We were delighted to award Mindy Wang a travel grant to present her work at the ASCO GU Cancer Symposium earlier this year. Mindy shared her experience at the conference and explained her work in the blog below.

I am a researcher at the Michigan Center for Translational Research, University of Michigan. I study different types of kidney cancers with a team of doctors. Our goal is to make the diagnosis of kidney cancer more accurate and to develop better treatments for patients.

I was delighted to receive the travel grant from the Myrovlytis Trust (who run the BHD Foundation). With the generous funding support, I attended the ASCO GU Cancer Symposium in San Francisco in February 2023. This conference focuses on cancers in the urinary system, including kidney cancer. At the conference, healthcare providers and scientists share new findings on cancers. We discuss about the biology, diagnosis, and care of cancers.

I presented my research on Birt-Hogg-Dubé syndrome (BHD) associated Hybrid Oncocytic Tumour (HOT) of kidney. This type of tumour is challenging to diagnose. I found two protein markers that can help identify HOT and distinguish it from other types of kidney tumours. 

BHD is a condition that increases the chances of getting kidney cancer. The most common types of kidney cancer that people with BHD get are chromophobe renal cell carcinoma (chRCC), oncocytoma and HOT. chRCC is an aggressive type of kidney cancer. Oncocytoma and HOT are non-cancerous tumours. Doctors called pathologists identify what type of tumour someone has by looking at the cancer cells under a microscope. Under the microscope, chRCC tumour cells are large with clear cell borders, and they may look pink or clear. Renal oncocytoma cells are round and pink. HOT tumour cells look like they have features of both chRCC and renal oncocytoma. This mixture of different cells makes it difficult to diagnose HOT. It is also unclear if the overlapping features means these tumours share commonness at RNA and protein level.

To help doctors diagnose HOT, I compared the RNAs (genetic materials that help cells make proteins) of chRCC, oncocytoma, and HOT. I found two protein markers, one expressed in the chRCC-like tumour cells and one in the oncocytoma-like tumour cells, in HOT. Both markers have a specific pattern in HOT that is different form chRCC and oncocytoma. These markers can help doctors tell if someone has HOT or a different type of kidney tumour.

To learn more about HOT, we used these markers to separate the RNAs from the two different types of tumour cells found in HOT. We compared the RNAs from the two types of tumours in HOT. We also compared the RNAs to chRCC and oncocytoma. We discovered that the RNAs from the two types of tumours in HOT are different from each other, and also different from chRCC and oncocytoma, even though the tumour cells look similar. This study helps us find out which proteins are changed in HOT. This information can help create new treatments that focus on these important proteins.

Roger had his first lung collapse in the 1970s. Now 50 years later he is sharing his story of Birt-Hogg-Dubé syndrome (BHD). In this interview, Roger discusses the challenges he has faced navigating a rare condition, the BHD symptoms he and his identical twin brother have had and his surgery for a parotid tumour.

What were the events that led you to be diagnosed with BHD?

In the early 70s, when I was about 20 years of age and studying at university, I suffered the first of a number of spontaneous pneumothoraces (lung collapses). Over the next 3 years I had further partial or full collapses of my left lung. Ultimately it was determined that I should undergo surgery at Green Lane Hospital in Auckland to permanently adhere my left lung to my chest wall. This pleurodesis surgery was undertaken in January 1974, and I have 10% less capacity in my left lung as a result. At that time there was no mention of it being BHD. I had some family history of lung collapses, with my father having suffered one soon after World War 2, and an older brother having suffered several pneumothoraces. However, there was no mention of a genetically caused syndrome, and indeed any thought of it being genetically caused was dismissed. It was simply regarded as a spontaneous event, possibly brought on by physical or mental exertion. That position was possibly understandable at the time, as BHD was only described (1974) and given a name in 1977, so it was not a known syndrome in the medical profession. That position continued until the same older brother suffered a further collapse in the late 90s, and consulted a local doctor, who came from India. He had knowledge of it and identified it as BHD. My older brother then made the diagnosis known, and the reason for the occurrence of it within the family then became clear. 

