RAREfest22: Unique Festival puts Rare Diseases into the Spotlight! 

The BHD Foundation is excited to attend RAREfest22 in November this year. We are also proud to announce we are media partners for this important event in the rare disease calendar!

Did you know that 3.5 million people in the UK are living with rare conditions? That’s around about the population of Wales. Hang on, didn’t we say RARE?! Well, with over 10,000 different rare conditions, what may be individually rare becomes collectively common. In fact, 1 in 17 of us may be affected in our lifetime so it’s something we should all be curious about. With this in mind, CamRARE is making it their priority to push rare diseases into the spotlight.

RAREfest22 is a rare disease-inspired, unique festival that will spark curiosity and challenge perceptions. It will showcase science and innovative tech while giving a voice to those living with rare conditions and their families. Taking place on November 25th and 26th, this is a FREE event for the experts and the curious of all ages. It promises a feast of expert speakers, immersive exhibits, films and art. It is a great opportunity to mix and mingle with the rare disease community. Scientists, medical professionals, companies developing tech and treatments will also be attending.

RAREfest22 highlights include:

Singing Science – Genomics The Musical –

A one-person show combining the basics of Genetics and the impacts on the rare disease community. The show provides an engaging way to familiarise yourself with key concepts – fit for all ages.

Illumina – The Cambridge DNA Journey –

A visual map and timeline of the journey from the discovery of DNA to the development and application of genetics and genomics to diagnostics and healthcare in Cambridge.

Rare Youth Revolution –

Join the RARE Youth Revolution for an immersive experience into the life of young people living with rare diseases and some invisible symptoms they experience. Talk to the team about internship opportunities for young people living with rare diseases.

Are you a person or family affected or perhaps you have a neighbour or friend who is? Maybe you’re curious about the world and love to share that with your kids? Are you a researcher based in a lab, a healthcare worker in a busy hospital? Perhaps you’re a teacher with a class full of inquisitive kids, or a student embarking on their next adventure? Whomever you are we guarantee this will be a fascinating day out and you’ll learn something new that will blow your mind. So come along, bring your friends and family and make a day of it! For the experts. For the curious. For all ages. For the whole family. For everyone. For FREE.

For more information visit the festival website. Tickets are free and available at https://bit.ly/rarefest22

The BHD Foundation aims to support, inform and connect the BHD community worldwide. We foster the relationship between patients, clinicians and researchers to build a strong and versatile community. We look forward to attending RAREfest22 and growing our network across the rare disease space.

Explaining the Different Types of Kidney Cancer

Kidney cancer is the most serious complication of Birt-Hogg-Dubé syndrome (BHD). There are many different types of kidney cancer. In this toolkit, we explain the different types of kidney cancer and find out if they’ve been reported in BHD.

Kidney Cancer Symptoms

There are often very few symptoms of early-stage kidney cancer. Symptoms are often similar regardless of which type of kidney cancer you have. When symptoms do occur, they include blood in your urine, a lump or swelling in your side and pain in the side or back below the ribs. If you have any of these symptoms (or other kidney cancer symptoms), please see your doctor.

How Do I Know What Type of Kidney Cancer I Have?

Although you may have different scans during your diagnosis, it is not often possible to tell which type of kidney cancer you have from these. Instead, the scans tell the doctors about the size of the tumours and where in the kidney they are located. These scans can also often show if the cancer has spread to other parts of the body. A small sample of the tumour (known as a biopsy) may be taken to confirm the type of kidney cancer. A pathologist will study the sample under a microscope and look for cellular features associated with the different types.

Knowing which type of kidney cancer you have may impact the treatment you receive. Some kidney cancer types grow faster and are more likely to spread than others. However, in some cases you may only find out what type of kidney cancer you have after treatment. Your doctor will always discuss this with you to ensure you receive the best treatment available. Generally, outcomes are good and kidney cancer can be treated successfully. However, the quicker kidney cancer can be identified, the easier it is to be treated.

Kidney Cancer Types

Below we outline some of the types of kidney cancer. Please note this list is not exhaustive and there are other rare kidney cancer types not on this list.

Clear Cell Renal Cell Carcinoma (ccRCC)
This is the most common type of kidney cancer in the general population. The name ‘clear cell’ refers to how the cells look when they are viewed under a microscope. People with VHL tend to get ccRCC.

How does it behave?
ccRCC can be fast or slow growing. If not treated, ccRCC can spread to other parts of the body.

How is it treated?
If found quickly, ccRCC normally responds well to treatment. Treatment depends on several factors including the stage of kidney cancer you have. If possible, surgery is the preferred option. However, you may have types of treatment including immunotherapy and targeted therapies. Sometimes, ablation or radiation may be used. This often occurs when a person cannot have surgery. This can happen if the tumour is close to blood vessels or removing it by surgery will impact kidney function.

Has it been reported in BHD?
Yes, although not common, ccRCC has been reported in people with BHD.

