Being a doctor with BHD

Dr Bob was diagnosed with BHD after a routine scan accidentally picked up a mass on the top of his kidney. In this interview, we discuss how being a doctor affects his perspective of BHD, how we can raise awareness of BHD among doctors and the importance of being a patient advocate.

The transcript is available here.

Resources discussed in the interview.

Information resources for people with BHD

Information resources for researchers and doctors

BHD and COVID-19

Having a rare lung condition can feel scary. Having a rare lung condition during the COVID-19 pandemic adds another layer of complexity.  You may have many questions about BHD and COVID-19. In todays blog posts we summaries what the expert advises regarding BHD and COVID-19.  We also interviewed BHD patient Anna Marie Dowling about her experience getting COVID-19 with BHD.

Lung Specialist, Professor Stefan Marciniak (University of Cambridge) discussed whether COVID-19 increased the risk of lung collapses in BHD patients. He reported that in his clinic he had not seen an increase in cases and was only advising his lung collapse patients to shield if they had severe lung diseases (most of his BHD patients did not fall into this category).  He also recommended that everyone should get the COVID-19 vaccine. You can read the interview with Stefan here. He also spoke about this at a Meet the Expert event last year, which is available to watch on our webpage.

Similarly, the International Kidney Cancer Coalition provide advice on the vaccine. They are an international charity supporting people affected by kidney cancer. They advised that the benefit of the vaccine outweighs the risk and that any concerns should be discussed with a doctor. Read their statement here.

Hearing from experts is important but we also wanted the patient perspective. Anna Marie Dowling is 55 years old and lives in Ireland.  We interviewed her about her BHD diagnosis and catching and recovering from COVID-19.

What were the events that led to you seeking a genetic test for BHD?

In 2015 my then 80 year old father, who has COPD (Chronic Obstructive Pulmonary Disease), was referred for genetic testing for BHD by Professor Michael Keane, Consultant Respiratory Physician, St. Vincent’s University Hospital, Dublin as he suspected my father had the condition. My father tested positive for BHD and was provided with a letter from the Department of Clinical Genetics at Crumlin Children’s Hospital, Dublin to send to family members to inform them about the condition. On hearing of my father’s diagnosis both my sister and I immediately assumed we likely had BHD given that it is autosomal dominant and that both of us had experienced spontaneous pneumothoraces in our 40s (my sister eight times). We were keen to have this clarified and to start the monitoring process and so we sought genetic testing which confirmed what we had suspected. Thinking about our family we recalled that both my father’s lungs collapsed immediately following a quadruple (heart) bypass in his early sixties. At the time we had simply attributed this to the surgery. My father’s brother had also experienced a collapsed lung when lifting a heavy carcass when working as a butcher in his younger days. We have another sibling, my brother who chose not to be tested and so far, on the verge of 50, has had no symptoms.

What happened when you had a collapsed lung? What were your symptoms and how was it treated?

I am asthmatic and get frequent chest infections for which I am generally prescribed antibiotics and steroid tablets in addition to my regular asthma medication. In 2007 I had a bad chest infection which was not clearing. I consulted my GP several times who finally sent me to the Medical Assessment Unit at Mayo University Hospital. I had no pain but I recall walking from the hospital carpark to the hospital and coughing the whole way. At the unit I was sent for an Xray and I seemed to be waiting quite some time in the changing room after the Xray. When I was called and opened the door there was someone waiting for me with a wheelchair. I got the fright of my life. I asked if they had found something and the man said yes but said that it was something that could be rectified. My experience of having the drain inserted was a difficult one. I found it quite traumatic. The first two insertions in two different locations were unsuccessful necessitating a third attempt, this time by the surgical team, which succeeded.  I was terrified to sleep that night while I had the drain in case it fell out and had to be reinserted. Following a few days in hospital and removal of the drain I was discharged home. It took me quite some time to fully recover as I was very tired following the experience and, possibly due to poor breath control, developed problems with talking due to hoarseness. I was diagnosed with vocal chord nodules and had to undergo sessions of speech and language therapy. I was off work for two months in total.

Since you’ve been diagnosed with BHD how have you managed the condition?

Since diagnosis I have followed the monitoring guidelines. I get regular MRI kidney scans and consultations with the renal consultant. So far all my renal scans have been clear thankfully, though my sister who is 13 months youngers has some small kidney cysts. I have regular check-ups with my respiratory consultant also and as there is a family history of colon cancer (my father, his sister and his mother) I have regular colonoscopies. I don’t seem to have any skin lesions. I think I probably had a consultation with a dermatologist early on but can’t fully recall now. For the first few years after my collapsed lung I was terrified every time I got a chest infection that I would get another collapsed lung. That fear has subsided considerably now but I never delay getting treatment when I get a chest infection.

How did the COVID-19 pandemic change this?