I am an identical twin, and my twin brother and I have suffered almost exactly the same BHD symptoms. My twin had initial surgery to correct pneumothoraces, about 2 years after me (in 1976), and also for the left lung. Subsequent to that, I suffered a collapse of the right lung, and underwent a pleural aspiration (small needle or tube is inserted into the space between the lung and chest wall to remove air). This corrected the issue. My twin also suffered problems with his right lung and underwent a chemical pleurodesis. Some years later the adhesion broke and had to be corrected by further surgery. In 1995 I underwent surgery for the removal of a tumour on my parotid gland in my left cheek, but my twin has had no such issue. Since achieving 50-plus, we have both had renal tumours dealt with, either by surgical removal or cryogenic freezing. We both undergo annual ultrasounds or scans to monitor such tumours. 

Parotid tumours have been reported in people with BHD. Currently, we do not know if these tumours are associated with BHD or if they are just a coincidence*. Please could you tell us about your experience being diagnosed with a parotid tumour?

In 1995 I had a tumour removed from the parotid gland in my left cheek. Initially, this was thought by my GP to be a sebaceous cyst. He took the precaution of referring me to a cancer specialist. As soon as that specialist saw it, he told me that I was to enter hospital the very next day for him to surgically remove it. That occurred, and the subsequent laboratory analysis of the tumour confirmed that it was malignant. My neck and cheek were bandaged for approximately 2 weeks (the skin was basically rolled back down to the necklines, and no scarring occurred). The surgeon did a very good job and subsequently recommended radiation therapy as he was not sure if he had managed to “get all the tentacles” of the tumour. I ultimately elected not to have that because of the side-effects (dry mouth, poor healing in gums, difficulty in clotting during dental work, possible effect on taste). Instead, it was suggested that I have regular ultrasounds of my cheek (every 2 years or so). I have not had any further issues with it. The only sign of it is a slight indentation in my left cheek profile. 

Have you faced any challenges having a rare condition and how have you navigated them?

The challenges faced as a result of BHD are:

1. The obvious inconvenience of having to undergo regular medical checks and resultant procedures for lung collapses, kidney tumours and skin papillae;

2. Not being able to participate in certain activities that might place stress on the lungs e.g. skydiving, parachuting – that said. I have been a long-distance runner for over 45 years and have not suffered any incidents during marathon events (84 to date and hoping to get to 100). My twin has done over 110 marathons without incident. My twin brother and I have also been serious trampers (=hikers) for over 55 years, with no BHD incidents occurring in all that time, despite hard physical exertion. At the age of 65, we also both managed to climb in Nepal, albeit gradually, to an altitude of 5,416  metres (17,769 feet) without any ill-effects.

3. Air travel – I have had to be wary, but to date have not had any incidents while flying.  I have never been advised not to fly.

4. Discussing the issue with our children – we have 4 sons, and they all decided to be tested for BHD when such tests became available. The result was that two of them have BHD and two of them do not. Interestingly, two of our sons are fraternal twins, and one of them has BHD and the other does not have BHD.

5. Loading of insurance premiums for life insurance – Both myself and my affected sons have encountered increased life insurance premiums as a result of disclosing BHD, which is now a recognised medical condition. I have also had life insurance declined. There seems to be a good deal of general ignorance in insurance companies as to the effects of BHD, which in my experience has not been life-threatening and only minimally inhibiting. 

6. Huge ignorance of BHD within the medical profession – most doctors that I have encountered have never heard of it. There is a gene clinic at Auckland Hospital, but outside of that there seems to be a lack of knowledge of BHD within the medical fraternity. 

7. General lack of knowledge of any others within New Zealand with BHD, which might enable the sharing of experiences and mutual support. Such sharing has only been within the immediate and wider family to date.

What advice would you give to others with BHD? 

My advice to others with BHD is to not let it hold you back  – get on with life, but be sensible and undergo the appropriate tests, diagnosis and procedures if problems arise. 

I hope that these comments may be helpful to others on the BHD journey. 

We would like to thank Roger for sharing his BHD story and raising awareness of the challenges that people with rare conditions may face. The first hurdle to overcoming these challenges is by identifying them and we are already tackling awareness of BHD among doctors by talking about it.

*Currently the only cancer associated with BHD is kidney cancer. We know that people with BHD do get other cancers, but it is not known if they are caused by BHD or are just a coincidence. To determine which it is you need data. Last year we launched the BHD International Registry (BIRT). This is a patient registry where you can input information about your BHD symptoms and any other symptoms you’ve had. The data from this registry (which is anonymous) will be accessible to researchers to increase our understanding of BHD. Sign up to the registry.