Papillary RCC
This is a type of non-clear cell RCC. The term ‘papillary’ refers to the shape of the tumour. Finger-like projections can be found in most of the tumours. There are two types of papillary RCC. Type 1 is more common than type 2 which is often associated with HLRCC

How does it behave?
Type 1 grows more slowly than type 2 which is faster growing and more aggressive. If left untreated, papillary RCC may spread.

How is it treated?
The most common treatment strategies for papillary RCC are surgery and radiation therapy. In some cases, where the cancer has spread and surgery is not possible, you may have chemotherapy.

Has it been reported in BHD?
Yes, although not common, papillary RCC has been reported in people with BHD.

Chromophobe RCC
This is a type of non-clear cell RCC. It is the most common type of RCC after ccRCC and papillary RCC in the general population. Under a microscope, the cells appear much larger than other types of kidney cancer cells.

How does it behave?
Chromophobe RCC tends to be slow growing and less aggressive. Although it can still spread to other parts of the body, this is less likely than in ccRCC and papillary RCC.

How is it treated?
If the cancer remains localised (i.e. it has not spread), surgery is the preferred option if available. In BHD, surgery is normally performed when the largest tumour reaches 3 cm.  If the cancer has spread, a combination of systemic anti-cancer therapy (treating the whole body) and a type of surgery called cytoreductive surgery may be performed. Common anti-cancer drugs used are sunitinib or everolimus. The aim of cytoreductive surgery is to remove as many cancer cells within the kidney as possible.

Has it been reported in BHD?
Yes, chromophobe RCC is one of the more common types of kidney cancer found in people with BHD.  

An oncocytoma is a type of tumour that is not cancerous (benign). They are unlikely to become cancerous but there have been reports of this happening in the literature. However, it is not possible to tell if a tumour is cancerous from an imaging scan alone.

How does it behave?
Oncocytomas are slow growing. They are often monitored by regular imaging scans to check their growth over time.

How is it treated?
If they reach a certain size, oncocytomas are normally removed by surgery. In BHD, surgery is normally performed when the largest tumour reaches 3 cm.  

Has it been reported in BHD?
Yes, oncocytomas are one of the more common types of kidney tumour found in people with BHD.

An angiomyolipoma is a type of tumour that is not cancerous (benign). These are tumours that that contain muscle, fat and blood vessels. They are often serious due to the risk of the tumours bursting and bleeding. Unlike many of the tumour types on this list, angiomyolipomas can be clearly seen on ultrasound scans. They are common in people with TSC.

How does it behave?
Angiomyolipomas grow very slowly. Their growth is often monitored regularly by imaging scans. The risk of the tumour bursting and bleeding increases with size.

How is it treated?
If an angiomyolipoma grows larger than 4 cm, treatment may be recommended. You may have surgery, ablation therapy or a procedure called an arterial embolization. This reduces blood flow to the tumour and causes the tumour to shrink. If you have TSC, the preferred treatment is everolimus.

Has it been reported in BHD?
Yes, angiomyolipomas have been reported in people with BHD.

Hybrid Oncocytic/Chromophobe Tumour (HOCT)
HOCT is a type of kidney cancer made up of cells from oncocytomas and chromophobe RCC. It is mainly found in people with BHD although sporadic cases have been reported.

How does it behave?
HOCT is slow growing and is unlikely to spread. There have been rare cases of HOCT spread reported. The growth of HOCT is normally monitored by regular scans.

How is it treated?
HOCT is normally treated by surgery. In BHD, surgery is normally performed when the largest tumour reaches 3 cm.

Has it been reported in BHD?
Yes, this is thought to be the most frequent type of kidney cancer in people with BHD.

Other rare types of kidney cancer include collecting duct RCC, medullary RCC and MiT Family Translocation RCC. To date, none of these cancers have been reported in people with BHD. Some kidney cancers cannot be classified into any of these groups. Unclassified kidney cancers have been reported in people with BHD.

Despite the number of studies and case reports on BHD and kidney cancer, there are still many unknowns. These include how many people with BHD develop kidney cancer and a comprehensive study of the types of kidney cancer found. The BHD Syndrome International Registry (BIRT) aims to answer these questions. We need as many people as possible to join the registry so we can help researchers answer these important questions. Understanding more about BHD and kidney cancer will help guide treatment, from surveillance guidelines through to the development of new treatments or a cure. Join the registry now.

The International Kidney Cancer Coalition is a network of patient organisations that support people with kidney cancer. Find support near you.

Read our other toolkits now.

Should People Who Have a Collapsed Lung be Tested for BHD?

Birt-Hogg-Dubé syndrome (BHD) is an inherited condition associated with mutations in the gene folliculin (FLCN). It is characterised by skin lesions called fibrofolliculomas, lung cysts, collapsed lungs and an increased risk of kidney cancer. As different people may have different symptoms, the diagnosis of BHD may be missed. It is therefore thought that BHD is underdiagnosed. Early diagnosis of BHD is important to identify and treat any kidney cancer as early as possible. Finding effective ways to diagnose BHD could help reduce any future burden of kidney cancer.