I was advised to cocoon/shield at the start of COVID-19. I am a health care professional but fortunately, due to the nature of my work, I have been able to work from home. My Occupational Health department have recommended this and my manager and colleagues have been very supportive (*Note from the BHD Foundation: Shielding is not recommended specifically for BHD patients, however each individual case is different and your doctor will be able to advise further if you have any questions). It has been isolating as I live alone but I have felt safe because of this. COVID-19 has been frightening due to the uncertainty of how it could affect me. I was delighted to get the vaccines and am currently triple vaccinated.

“COVID-19 has been frightening due to the uncertainty of how it could affect me. I was delighted to get the vaccines and am currently triple vaccinated.”

What were your concerns about getting COVID-19 with BHD Syndrome?

My main concern about getting COVID-19 with BHD was how it would affect my chest and would it cause a collapsed lung. I understand that COVID-19 affects the same part of the lung as where the BHD cysts are usually located. (*Note from the BHD Foundation: COVID-19 can affect the whole lung. BHD cysts are normally found at the base of the lungs).  I also was fearful that if I needed ventilation that that would be problematic due to BHD as there would be an increased risk of pneumothorax with ventilation and that might affect my chances of recovery (*Note BHD Foundation: Read more about lung collapses and COVID-19 here). I thus kept my contacts to an absolute minimum and apart from my father and my partner, only met one or two people outdoors and wearing a mask.

What happened when you got COVID-19 and how was the recovery process?

Despite barely meeting anyone in two years I somehow contracted COVID-19 after Christmas this year. I had no contact with anyone who tested positive so have no idea how I caught it. I live alone so isolating was not a problem. I tested positive on an antigen test the day prior to developing symptoms. As soon as I developed symptoms I contacted the out of hours doctor and asked for a prescription for steroids as COVID-19 went straight to my lungs (*Note from the BHD Foundation: Steroids are not a standard treatment for people (including BHD patients) who develop COVID-19. It depends on severity of COVID-19 symptoms and medical history. Discuss with your doctor if you have any concerns). These definitely helped, though as they are immunosuppressive, there is caution in prescribing these with COVID-19. I have a nebuliser at home because of my asthma and I used that when I was struggling with coughing. I also monitored my pulse rate and oxygen saturation regularly. While I had a headache one or two days and gastric symptoms one day, my respiratory symptoms were the main issue. It was a little frightening not knowing how the COVID-19 would progress as I was aware that things can take a turn for the worse in the second week. The second week was certainly more difficult for me in that I was more fatigued and had muscle weakness. However, unlike when I have a regular chest infection and am awake coughing during the night, I managed to sleep well each night with COVID-19 which was a relief. I also got up, showered and dressed each day as I felt it was better to be up and moving around than lying in bed. I was back working from home after two weeks though I was tired and also developed an earache which lasted for a further week. I am fully recovered now thankfully.

“Unlike when I have a regular chest infection and am awake coughing during the night, I managed to sleep well each night with COVID-19”

What advice would you give to someone who has been newly diagnosed with BHD?

I would say not to panic. I believe knowledge is power. Everyone has something or will develop some health problem at some stage and knowing what we are susceptible to developing means that we have an advantage as we can be monitored and catch things early if they develop. I would say don’t delay seeking help if you have suspicions that you are developing a collapsed lung as the treatment can be less intrusive if the collapse is partial as opposed to complete. I would also say not to get caught up in fear about it and live your life and enjoy it. I understand BHD is not a life-limiting condition which is good to know. Also, inform people about the condition as not many people know about it. My respiratory consultant had not heard of BHD before I told him about it but I found out at a later appointment that he had subsequently diagnosed people with it. Also, it’s important to let your family members know about it in case they may have it.

How can the BHD Foundation support the BHD Community?

It is great to have an organisation in relation to our condition. I think educating the public and doctors about BHD is important as, given the inheritance mechanism, there must be many people out there who have BHD but are not aware of it. The more people know about it the greater likelihood that those with BHD will get the correct diagnosis and there will be a better chance of more research into the condition.

We greatly appreciate Anna Marie sharing her experience of having COVID-19 with BHD. 

If you have any questions about BHD and COVID-19, please contact us at contact@BHDFoundation.org

New BHD Awareness Leaflet for Doctors

It takes on average 4 years for a rare disease patient to reach a diagnosis and the BHD community is no different. Nearly every person we talk to describes the challenges of being diagnosed with BHD and how many doctors have never heard of it.

To raise awareness of BHD among doctors we have created a leaflet dedicated to the symptoms of BHD. We hope that this resource will prompt doctors to consider BHD when investigating patients with collapsed lungs, lung cysts, skin bumps and kidney cancer. The leaflet also signposts to genetic test centres so that doctors have the information to correctly refer their patients.

We will be distributing the leaflet at key conferences and events, and you can help too by sharing it with your doctors.  

View the leaflet PDF. The printable version can be found here.

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.


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/

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.