We launched the BHD syndrome International Registry (BIRT) 1 year ago today! BIRT is a patient registry for Birt-Hogg-Dubé syndrome (BHD). We hope to use the data to reach consensus on the diagnosis and management of BHD and, ultimately, to help researchers develop treatments or a cure.

We are delighted to have 239 active participants in BIRT. We would like to say a massive thank you to each and every one of you for signing up to BIRT. Your participation in the registry will truly make a difference to BHD research in the future. As BHD is so rare, it is often difficult to get enough data to make solid conclusions to some of the common questions about BHD. This includes finding out if other types of cancer such as colon or thyroid cancer are associated with BHD. Taking part in studies such as BIRT will help researchers gather enough data to answers these questions and find new treatments.

On our 1 year anniversary we are sending out a call to action to the BHD community to join the registry, strengthen our community and drive forward research into BHD.

How do I get involved?

Getting involved is simple.

1. Visit https://birt.healthie.net and fill out the registration form.
2. You should then be sent an email to activate your account.
3. Sign the consent form.
4. Complete the surveys (this does not need to be completed in one go).

If you encounter any problems during the registration process, please email us.

I’m already taking part, what can I do?

If you’ve already signed up to BIRT, there are still things you can do to help us spread the word! You can help us by telling your family and healthcare professionals about the registry. We have a letter you can use to tell your family members, and there is a leaflet advertising the registry to doctors.

We also know there are lots of people who have signed up, but either haven’t completed their registration or filled out a survey. If everyone who has signed up fills out the surveys, we would have data from almost 400 people. Data from this many people would allow us to make the data from BIRT accessible to researchers. This would be done through a strictly controlled process. Researchers would have to apply to us for access. Their application would be assessed by the BIRT working group which consists of BHD expert doctors and people with BHD. All data will be deidentified to ensure your personal information is safe. This means removing all data that could be used to identify a specific person such as name or email address.

We recently published an FAQ to answer some of the common questions about BIRT. We are happy to answer any questions you have about the registry by email.

Over the next month we will be sharing highlights from the year across Facebook and Twitter. We would also like to say a massive thank you to our partners, Pulse Infoframe for hosting BIRT and their support over the last year. We look forward to working with them to develop BIRT in the future.

Birt-Hogg-Dubé syndrome (BHD) is characterised by skin bumps, lung cysts, collapsed lungs and an increased risk of kidney cancer. The condition is associated with faults (also called variants) in the folliculin (FLCN) gene. There is a lot of variation in the clinical features seen between individuals and families. There is no way of knowing which feature(s) you may get. For example, some family members will have lung collapse while others may only have skin bumps. The penetrance of the clinical signs of BHD is also not clear. Penetrance refers to the proportion of people with the genetic variant who exhibit the signs or symptoms of a genetic disorder.

A new study* has estimated the penetrance of different features of BHD syndrome. The authors of the study gathered all available data that was published between 2002 and 2016 that describes one or more features from one or more families. The authors of these papers were contacted and asked to provide additional information on families and/or additional cases. The final dataset included 552 families. However, 348 of these had to be excluded as there wasn’t enough data. This left a total of 204 families that were included in the study. However, not every family had data on every feature of BHD. This study also included data from family members who did not have a FLCN variant. The authors calculated the cumulative risk for each feature for men and women. This is the chance that by a certain age you will have a certain feature.

Skin Features

67 families (767 individuals) were used to inform the risk of skin involvement. Of these, 560 people had a FLCN variant and 356 (64%, almost two thirds of people) had skin features of BHD. Fibrofolliculomas were the most commonly reported feature, followed by trichodiscoma. However, the type of skin bump was not reported in a quarter of individuals. The cumulate risk for skin bumps by age 70 was 87% (almost 9 in 10 people) for men and 78% (almost 8 in 10 people) for women.

Lung Features

63 families (763 individuals) were used to inform the risk of lung involvement. This included lung cysts and/or collapsed lungs. 599 people had a FLCN variant. 519 out of 599 people (87%, almost 9 in 10 people) had lung cysts or a collapsed lung. Of these:

• About 1 in 4 people had lung cysts but had not had a collapsed lung.
• Around 1 in 3 people had lung cysts and a collapsed lung.
• Around 1 in 3 people had a collapsed lung but did not have lung cysts.
• However, not everyone had a scan of their lungs, and the type of lung involvement was not reported in a small number of people.