A new study has been published looking at the prevalence of BHD among people who have a collapsed lung for no apparent reason (e.g. not as a result of a direct injury). This is called a primary spontaneous pneumothorax (PSP). Currently, a CT scan is not routinely performed on people who have a PSP. However, it is thought that at least 8 in 10 people with BHD have lung cysts. These lung cysts have features that are unique to BHD. For example, they are typically found at the base of the lungs and have an irregular shape. Therefore, CT scans may be useful in diagnosing BHD. The authors also discussed whether CT scans should be performed on everyone who experiences a PSP to aid the diagnosis of BHD.

A questionnaire was sent to 475 people who had a PSP between 2004 and 2017 at the Rijnstate Hospital in Arnhem, the Netherlands. 178 people completed and returned the questionnaire. Of these, 88 were included in the study for genetic testing. 3 people were found to have a mutation in FLCN. 2 of these people were related and had multiple family members with a history of collapsed lungs. The other person had a family history of kidney cancer. All 3 people had fibrofolliculomas. One person was found to have kidney cancer. This was successfully treated with surgery.

A chest CT scan was available for 83 out of 88 people. Cysts were found in 14 people, of whom 6 had multiple cysts. All 3 people with BHD had multiple lung cysts. Most of these were found in the base of the lungs, typical of BHD.

In retrospect, all 3 people who were diagnosed with BHD in this study had features that could have allowed them to be diagnosed earlier. This highlights the importance of raising awareness of BHD among doctors who would see someone with a PSP including lung doctors, radiologists and emergency doctors. For this purpose, the BHD Foundation has created a BHD awareness leaflet.

Based on this study and other previous studies done, the authors recommend that a CT scan should be performed for everyone who presents with a PSP. They also suggest that if lung cysts are present, genetic testing for BHD should be done. A lung collapse is often an early symptom of BHD and so this would hopefully result in an earlier diagnosis of BHD. It would also allow their family members to be tested. Additionally, performing a CT scan in everyone that has a PSP could allow the diagnosis of other cystic lung diseases such as LAM.

In the future, we would like to see more studies like this being done on larger groups of people. The more people involved in research in BHD, the more confidence you can have in the data. Better quality data will help us better inform guidelines on the diagnosis and management of BHD. We launched the BHD syndrome International Registry (BIRT) to help us collect as much information about BHD as possible and drive forward research. Take part in the registry now.

Can Cigarette Smoking Cause Loss of Folliculin?

Birt-Hogg-Dubé Syndrome (BHD) is caused by mutations in the gene folliculin (FLCN). It is characterised by skin bumps called fibrofolliculomas, lung cysts, collapsed lungs and an increased risk of kidney cancer. The changes taking place in the cell that lead to these symptoms are not well understood. However, there have been a few studies trying to look at how loss of FLCN can lead to lung cysts. One possibility is that loss of FLCN may lead to damage in the lung tissue which causes the formation of lung cysts. The lung cysts in BHD are not thought to affect the function of the lungs. Most people with BHD have good lung function which does not get worse over time.

Another condition that is caused by damage in the lung tissue and the formation of lung cysts is emphysema. Emphysema is a type of chronic obstructive pulmonary disease (COPD). People with COPD often have a cough and can feel breathless or have trouble breathing. It is a progressive disease meaning it gets worse over time and there is no cure. Treatments are available that can slow the progression of lung disease. The most common cause of COPD is smoking.

In people with BHD, smoking is not thought to impact lung cyst formation or lung function. However, it is not clear whether smoking and COPD affect FLCN function. A recent study aimed to look at the effect of cigarette smoking on FLCN.

First, the researchers took samples of lung tissue from people who smoked and had COPD, people who smoked but had no lung disease and non-smokers with no lung disease. They looked at the amount of FLCN protein in the samples and saw that those with COPD had less FLCN protein compared to people with no lung disease.  There was no difference in the amount of FLCN protein between people who smoked (with no lung disease) and those who didn’t. Next, the authors looked at the effect of cigarette smoke exposure on FLCN. They used a mouse model and exposed them to cigarette smoke for 6 weeks, 6 months, or to no cigarette smoke at all. The researchers saw a strong reduction in the amount of FLCN protein in the lungs of mice exposed to cigarette smoke for 6 months. They saw no difference in FLCN between the other two groups. This indicates that loss of FLCN protein is a consequence of long-term exposure to cigarette smoke.

The researchers also looked at the function of FLCN. They exposed cells grown in the lab to cigarette smoke and saw that there was more cell death compared to normal cells. They then changed these cells to either have more or less FLCN protein and repeated the experiment. The authors saw that there was more cell death in cells with less FLCN protein. The opposite effect was seen in cells with more FLCN protein. There was less cell death in these cells and so the authors suggested FLCN was able to protect against cell death caused by cigarette smoke.

