Driving research, providing support and improving outcomes for rare disease patients and their families



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/