 From analysing the available data the cumulate risk for lung features by age 70 was 87% (almost 9 in 10 people) for men and 82% (just over 8 in 10 people) for women.

Kidney Cancer

88 families (1076 individuals) were used to inform the risk of kidney tumour involvement. Of these, 733 had a FLCN variant and 138 (19% or just under 1 in 5 people) had a kidney tumour. The average age at diagnosis was 50 years old. Different types of kidney cancer were reported:

• 15 in 100 people had clear cell kidney cancer.
• 15 in 100 people had chromophobe kidney cancer.
• 4 in 100 people had papillary kidney cancer.
• 9 in 100 people had an oncocytoma.
• 2 in 100 people had sarcomatoid kidney cancer
• 27 in 100 people had a mixed type kidney cancer.
• The type of cancer was not reported in 28 out of 100 people.

The cumulate risk for kidney tumours by age 70 was 19% (around 1 in 5 people) for men and 21% (around 1 in 5 people) for women.

Colon Polyps

29 families (221 individuals) were used to inform the risk of colon polyp involvement. Around 1 in 5 people reported having colon polyps. The cumulate risk for colon polyps by age 70 was 21% (around 1 in 5 people) for men and 32% (just over 3 in 10 people) for women. However, it is estimated that the prevalence of colon polyps in the general population over the age of 50 is between 25 and 38%. Therefore, people with BHD syndrome do not appear to be at an increased risk of colon polyps, based on this data. The authors were unable to look at the risk of colon cancer due to the lack of data in this study.

Summary

This study shows the variation of BHD presentation in a large dataset, including information from 99 new families. Skin and lung features were very common (had a high penetrance) and it is known that they tend to occur at an earlier age than kidney cancer. There didn’t appear to be a huge difference in the penetrance of features between men and women. Altogether, there is a need to raise awareness among doctors, particularly skin and lung doctors who are in a position to spot and diagnose BHD early. This allows kidney screening to occur earlier so any kidney cancer can be identified as early as possible.

However, more information is needed to answer questions about other features such as colon (or other) cancers. The BHD Foundation launched their patient registry to help answer some these questions and give people with BHD opportunity to take part in research. Find out more about the registry.

*Unfortunately this paper is not open access. Please contact us with any additional questions.

What is the BHD Syndrome International Registry (BIRT)?

The BHD syndrome international registry (BIRT) is a patient-reported database. A patient registry is a centralised database that collects information about people with a specific condition or set of conditions. This includes information on the diagnosis, symptoms and management of BHD syndrome. Find out more about the aims of BIRT.

Why are registries important?

One of the major problems that slows down rare disease research is the lack of consolidated data. A registry can help overcome this and be a source of data to drive forward research. The more information we have about BHD, the easier it is for researchers to answer some of questions about BHD that are currently unknown. It also gives people with BHD the opportunity to get involved with research. The data collected within this registry is high quality and organised to help researchers and healthcare professionals better understand BHD syndrome. This will help the development of new treatments or even a cure in the future.

What information is collected?

BIRT contains 4 surveys:

1. Medical History survey 

This survey asks questions concerning the diagnosis, symptoms, management and treatment of BHD syndrome.

2. Background survey

This survey collects your personal information such as your name and country. No information provided to the registry is viewable by other participants. This information collected through this survey provides important information for linking with health records in the future.

3. Demographics survey

The questions in this survey are optional. This data can help researchers and drug developers improve patient care.

4. Quality of life survey (SF-36 survey)

This survey asks questions to understand how having BHD syndrome impacts your daily life. This survey is also optional.

Why should I get involved?

This is your opportunity to get involved with research and be part of a large community of people with BHD syndrome working together to find new treatments and a cure for BHD. We need as many people to get involved as we really do have strength in numbers.

We would encourage you to tell your family members about the registry. To help, we have written a template letter explaining the BHD registry and inviting them to join. You can download and personalise the letter here.

How do I get involved?

Getting involved is simple.

1. Visit https://birt.healthie.net and fill out the registration form.

2. You should then be sent an email to activate your account.

3. Sign the consent form.

4. Complete the surveys.

If you encounter any problems during the registration process, please email us.