The last part of the study was investigating how cigarette smoke exposure caused loss of FLCN protein. This could be due to there being a change in the amount of FLCN protein being made or something that causes the destruction of the existing FLCN protein. The authors checked the amount of FLCN mRNA (the precursor to protein) in the lung samples from people with and without COPD. They saw no difference in the amount of FLCN mRNA between the samples, indicating that the same amount of FLCN protein was being made. This led the researchers to hypothesise that FLCN protein was being specifically destroyed because of cigarette smoke exposure. Indeed, they identified a specific change to the FLCN protein that allowed degradation of the FLCN protein in response to cigarette smoke. They could stop the destruction of FLCN protein by either blocking the change or using a drug to inhibit the degradation pathway.

To find out more, we spoke to lead author of the paper Dr Toru Nyunoya:

“Our research results show that cigarette smoking depletes folliculin protein in lung cells.  So, we show that folliculin loss occurs in the presence of smoking habits, even in the absence of a hereditary cause.

According to the previous studies, people with BHD have pretty normal lung function.  However, I am not aware of any long-term studies to investigate the interaction between genetics (FLCN loss) and the environment (smoking). So, I still highly recommend for people with BHD to stop smoking.”

In summary, this study showed that cigarette smoking leads to a loss of FLCN protein. However, it did not explore whether loss of FLCN can cause COPD. Further work will need to be done to understand if and how loss of FLCN is linked to development of COPD. The studies that exist following people with BHD over time have not shown an increase in the rates of COPD. However, given the known risks associated with smoking, it would be advisable for BHD patients to avoid smoking.

By Which Steps Could Loss of FLCN Lead to Kidney Cancer?

Birt-Hogg-Dubé syndrome (BHD) is associated with an increased risk of kidney cancer. It is important to understand how kidney cancer develops so we can know how to best treat it. BHD is typically caused by mutations in the gene folliculin (FLCN). Everyone has 2 copies of FLCN. A mutation in just one of the copies is enough to cause the symptoms seen in BHD including the skin bumps, lung cysts and collapsed lungs. However, it is thought that for kidney cancer to develop, a mutation in the second copy of FLCN is needed. This results in a complete loss of functional FLCN protein. How loss of FLCN is able to cause cancer is currently not fully understood.

There has been a lot of research in recent years to understand how FLCN works inside our cells. FLCN can influence many different cellular pathways. Many of these pathways are important for normal cellular function such as growth, division and survival. When these pathways are disrupted, cancer can develop. Cancer cells need to be able to survive and as opposed to normal cells grow in an uncontrolled fashion.  Developing new treatments to treat cancer requires an in-depth understanding of these processes. A new study has furthered our knowledge of how FLCN controls signalling pathways important for cancer development.

The authors of the study looked at changes in phosphorylation between kidney cells containing FLCN and those lacking FLCN. Phosphorylation is a type of change that can happen to proteins in our cells and can act as an on/off switch. Proteins called kinases control this process, adding phosphates to other proteins to turn them on or off. The authors found several differences between the cells with and without FLCN. Among the changes seen, the researchers found that kinases called EGFR, MET and MAPK were activated upon loss of FLCN. These kinases control signalling pathways that have been shown to be potentially involved in the development of cancer. For example, activation of MET is involved in the development of both inherited and non-inherited kidney cancer.

The researchers used different drugs to block the activity of each of the kinases in cells with or without FLCN. They also tested these drugs in cells that were derived from a BHD kidney tumour. They looked to see if there was more cell death in the cells lacking FLCN. The researchers found that there was more cell death when the activity of EGFR and MAPK were blocked, but not when MET activity was blocked. Further work testing these drugs in different models of BHD is needed to see if they would be able to slow down BHD tumour growth.

Previous work has shown that loss of FLCN leads to the activation of a protein called TFEB. TFEB is a type of protein called a transcription factor. When active, TFEB moves to the nucleus so it can drive the activity of a specific subset of genes. These genes are involved in altering cell division and cell metabolism which can lead to cancer development. FLCN acts to keep TFEB in the cytoplasm in an inactive state. In this study, the authors found that loss of FLCN led to dephosphorylation of TFEB. This led to TFEB becoming active and moving into the nucleus. However, the researchers could not yet identify how FLCN led to the dephosphorylation of TFEB. Further work is required to understand this process fully.

In summary, this work has identified new ways in which loss of FLCN in kidney cells may result in the early stages of cancer development. It has also highlighted that there may be specific pathways that are worth investigating for potential new targeted treatments for BHD-related kidney cancer. Currently, there is no medication available to treat BHD-related kidney cancer. Surgery is performed to remove any tumours when they get to a certain size.

These results are encouraging us a lot to continue exploring personalised medicine as an additional strategy to treat cancer in BHD

Professor Rob Wolthuis, senior author of the study

Finding additional treatments for kidney cancer is of great interest to the BHD Foundation and Myrovlytis Trust. For example, there may be cases where kidney sparing surgery is not possible or would not be sufficient to treat the cancer. We look forward to seeing further research bringing us closer to new personalised treatments or even a cure for BHD.

