease Network, this one-day event brought together patients, advocates and experts to discuss the challenges facing the rare disease community.

The first session focused on equality, diversity and inclusion (EDI) in rare diseases and featured a panel discussion in which individuals shared their personal experiences of EDI barriers, particularly on the journey to diagnosis. Your ethnic background, gender and where you live can all be a barrier to diagnosis and an individual affected by a rare disease often has to persist to be listened to compared to those without such barriers. The lack of diversity in clinical trials was also spoken about, and the need to identify ways to increase trial participation among ethnic minorities. There was also a discussion on health literacy, and the need for patient advocacy groups to create resources that are suitable for the target audience.

The discussion of health literacy led nicely into the second session entitled “Rare Disease Health Information Delivered Well”, which underlined the importance of providing clear reliable knowledge to enable informed decisions. Getting a rare disease diagnosis can be an extremely overwhelming situation. Individuals or their carers are often given a lot of information which is not always related in the most accessible format, for example the use of very technical or medical language. It has been shown that 40-80% of information discussed in a medical consultation is immediately forgotten and therefore a great deal of thought needs to go into providing this information in the most sensitive and accessible formats. There is also the additional complication of accessing high quality, reliable information due to increasing amounts of information available on the internet, some of which will be outdated or incorrect.

Following on from the discussion on delivering health information, was a session on amplifying the patient voice through patient voice publications. It was agreed that this is extremely important to better understand the disease and burden on the community and that it is the patient voice that can drive engagement with other stakeholders e.g. industry. It was noted that needs outside of healthcare are often unheard and unmet, and a patient voice publication can help address this issue. It is not just other stakeholders that can benefit from a patient voice publication, they can be useful for other individuals affected by rare diseases and provide a reassuring voice that you are not alone in your rare disease journey. However, there needs to be a considerate strategy for how and where to publish a patient voice publication. For example, publication in a medical or scientific journal is probably not the best approach as some of them are not accessible to the public, and even if they are, there are still barriers to finding them in the first place. It is also not sufficient to just create a public voice publication without an appropriate strategy of how to effectively use it and engage with other patients, industry and healthcare professionals.

Engaging with industry can be a challenging task for a small patient advocacy group. The afternoon session entitled “Patient Group and Industry Partnering: What are the right ingredients to help catalyse new treatments?” gave an excellent overview of what a successful industry partnership looks like. The discussion focused on being ‘industry ready’ and that partnering with industry is a long-term goal. The first steps towards this include raising an awareness and having an in-depth understanding of the condition. A clear goal and outcome for patients is required and industry need to understand the immediate benefits to patients. Partnering with industry can be a long road, but persistence from the patient group is key, and making those connections is important. Most conversations can be beneficial, even if it is not appropriate to form a partnership, patient groups are raising awareness and representing their community through these conversations. Additionally, it may open doors for other opportunities with different companies, and an opportunity to have another discussion in the future.

The day ended by featuring a successful partnership with the rare disease patient organisation Ring20 which provides support for an ultra-rare form of epilepsy, and their partnering with the company Illumina. This was a really uplifting way to close RAREsummit, and demonstrated that hard work and persistence, along with an engaged patient community and voice can make a real difference to the lives of individuals affected by Ring Chromosome 20 Syndrome.

Take home messages

The underlying theme of the day was that patients are central to, and critical for, the success of a patient advocacy group. The mission of the Myrovlytis Trust and BHD Foundation is to improve the quality of life for individuals with rare conditions. To enable us to do this, we need to raise awareness of BHD, drive research and engage with industry, all of which require a strong patient voice. Going forwards we would like to further engage with the BHD community and create more patient-centred resources to raise awareness among clinicians. We would also like to take steps towards partnering with industry such as creating a patient registry to increase our understanding of the full range of symptoms associated with BHD.

New BHD Case Reports

This summer saw the publication of two new Birt-Hogg-Dubé Syndrome (BHD) case reports. A case report is a published research paper discussing one patient’s story. This is particularly beneficial for rarer conditions such as BHD as clinicians can learn from these cases and potentially reach a diagnosis more easily.