You can also download the BIRT user guide as a pdf or word document.

How long does it take to complete the surveys?

We estimate it will take between 30 minutes and 1 hour to complete all the surveys.

Do I have to complete the surveys all in one sitting?

No, the platform automatically saves your progress and you can return at any point.

Will anyone else know I am taking part in the registry?

No one else will know you are taking part in BIRT and your personal identity will never be revealed to researchers accessing the data.

Are researchers able to access the data?

We will be allowing researchers to access the data soon. Any researcher requesting access to the database will have to submit an application to us. This will be reviewed by the BIRT working group. All data will be deidentified. This means removing all data that could be used to identify a specific person such as name or email address.

Who owns my data?

You own your data at all times.  By taking part in BIRT you agree to share your data for the purposes outlined in a consent form that is digitally available and verified by DocuSign. Ultimately you have access to your own data and can consent to share the data with providers and other relevant parties. If you have any questions about the consent process please contact us.

Can I change my mind about participating in the Registry?

Participation in BIRT is completely voluntary. You can leave the registry at any time.

You can withdraw your consent on your profile. Sections 6.5b and 6.5c of the user guide explain this process. Download the user guide as a pdf or word document.  You can also email us with any queries about this process.

Is my data safe?

Privacy and data security is of extreme importance to us and our partners Pulse Infoframe. Security processes and technologies are integrated into all aspects of the BIRT platform.  Find out more about the security of the BIRT platform here: https://youtu.be/_LtM4gqCJoI

Is BIRT available in multiple languages?

BIRT is currently available in English. However, the registry will soon be available in French, Spanish and German. We hope to expand into other languages in the future.

Where can I see preliminary results?

We aim to provide regular updates about the data from the registry. Read our most recent update.

Who should I contact with additional questions or concerns?

Please email us with any additional questions or concerns. Please also contact us if you are having trouble registering.

Birt-Hogg-Dubé syndrome (BHD) is a rare genetic condition that causes lung cysts, lung collapses, skin bumps (fibrofolliculomas) and kidney cancer. It is likely that you, your family and even your doctor had never heard of BHD before you were diagnosed. This lack of awareness often results in misdiagnosis, late diagnosis and uncertainty. This experience is shared by the 30 million people living with rare diseases.

This Rare Disease Day we are highlighting the health inequalities that people with rare diseases face in particular the challenge that has to be overcome to reach a diagnosis. The BHD community have come together to share their experience and give advice to others navigating the healthcare system. If you are currently waiting for a diagnosis they want you to know that you are not alone.

How long does it take to be diagnosed with BHD?

It takes on average 4 to 5 years for someone with a rare condition to be correctly diagnosed. Data from the BHD patient registry allows us to take a closer look at the diagnostic journey of people with BHD. The BHD registry is a centralised database that collects information from people with BHD. The more data collected the easier it is to study BHD and further our understanding of the condition (take part in the registry today).  

As of September 2022, 101 people had recorded information about when they developed symptoms and were subsequently diagnosed with BHD. People typically had their first symptoms at 30 years old. Their first contact with a healthcare service in relation to symptoms was typically at 43 followed by a diagnosis of BHD at 44 (find out more about this data in our 6 month registry review blog post). These results suggest that on average it takes 1 years to be diagnosed after contact with a healthcare service. However, we know for some people it’s a lot longer. The BHD community shared their diagnostic journey which ranged from 6 months to 50 years.

Why does it take so long for a diagnosis to be reached?

Several barriers to being diagnosed with rare diseases have been identified through research. This includes a lack of awareness among doctors, a shortage of experts and the variety of symptoms someone may present with. This means that people may be bounced between different experts as their symptoms do not fit into those of more common conditions. This is echoed by members of the BHD community who describe how their doctors had never heard of the condition. Some people have also had incidences where they have not been listened to when advocating for themselves.

How do we overcome the barriers?

Listing the reasons why rare diseases are not diagnosed can seem daunting. However, identifying the barriers is the first step to making change. Rare Disease Day is an opportunity to highlight the challenges and raise awareness of rare conditions. The more people know about them, the more likely someone will get correctly diagnosed. Additionally, at the BHD Foundation we have resources to support your diagnostic journey:

We have an interactive map of BHD doctors to make it easier for you to find someone who can support you. Or contact us directly and we can help to identify someone in your area.