What Tuberous Sclerosis Complex can teach us about BHD

Tuberous sclerosis complex (TSC) is a rare inherited condition. It shares some features with Birt-Hogg-Dubé syndrome (BHD). TSC is a complex condition in which non-cancerous tumours called hamartomas can develop in different parts of the body. They most commonly appear in the brain, skin, heart and kidney. People with TSC can also get lung cysts and have collapsed lungs. Like BHD, the symptoms and severity of TSC can vary between people, even within the same family.

A recent paper reviewed the diagnosis and management of TSC. Here, we compare this with the current recommendations for BHD. 

Diagnosis of TSC

There has been more research into TSC than BHD. Although they are different conditions, there is plenty that can be learned from TSC. Diagnostic criteria for TSC were first established in 1998. In 2012, they were updated and renewed based on a number of major and minor criteria. A definite diagnosis requires 2 major features or 1 major feature and at least 2 minor features. A mutation in either TSC1 or TSC2 is also sufficient for a diagnosis of TSC.

There are currently no official diagnostic criteria for BHD. However, different criteria have been proposed. A diagnosis of BHD relies on a combination of:

•             clinical evaluation (looking at what symptoms a person may have)
•             family history (if there is a family history of any of the symptoms of BHD)
•             genetic testing (looking for a mutation in the gene folliculin, FLCN)

Early diagnosis in BHD is important to identify and treat any kidney cancer as quickly as possible.

The creation of diagnostic guidelines for BHD is a top concern for the BHD Foundation. Early diagnosis in BHD is important due to the risk of kidney cancer. Around 1 in 3 people with BHD will get kidney cancer. Everyone with BHD should get regular kidney scans to identify and treat any kidney cancer as quickly as possible.  Understanding how other, similar conditions are diagnosed can help inform the best approach to create diagnostic criteria for BHD.

Management of TSC

Managing TSC is not straight-forward due to the wide range of symptoms a person may get. Like BHD, a team of different specialists is required for the best standard of a care. It is recommended that people with TSC get several types of scans and tests to check the function of key organs that may be affected. This includes skin and dental exams, scans of the brain, kidney and chest. These are performed at diagnosis and to monitor the condition. Below we look at the management of the three main symptoms of BHD and compare with how they are managed in TSC.

Management of the Kidneys

Tumours growing in the brain and kidney are the most serious complication of TSC. It is recommended that people get kidney scans every 1 -3 years. The kidney tumours in TSC are normally angiomyolipomas, (tumours that contain muscle, fat and blood vessels) which can be seen clearly on an ultrasound. These are different to the kind seen in BHD as they are not cancerous. They are often serious due to the risk of the tumours bursting and bleeding. However, people with TSC may still have an increased risk of getting kidney cancer.  

In BHD, monitoring of the kidneys is also very important. However, how often people get scans, and the best type of scan is still up for debate. Some experts recommend a kidney scan every year while others recommend one every 3 years. Other experts say how often you get a kidney scan may depend on if you have any tumours or not. It is generally thought that an MRI scan is the best type of scan as it is very sensitive and can detect small tumours and does not emit any radiation. If an MRI is not available, a CT scan is recommended, however this does emit radiation.

Management of the Lungs

The lung involvement with TSC is known as lymphangioleiomyomatosis (LAM). On World Pneumothorax Day we wrote a blog post describing the differences between BHD and LAM. Unlike BHD, the lung symptoms in LAM often get worse and affect the function of the lungs. It is therefore recommended that a CT scan of the lungs should be performed every 2-3 years. Tests to check lung function should be done every year.

In BHD, regular lung scans are not normally required. However, this may vary from person to person depending on your symptoms and lung function. Many people with BHD will have had a lung scan if they have had a collapsed lung. Other people may have a lung scan when they are diagnosed with BHD to check for lung cysts.

Management of the Skin

Skin symptoms are very common in TSC. These normally appear between the ages of 2 and 5 and increase in size and number. A detailed skin exam should be done at diagnosis and further exams should be done every year. A skin biopsy (where a sample is taken to check in a laboratory) is not normally required in TSC, although it may help diagnosis.

In BHD, a skin exam is often performed as this can help diagnosis. You may not need to see a skin specialist regularly unless you choose to have treatment to remove your skin bumps.

Treatment of TSC

TSC is caused by mutations in the genes TSC1 and TSC2. Like FLCN, these genes play a role in the mTOR pathway. Faulty TSC1 and TSC2 genes result in the mTOR pathway being constantly turned on. The mTOR pathway can be thought of as a master regulator of cell growth and survival. Having this pathway constantly turned on can lead to the growth of tumours and/or cancer. Drugs called sirolimus and everolimus can turn this pathway off by blocking a key protein in the pathway called mTORC1. These drugs have been approved to treat certain symptoms of TSC including brain and kidney tumours. Sirolimus can also be used to treat moderate to severe LAM and for a type of skin bump called angiofibroma.

There have been 2 previous clinical trials looking at mTORC1 inhibitors to treat BHD. The first one studied the effect of using a topical treatment (something that can be applied directly to the skin) to treat fibrofolliculomas. It was found that this was not an effective treatment. The second trial examined the use of everolimus for BHD-associated kidney cancer. This trial was stopped due to a low participation rate.