In the first case, a 52-year-old Caucasian man presented to the dermatologist with multiple skin complaints (1). For several years he had been developing sebaceous cysts which required minor surgery to remove. He also had numerous 0.2-0.4cm white facial bumps on his nose, jaw and forehead; they neither caused him discomfort nor had been previously commented on in his medical records. However, it was these bumps that raised the possibility to the dermatologist that there may be a genetic basis to this condition, and a skin biopsy showing fibrofolliculomas followed by genetic testing confirmed BHD.

Although there was now an answer for the fibrofolliculomas the cause of the recurrent sebaceous cysts was uncertain. Sebaceous cysts are rarely seen in BHD but they can occur, raising the question of whether sebaceous cysts are a less common skin manifestation of BHD. A case study is not able to answer this question because you need several patients to determine whether a symptom is a correlation (occurs at the same time as the syndrome but is not caused by the syndrome) or causation (the syndrome directly causes the symptom). This is why we are very excited to get the BHD registry up and running, where data can be collected from lots of BHD individuals, and we can answer questions such as ‘Are sebaceous cysts a symptom of BHD?’. 

The second case was a 26-year-old Asian woman with a history of recurrent pneumothorax (2). After the 5th pneumothorax in 8 months and the discovery that it ran in the family, she was investigated further. A scan showed cystic changes in the lung and examination of the skin showed multiple white-domed bumps on the neck and ears in keeping with fibrofolliculomas. It has been previously noted that the skin manifestations of BHD are less common in the Asian community compared with the Caucasian community and whether it is under-diagnosed or there is a genetic difference is yet to be determined.  The patient and her family underwent genetic testing which showed a mutation in her FLCN gene inherited from her mother’s side. She and her family members were diagnosed with BHD.

Both these cases highlight just how important it is for respiratory physicians and dermatologists to have the tools to recognise and diagnose BHD. In the first case, the patient had no symptoms of BHD except for the fibrofolliculomas and no significant family history. Therefore this diagnosis was dependent on the dermatologists recognising the skin symptoms alone. In the second case, it was the recurrent pneumothorax that led the respiratory physicians to question why they continued to reoccur and genetic testing.

The BHD Foundation is working to raise awareness of BHD among clinicians and are excited to be running the first virtual BHD symposium in 2 weeks. Find out more here.

References

 1.         Medhus E, Siegel M, Boscia J. A Unique Presentation of Birt-Hogg-Dube Syndrome. Cureus [Internet]. 2021 Aug 16 [cited 2021 Oct 6];13(8). Available from: /pmc/articles/PMC8443214/

2.          Lu Y-R, Yuan Q, Liu J, Han X, Liu M, Liu Q-Q, et al. A rare occurrence of a hereditary Birt-Hogg-Dubé syndrome: A case report. World J Clin Cases [Internet]. 2021 Aug 26 [cited 2021 Oct 6];9(24):7123. Available from: /pmc/articles/PMC8409184/

BHD Toolkit: What is a mutation?

When researchers talk about BHD mutations they use phrases such as ‘Missense, Deletion and Frameshift’. But what do these words mean, how do mutations occur and what type of BHD mutation do you have? In today’s BHD toolkit we explore these terms and explain the different types of genetic mutations.

DNA carries all your genetic information, in the form of a code. Imagine a computer code tirelessly running to make sure everything is working smoothly. It is made up of components called nucleotides and it is the order of these nucleotides that determines the bodies programming in other words which proteins are made. Every 3 nucleotides encode for one amino acid, the building blocks of protein, so a change in the nucleotide sequence, can alter the amino acids which ultimately changes the final protein product. This change is called a mutation. Mutations can be caused by the environment or inherited from family members. In BHD, the change in nucleotide sequence and resulting amino acids changes the function of folliculin (FLCN). Several types of FLCN mutations have been identified across the world.

Types of genetic mutation found in BHD

* Splice-site mutation diagram

It can be surprising how one nucleotide change can have the same impact as a large deletion of genetic material, however, going back to our computer analogy it just takes one mistake in the code to stop the programme from working. Therefore, any changes to FLCN which stops it from functioning will result in BHD.

Currently, the management for BHD patients is the same regardless of mutation type but scientists are interested in discovering whether certain mutations are associated with particular BHD characteristics. This could lead to a patient-tailored treatment plan including kidney cancer screening.

In our next BHD Toolkit, we will be diving further into specific FLCN mutations, how to understand your sequencing results and what to expect when you see a clinical geneticist.