We also have resources that you can share with your doctor including information on our webpage and leaflets. This can make it easier for them to learn about your condition. We understand that having BHD means you may have to be your own advocate and we are here to support you all the way.

The BHD community are here for you too. There is a patient-led Facebook group where you can ask questions and hear from other people with BHD.

For the creation of this blog members of the BHD community shared their experiences. They also have some advice for those who are in the diagnostic process or are newly diagnosed.  

Here is their advice:

‘Talk with a genetic counsellor…they were so helpful in how testing works, how to get tested and why do you think you should get tested.’

‘Get in touch with BHD Foundation to identify someone nearby to assist them in getting diagnosed.’

‘Even if it is only one organ involved, push to get tested!’

‘Push for genetic testing and move away from doctors that do not listen to you.’

‘Try to live as normal a life as you can. We are all different; some will have more challenges than other.’

‘Get tested!’

‘Don’t stress and get your kidneys checked often’.

‘Request to see a specialist.’

‘Look into genetic testing early.’

‘Get as much family history as you can beforehand. Be patient.‘

‘Get referred to a geneticist and get tested’.

‘Be proactive and persistent with your doctors.’

‘Get a DNA test!’

‘See the right kind of doctor…also get the genetic test.’

‘A positive diagnosis is not the end of the world…it’s best to know so we can get the needed surveillance tests…I would also recommend to have family members & relatives tested.’

‘Read reliable information about BHD & don’t be afraid to teach your medical team about BHD as they likely know nothing about it.’

‘Join a BHD support group. Many potential patients are going to want to learn all they can about DNA and hereditary (conditions) and how BHD fits into this.’

This Rare Disease Day we come together to shed light on the time people have to wait to be diagnosed with a rare condition. Together we are not rare, we are everywhere and it’s time we are seen.

Thank you to everyone who took part in the survey to make this blog possible.

Every few months we highlight some of the recent Birt-Hogg-Dubé syndrome (BHD) case reports. A case report is a detailed account of (normally) a single person’s diagnosis and treatment journey. Case reports are published in medical journals and are an opportunity for clinicians to learn about how different conditions may present.

In this blog we look at two cases of rare cancer in people with BHD.

A rare soft tissue tumour

The first case described a 60-year-old woman with a pink nodule on her shoulder that had been growing for 12 months. She was known to have BHD and had skin bumps on her face, in keeping with fibrofolliculomas, a history of lung collapses and suspected kidney tumours.

A sample of the pink nodule was taken and examined under a microscope. The nodule was confirmed to be a cutaneous leiomyosarcoma (cLMS). cLMS is a type of rare soft tissue tumour that occurs in the skin. The woman had a surgical procedure called a wide local excision to remove the tumour.

The team took samples of the cLMS, normal skin and blood to check for folliculin (FLCN) variants. Faults (also called variants) in the FLCN gene are associated with BHD. Everyone has 2 copies of FLCN and only one copy needs to be faulty to lead to the skin bumps and lung cysts seen in BHD. However, it is thought that for kidney cancer to develop, the second copy of FLCN also needs to develop faults (known as loss of heterozygosity, LOH). When the team tested normal skin and blood samples they found a single FLCN variant. However, in the cLMS sample they found LOH as both copies of FLCN were faulty.

This is the third report of cLMS in someone with BHD. The other two cases also had faults in the FLCN gene. The researchers suggested that folliculin variants may drive the development of cLMS. However, there are also other genes that, when faulty, can cause it. They recommend that people diagnosed with cLMS should have a clinical assessment to see if they have any features of BHD.

A tumour in the parotid gland

The next case described a 68-year-old man with a mass on his face that had been growing in size for 2-3 years. At this point he was not known to have BHD. He had a CT and MRI scan which showed that he had a growth in his right parotid gland. He had surgery to remove the whole gland.

To identify what had caused the growth a sample of the gland was examined under a microscope. This showed a type of cancer called an oncocytic carcinoma. Oncocytic carcinomas are different to parotid oncocytomas, which have previously been described in BHD. Parotid oncocytomas are benign. This means that they are not cancerous and do not spread to other parts of the body. The rarer oncocytic carcinomas are malignant. This means there is a risk that they can spread to other parts of the body. Therefore, the patient had further surgery and radiotherapy to reduce the risk of this happening.