Future Research

Although there are drugs to treat some of the symptoms of TSC, more work needs to be done. How to choose the best drug and dose, who, what and when to treat are important questions. It has also been shown that many of the symptoms of TSC can return when a person stops the drug they are taking. Therefore, the long-term side effects of taking a drug need to be considered. Work is also being done to develop new treatments for TSC. This includes better, safer mTORC1 inhibitors as well as new approaches such as gene therapy.

There are no drugs approved to treat BHD. Research into developing new treatments, including gene therapy for BHD, is a top priority for the BHD Foundation and Myrovlytis Trust (who manage the BHD Foundation). The guidance on diagnosis, management and indication for treatment in TSC has been partly shaped by the TuberOus SClerosis registry to increase disease Awareness (TOSCA) registry. This international registry recruited over 2000 people with TSC and recorded information including symptoms, treatments and outcomes over 5 years. Earlier this year, we launched the BHD Syndrome International Registry. With this, we aim to put people with BHD at the centre of research, and drive it forward to find new treatments or even a cure for BHD. However, we need as many people to take part as possible to get meaningful results that can truly impact the BHD community. Find out more and join the registry.

How common are genetic causes of kidney cancer?

Kidney cancer is the 6th most common cancer in the developed world. There are many different types of kidney cancer. The most common is called clear cell kidney cancer. 75 out of 100 (75%) people with kidney cancer have clear cell kidney cancer. Other types of kidney cancer (non-clear cell kidney cancer) include papillary, chromophobe and other rarer forms.

There are several factors that can increase the risk of kidney cancer. These include smoking, obesity, high blood pressure as well as genetics. Many genetic conditions are linked with kidney cancer including Birt-Hogg-Dubé syndrome (BHD). It is thought that around 1 in 3 people with BHD will get kidney cancer. It is recommended that people with BHD get regular scans to monitor their kidneys to identify and treat any kidney cancer quickly. Other inherited kidney cancer conditions include von Hippel-Lindau (VHL) and hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC).

Genetic Causes of Kidney Cancer

For every 100 people diagnosed with kidney cancer, 3 will have another family member who has also had kidney cancer. However, mutations in genes known to increase the risk of cancer have been found in up to 16 of every 100 kidney cancer cases. This number can vary significantly based on which genes are tested.

A recently published study provided a deeper understanding of the link between genetics and kidney cancer. The researchers looked at the genetic sequence of 1336 individuals with kidney cancer in the UK 100,000 Human Genome Project. They looked at several genes that were linked to increasing the risk of cancer and how many cases of kidney cancer were linked to each gene.

They split the genes into two groups – one with genes that had been previously linked to kidney cancer and the other group with genes which had not. In total, 88 out of 1336 cases were found to have a mutation in one of the genes. 60 of these came from the group of genes previously linked to kidney cancer. 4 out of 1336 cases had a mutation in the gene folliculin (FLCN), the gene associated with BHD. There were 7 cases linked to VHL and 3 cases linked to HLRCC.

People with a mutation in a gene known to be linked with cancer tended to get kidney cancer earlier (58.6 years versus 61.5 years in those without a mutation). 19 people got kidney cancer under the age of 45. This included all 7 individuals with VHL and 2 with BHD.

Type of Kidney Cancer

912 people in the dataset had clear cell kidney cancer. Of these, 53 people had a mutation in a gene linked with cancer (5.8%). There were 224 people with non-clear cell kidney cancer in the dataset. 19 people had a mutation in a gene linked with cancer (8.5%). Genetic mutations were therefore more commonly associated with non-clear cell kidney cancer types. 2 people with BHD had chromophobe kidney cancer and 1 person had an oncocytoma. There was no information about the type of kidney cancer for the other person with BHD in this study.

Other Symptoms

None of the 4 individuals with a mutation in FLCN were reported to have any other symptoms of BHD aside from kidney cancer. This was the same for HLRCC. 4 of the 7 individuals with VHL had other symptoms of the condition.

Genetic Testing

In the UK, people who have suspected inherited kidney cancer are offered genetic testing that includes a panel of genes, including FLCN. Based on the findings of this study, the authors suggest that the panel of genes should be expanded to include other genes they found to be associated with kidney cancer.


This study found that around 6 in every 100 cases of kidney cancer had a genetic link. 4 out of 1336 people in the dataset had BHD (roughly 3 in 1000 kidney cancer cases). It was interesting that these individuals did not have any other symptoms of BHD. However, this could be due to a lack of reporting as the authors did suggest that this kind of data was not available for all participants. A central database, such as the BHD Syndrome International Registry, could be used in the future to help provide a complete picture of BHD as a condition. Find out more about the registry here.

Studies like these also help us better understand the link between genetics and kidney cancer. They can also help influence guidelines for kidney cancer screening and genetic testing.

BHD Case Reports: Summer Round-Up

Every few months we like to highlight some of the recent case reports of Birt-Hogg-Dubé syndrome (BHD). A case report is a detailed account of (normally) a single person’s diagnosis and treatment journey. In this blog, we present 3 cases of BHD and cancer.

A case of two types of kidney cancer

In this case report, a 36-year-old woman underwent an MRI scan which showed she had two tumours in her left kidney. She had surgery to remove the tumours. Samples were taken from the tumours to confirm what kind of cancer she had. One of the tumours was confirmed to be clear cell kidney cancer and the other was chromophobe kidney cancer. Genetic testing showed a mutation in the gene folliculin (FLCN), the gene associated with BHD. It turned out that the patient also had a history of collapsed lungs but did not have any skin bumps. Multiple members of her family also had lung cysts, but they did not consent to genetic testing.

This case is interesting due to the tumours being different types of kidney cancer. It highlights the complex nature of BHD and the need for a better understanding of the different types of kidney cancer linked with BHD as well as how BHD causes kidney cancer.

A case of BHD with only kidney symptoms

In this report*, a 51-year-old woman with breast cancer had a CT scan of her chest and stomach to help stage her breast cancer. She was found to have several tumours in both her kidneys. They took a sample of the tumour to confirm they were not caused by her breast cancer spreading. At the time, BHD was not suspected due to the lack of skin symptoms and no family history of any BHD symptoms. The patient received treatment for her breast cancer and soon after had surgery to remove her kidney tumours. In total, 12 tumours were removed, and they were all confirmed to be hybrid oncocytic/chromophobe tumours. Although much of the kidney was preserved, this did slightly reduce her kidney function. This diagnosis prompted further investigation for BHD. Genetic testing showed a mutation in FLCN, c.602A>C, that has not previously been reported (see our guide on understanding genetic sequencing results for more information). The same mutation was also found in the patient’s mother who did not have any symptoms of BHD. The patient also had no other symptoms of BHD.

This report highlights one of the few instances of BHD with only kidney symptoms. Currently, it is unclear if only kidney symptoms can be linked to particular FLCN mutations.

BHD and testicular cancer

In this case report* a 34-year-old male presented to the clinic with a history of skin bumps on the face, neck and chest. The patient had also had 2 collapsed lungs which required a pleurodesis. A review of his family history showed that multiple members had similar skin symptoms. There was also a family history of skin cancer (melanoma). Genetic testing confirmed a mutation in FLCN confirming the diagnosis of BHD. Of interest, the patient also had a left-sided testicular seminoma (a type of cancer) at the age of 29. Then at the age of 34, he was found to have a right-sided testicular seminoma. Both were treated by surgery.

Testicular cancer has only been reported in BHD once before, however that individual also had neurofibromatosis type 1 (NF1). The authors of the previous report could not conclude if this was linked to BHD, NF1 or was just a coincidental finding as testicular cancer is a common cancer among men aged 15-34 years. However, this type of cancer has been previously linked to the same molecular pathway as FLCN. Due to this patient having cancer in both testicles at different times, the authors of this case report suggest that the association needs further investigation. Given that this is only the 2nd report of testicular cancer in BHD, if there is any association it appears to be extremely rare.


These three case reports highlight the need for a better understanding of BHD. Although case reports are useful for revealing possible conditions associated with BHD, a larger sample of people is needed to confirm whether they are linked. This is one of the reasons why we launched the BHD Syndrome International Registry earlier this year. We need a centralised database to collect this information on a global scale to drive forward research and find new treatments or even a cure for BHD.

*Please note these papers are unfortunately not freely available.

How Common is BHD? A Study in a Healthcare System Population

The prevalence of Birt-Hogg-Dubé syndrome is currently unknown. Some reports have estimated the prevalence to be 1 in 200,000 people, but this is likely an underestimate of the true figure. There have been multiple reports looking at how common BHD-related features are. For example, it is thought that:

•             around 9 in 10 people develop skin bumps.

•             around 1 in 4 people will have a collapsed lung.

•             up to 1 in 3 people will get kidney cancer.

These figures can be biased based on multiple factors. For example, a study carried out in a lung centre may find that lung symptoms are more common. This is often due to the underlying bias that most individuals who are seeing a lung doctor have lung problems. The demographics of the population being studied is also important as there have been differences in the symptoms reported in different ethnicities. Understanding the true prevalence of BHD is important as it will influence the counselling and future management of the condition.

A recent paper has estimated the prevalence of BHD. One of the best ways to do this is to look at how many people have a mutation in the gene associated with BHD, folliculin (FLCN) The authors looked at FLCN variants in a specific healthcare system-based population in Pennsylvania. They then went on to estimate how many people with a FLCN variant had any symptoms using electronic health records (EHR).

They found a FLCN variant in 35 people out of 135,990 people tested (1 in 3885 people). This is very different to the previously estimated 1 in 200,000 people. However, the 35 individuals came from 28 different families in the cohort.When this was taken into account,the prevalence of FLCN variants increased to 1 in 3234 people. A total of 13 unique FLCN variants were identified, 9 of which had been reported previously. It should be noted that the authors only look for pathogenic or likely pathogenic FLCN variants. When the authors looked at the EHR of the 35 people, 24 of them had at least one BHD-related feature documented.