During his treatment he had a CT scan of his chest. This revealed lung cysts. He also had skin bumps in keeping with fibrofolliculomas. His team recommended genetic testing for BHD. The test confirmed that he had BHD.

This is the first case of an oncocytic carcinoma of the parotid gland in BHD. It’s a very rare cancer, however it’s important to distinguish it from parotid oncocytomas as it requires different treatment. Any parotid mass should be fully investigated.

This case also highlights the role that radiologists can play in diagnosing BHD. The incidental findings of cysts, on a CT scan, was instrumental in diagnosing him with BHD.  

What we can learn

These cases describe two rare cancers in BHD. A case report on its own cannot prove a link between BHD and a cancer. However, we can learn from them. These cases show us:

• The importance of investigating a lump/bump that is growing.
• Doctors should investigate people with cLMS for BHD.
• Incidental findings of lung cysts on scans should lead to further investigation.
• It’s important to distinguish between different causes of parotid masses as the treatment will differ.

To increase our understanding of BHD it is crucial that we get more data. Last year we launched the BHD syndrome international registry (BIRT). BIRT is a patient-reported database where people with BHD can upload information about their condition. This data will feed into research and help answer vital questions such as whether BHD is associated with any other conditions.

Take part in the registry now. You can also email us with any questions at contact@bhdsyndrome.org.   

Rare disease day takes place on the 28th of February every year. This year the theme is health equity. People with rare diseases are more likely to experience treatment inequality, misdiagnosis and isolation compared with other more common health conditions. This needs to change.

We will be actively involved in Rare Disease Day and would love for you to join us.

There are many different ways to get involved, from being part of our BHD Blog to lighting up your house. Below we have included several ways that you can get involved.
 
Be part of our Rare Disease Day blog and raise awareness of delayed diagnosis.

This Rare Disease Day we are talking about health equity and challenging doctors to think rare. We are putting together a blog post about the challenges people have had to overcome to be diagnosed with BHD.

You can add your voice to the blog by letting us know.

• How long did it take you to be diagnosed with BHD?
• What challenges did you face when being diagnosed?
• What advice would you give to people who think they may have BHD?

The answers will be anonymously included in the blog to highlight to clinicians the challenges people with BHD face and why it’s so important to think BHD.
 
If you would like to get involved please complete this short anonymous survey.
 
Attend an event.   

Find an event in your area by visiting the Rare Disease Day website.

• Attend the NIH Rare Disease Day.
• Attend the virtual FDA Rare Disease Day public meeting.

Spread the word on social media.

Rare Disease Day have a social toolkit and downloadable resources.

Don’t forget to tag us on Twitter @BHD_Foundation or Facebook @birthoggdube so we can share your posts.

Fundraise for BHD

You can also fundraise for the BHD Foundation. We greatly appreciate any donations. All the money raised on Rare Disease Day will go towards the new BHD website that will launch later this year. The aim of the new website is to better support the BHD community. Visit our Fundraising page to find out more. 

Share your colours

• Take part in Global Chain of Lights.   

You can also let us know if you have any ideas for rare disease day and we can help make it happen!

Together we will show our colours on Rare Disease Day and challenge doctors to think BHD.

At the BHD Foundation we are passionate about driving research into Birt-Hogg-Dubé syndrome (BHD). Through the Myrovlytis Trust, we have funded over £6 million of research into BHD since 2007. We are now pleased to announce the first 2 projects we funded in 2022.

Understanding how Kidney Cancer in BHD develops

We awarded funding to Professor Masaya Baba (Kumamoto University, Japan) for a PhD scholarship to investigate BHD kidney cancer. BHD is associated with changes in the gene folliculin (FLCN). Everyone has 2 copies of the FLCN gene, however changes in only one of them gives rise to many of the features seen in BHD. However, for kidney cancer to develop it is thought that changes in the second copy of FLCN are required (often known as a “second hit”). Masaya’s team will investigate what happens in cells lacking FLCN. They will identify pathways and specific proteins that are essential for cells lacking FLCN to survive and form tumours. In the longer term, these proteins could be targets for the development of new therapies to treat kidney cancer in BHD.

Watch Masaya describe his work in this short video or find out more. A transcript of the video is also available.