21 people had seen a dermatologist and/or had a skin biopsy performed. However, only 3 out of 21 people had a BHD-related skin finding. This is in contrast to the literature which reports a high number of skin symptoms among people with BHD. The authors did not suggest why there was a lower frequency of skin symptoms reported in this study.


23 out of 35 people had lung symptoms. However, only 29 of 35 people had a CT or MRI scan that included at least part of the lungs. Lung cysts were confirmed in 23 out of 29 people. However, only 13 of these had scans in which the entirety of the lungs could be visualised. Of these, all 13 had lung cysts. It is possible that lung cysts were missed in people who did not have a lung scan or partial lung scan. 6 out of 23 people had experienced at least one collapsed lung. 4 people had repeated instances of collapsed lungs.


Only 1 person was found to have kidney cancer (chromophobe renal cancer). Of the remaining 34 people with a FLCN variant, 27 had imaging that included the kidneys. Of these, 23 had imaging that showed the entire kidneys. 3 people had renal masses, however these had not been confirmed to be kidney cancer or associated with BHD.

Other symptoms

The authors also reviewed the EHR of the individuals to determine if they were any other BHD-related features. They noted one case of parotid oncocytoma. No individuals had thyroid cancer and they did not report on colon cancer.


Only 4 of the 35 people had a diagnosis of BHD in their EHR. All 4 had at least one BHD-related symptom, including lung cysts. The authors comment on the fact that although 23 people had lung cysts, this did not warrant further investigation such as referral for genetic testing. Additionally, lung cysts in the 9 of 23 people were only found on review of the data by a radiologist and were not originally documented in the EHR. Improved clinical recognition of seemingly harmless signs such as lung cysts is needed. Recognising these features should prompt additional evaluation for an underlying genetic cause. Early diagnosis of BHD is important for the management of the condition to identify and treat any kidney cancer as soon as possible. It may also influence treatment of other BHD symptoms such as collapsed lungs. A pleurodesis may be performed earlier in people with BHD to prevent recurrent episodes of lung collapses.


The authors of this study found 1 in 3234 people with a FLCN variant in their healthcare system-based population. When considering symptoms, 1 in 5663 individuals had a FLCN variant and at least one BHD-related feature. In this study, only 4 out of 35 individuals were diagnosed with BHD. The authors noted some limitations to their current study. Firstly, most individuals in the cohort are of European ancestry and from the same healthcare system. It is therefore unclear if the findings in this study can be generalised across different populations. Secondly, the estimates of the frequency of symptoms in this study were dependent on data found within the EHR. For example, not every individual had sufficient imaging done to fully assess the symptoms. This further highlights the need to raise awareness of BHD among healthcare professionals to aid early diagnosis.

European Conference on Rare Diseases 2022: Report

We were delighted to attend the 11th European Conference on Rare Diseases & Orphan Products 2022 which was held from 27th June to 1st July. Over 840 participants from 61 countries came together with the goal of improving the quality of life of those with rare conditions. Although there are thousands of rare diseases, collectively they can be thought of as common. It is critical for our voices to be heard and represent the rare disease community to drive change.  

Patient Data 

The event discussed the use of patient data in research. It was stressed that the use of any patient data must lead to a direct impact on the patients themselves. It was also highlighted that research and healthcare need to be interlinked. For example, generating real world evidence through the use of patient registries is an important aspect of driving research. However, using patient health data to inform changes in healthcare policy is also critical. Better integration of patient health data into healthcare systems is needed.  

Journey to Diagnosis 

The importance of early diagnosis was also featured at the event. Some initial results from the Global Rare Barometer Survey were presented. This survey ran from March to June 2022 and had 13000 respondents from around the world. The results showed there were many barriers and delays to being diagnosed. These included a lack of awareness at the primary care level and a lack of coordination of care. The task of finding doctors also often fell on the patient. The solutions to these problems are not simple. It is impossible for doctors to be aware of every rare condition. Instead, they need to be educated on how to find the right information to help a patient. Management of rare conditions could also be improved through the creation of centres of expertise. These could coordinate the care a patient requires.  

BHD Syndrome International Registry 

Katie Nightingale, Charity Officer at the BHD Foundation and Myrovlytis Trust, presented her work developing the BHD Syndrome International Registry (BIRT). This poster has been approved and published at the European Conference on Rare Disease & Orphan Products 2022 and republished here with their permission.  

BIRT is needed to generate high quality patient data that can drive forward research. The overall aims are to: 

  • Improve quality of life for BHD patients. 
  • Facilitate faster diagnoses and reach a consensus on diagnosis and management guidelines. 
  • Help develop treatments or a cure for BHD. 

Anyone with BHD can take part in the registry and help to advance research into BHD.  

We were delighted to be able to join the conference and present our work. We would like to thank the organisers of the conference for hosting such a thought-provoking event. We are committed to improving the quality of life of those with Birt-Hogg-Dubé syndrome. We look forward to what the future holds for improving diagnosis, care and treatment of rare diseases.