Natural Killer Cell Therapy for Kidney Cancer

Our second grant holder, Professor Mark Lowdell (University College London, UK) is interested in the interplay between the immune system and cancer. His group have a particular focus on a type of cell called natural killer (NK) cells. These can directly kill target cells, including cancer cells. However, many cancers develop strategies to avoid recognition by the immune system. Mark’s group have developed a drug to activate NK cells to make them better at killing cancer cells. We have awarded funding to Mark’s team for a 1-year project looking at whether people with kidney cancer have NK cells that can be enhanced with this drug. They hope to identify which patients will benefit most from this drug and use the data to design and support a clinical trial. Although this project isn’t looking at kidney cancer in people with BHD, we are still excited by the prospect of a new type of treatment for kidney cancer. Future work could be done to look at this type of treatment in BHD kidney cancer.

Watch Mark describe his work in this short video or find out more. A transcript of the video is also available.

At the BHD Foundation we are driven to find new treatments and eventually a cure for BHD. We have just launched our grant funding round for 2023. Find out more including what we fund and how to apply. We also welcome informal enquiries by email.

Birt-Hogg-Dubé syndrome (BHD) is characterised by skin lesions, lung cysts, collapsed lungs and an increased risk of kidney cancer. It is associated with changes in the gene folliculin (FLCN). Our genes are organised into thread-like structures called chromosomes. Humans have 23 pairs of chromosomes. The FLCN gene is found on chromosome 17, in a specific region called “17p11.2”. Another condition, called Smith-Magenis syndrome (SMS) is also associated with a deletion of this 17p11.2 region.

Unlike BHD, SMS is not normally inherited and occurs in every 1 in 15,000 – 25,000 people. Individuals with SMS often have a distinct facial appearance and varying degrees of developmental delay and intellectual disability. People with SMS also have distinct behaviours such as sleep disturbance and hyperactivity. However, this condition is distinct from BHD, as this 17p11.2 region also contains a gene called RAI1. Research has shown that a loss of RAI1 is responsible for most of the features seen in SMS. As such, people with BHD do not get the features seen in SMS. However, people with SMS may also be missing a FLCN gene and therefore may be at risk of the features seen in BHD. As the most serious complication of BHD is kidney cancer, people with BHD should get regular scans to monitor their kidneys. So far, cancer has only been occasionally reported in people with SMS and individuals do not have regular kidney scans.

To date, there have only been a few reports of people with SMS having features of BHD. A recent survey*, carried out by PRISMS (Parents and Researchers Interested in Smith-Magenis Syndrome) looked at the prevalence of BHD features in people with SMS. Of 117 respondents, 7 people reported at least one feature of BHD. 5 people had a collapsed lung, and 2 people had fibrofolliculomas. There were no cases of kidney cancer. However, most people in this survey were under 30 years of age. It is thought that the average age of onsent of kidney cancer in people with BHD is 50.

A recent paper* has summarised 4 cases of BHD in people with SMS and provides recommendations for cancer screening. All cases were confirmed to be lacking a copy of the FLCN gene. The first case decribed a patient (aged 50) who was found to have hybrid oncocytic tumours in both their kidneys and underwent surgery to remove these tumours. They did not have any skin lesions or lung cysts. The second patient was diagnosed with SMS aged 37. Aged 45, they were found to have diffuse B cell lymphoma. Scans also showed they had lesions on their kidney and further tests revealed this to be chromophobe kidney cancer. They had no skin or lung features of BHD. The third patient, aged 25, had lung cysts and skin lesions consistent with BHD. They had no kidney tumours. The last patient was aged 42 and had surgery to remove a 3.6 cm tumour that was confirmed to be chromophobe kidney cancer. They had no skin lesions or lung cysts.

In summary, this recent report identified 4 cases of people with SMS who also had features of BHD. 3 of these had kidney tumours. The authors of this study recommend screening for kidney cancer in adults with SMS in line with the current BHD guidelines, where kidney scans are recommended at least every 3 years starting from age 20.  Most of the studies in SMS so far have been done in children and adolescents and so it is still unclear how common features of BHD in SMS are, considering the features in BHD typically appear in adulthood. Further work, particularly long-term studies are required to fully characterise BHD in people with SMS.

*Unfortunately these papers are not open access. Please email us at contact@bhdsyndrome.org if you have any questions.