Are there pathogenic variants of FLCN that do not cause kidney cancer, thus avoiding a requirement for lifelong surveillance?

Guest Blog by Richard Thrift

Birt-Hogg-Dubé Syndrome (BHD) is an inherited autosomal dominant disorder caused by mutations in the folliculin (FLCN) gene. About 200 pathogenic variants in FLCN have been identified to date. The three classic symptoms of BHD are spontaneous pneumothoraces, characteristic skin lesions associated with hair follicles (the most common of which are fibrofolliculomas), and kidney cancer (also known as renal cell carcinoma, RCC). Not all BHD patients have all symptoms. In particular, only about 1 in 3 patients develop RCC. It has been suggested, based on very limited data, that some FLCN variants may not give rise to RCC. If it were possible to identify variants that do not increase the risk of RCC, expensive and uncomfortable imaging (typically CT or MRI every three year) could be avoidable for people with those variants.

Matsumoto et al. undertook an extensive literature search to try to identify pneumothorax only pathogenic variants(POPVs) (1) . They found 158 articles, which described 1059 individuals from 575 families. 194 unique pathogenic FLCN variants were identified, with patient details provided in most reports. Patients were evenly split between East Asia (Japan, South Korea, China and Taiwan) (33.3%), North America (32.7%), and Europe (31.7%). They broke down the data to make several interesting observations.

Of the documented patients, 91.9% were shown to have pulmonary cysts. The prevalence of pneumothorax, characteristic skin lesions, and RCC in BHDS were 50.9%, 47.9%, and 22.5% respectively. The median age at first pneumothorax was 34 years (range 10–78 years). The median age at which skin changes were first noted was 38 years (range 20–65 years). The median age at first diagnosis of RCC was 47 years (range 14–83 years).

In previous reports there appeared to be a higher percentage of pneumothorax and fewer dermatological findings and RCCs among patients from East Asia. The current study bears this out and provides a more detailed overview. The prevalence of pneumothorax in East Asians was 74%, vs 45% in Europe and 35% in North America. It’s not clear whether this might be explained by genetic and physiological or environmental differences, but there does seem to be some sampling bias due to differences in diagnostic pathways. Pneumothorax recurred in 2 out of 3 patients (geographic differences were not mentioned).

It typically took 6 years for patients to be diagnosed with BHD following a pneumothorax, compared with 0 years for diagnoses following RCC or skin changes. Lack of awareness by clinicians can delay life-saving screening for RCC.

Out of 991 patients identified, only one had RCC below age 20 (at 14 years of age), while 14 had a pneumothorax before age 20. This bears on the minimum age at which genetic testing should be performed. Ethical considerations are discussed by Borry et al, (2); generally, testing is discouraged before the age at which diagnosis might influence management of the condition.

Matsumoto et al. discuss some of the unavoidable limitations and potential biases of a study based on a review of the literature. FLCN variants were analyzed according to the type of mutation, because different mutations behave differently. 68% were nonsense and frameshift variants, 16% were intronic variants, 6% were missense variants/in-frame deletions, 7% were large deletions/duplications, and 4% were variants affecting transcription initiation. The class of large deletions is significant because these variants are not readily identified by DNA sequencing. These are identifiable by copy number analysis, a technique that has only become common in recent years. Patients with large deletion variants who were tested more than a few years ago have often been told they were negative for BHD.

Ideally, there would be enough data to pinpoint which variants are associated with RCC and which are not. But BHD is a rare disease, and there simply aren’t enough documented patients. Many variants have only been documented a few times; not enough to say “this variant, although known to have caused pneumothoraces, will never give rise to RCC.” So, in order to get a little traction, we can try to focus on the variants that seem least likely to cause major problems.

For most of these classes of variants, it is thought that the mutation either causes the variant protein to be destabilized and rapidly degraded, or causes much less protein to be made because the mRNA is either rapidly degraded or just not functional. Missense variants, small in-frame deletions, and a small percentage of nonsense / frameshift variants (those near the last exon) are the only ones with much hope of making a normal amount of (possibly only slightly defective) protein. It is assumed that in general, inadequate amounts of protein being made will absolutely prevent normal function of FLCN, while normal amounts of (slightly defective) protein might have selective effects on function, perhaps leading to a milder condition that does not progress to RCC.

Of the 194 pathogenic FLCN variants (after eliminating variants known to be associated with RCC), 76 appeared, given the limited data, to be POPV. The authors looked for differences between POPVs and non-POPVS by assessing variant type, location within the gene, age of patients, and number of patients with that variant. There were no statistical differences in type or distribution. Almost 90% of POPVs were found in only three or fewer individuals; clearly there is a decent chance that for many of these variants, RCCs will be found if more patients are tested. There was a tendency for patients with POPVs to be younger than those with non-POPVs; if these patients are observed for a longer time, RCCs may develop in them.

Given the above, of the 76 apparent POPVs, it seems unlikely that the majority of these variants are only linked to pneumothorax. However, it cannot yet be ruled out that some of these may be genuine POPVs. The ability to follow BHD patients with these variants over time and assess whether they develop further BHD-associated manifestations would be greatly beneficial in furthering our understanding of whether certain variants are linked to particular manifestations.

Based on this conclusion, the authors recommend lifelong monitoring for RCC (by CT or MRI) of all BHD patients, since pneumothorax-only FLCN variants are likely to be rare.


1) Matsumoto K, Lim D, Pharoah PD, Maher ER, Marciniak SJ. A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours. Eur J Hum Genet (2021). Online ahead of print. 2) Borry P, Evers-Kiebooms G, Cornel M, et al. Genetic testing in asymptomatic minors. Eur J Hum Genet 17, 711–719 (2009).

2) Borry P, Evers-Kiebooms G, Cornel M, et al. Genetic testing in asymptomatic minors. Eur J Hum Genet 17, 711–719 (2009).

Exploring a molecular link between Birt-Hogg-Dubé Syndrome and Tuberous Sclerosis.

Tuberous Sclerosis (TSC) is an autosomal disorder caused by mutations in the genes TSC1 or TSC2. It is characterised by the development of tumours that affect several organs including the brain, heart, kidney, lung and skin. Most TSC-associated tumours are benign however malignant tumours do occur, particularly in the kidneys. As such, TSC and Birt-Hogg-Dubé Syndrome (BHD) share some similar features as well as manifestations that are unique to each condition. Like folliculin (FLCN), which is mutated in BHD, TSC1 and TSC2 also regulate the activity of mTOR signalling. We recently published a blog that reviewed the function of FLCN in regulating mTOR signalling. The authors of the review highlighted work which demonstrated that in kidney tumours derived from BHD patients, the loss of FLCN led to hyperactivation of mTOR. Similarly, in TSC, loss of either TSC1 or TSC2 leads to hyperactivation of mTOR which is believed to be the main driver of tumourigenesis.

A recent paper by Alesi et al., investigated the role that TSC1 and TSC2 play in the regulation of lysosome biogenesis and mTOR signalling (1). Lysosomes are organelles responsible for degradation and recycling of cellular waste. Studying lysosomes is important in this context as they have been increasingly shown to be a driver of tumourigenesis. The activity of mTORC1 (a key player in the mTOR signalling pathway) tightly regulates the transcription factors TFEB and TFE3, master regulators of lysosome gene expression, biogenesis and autophagy. In theory, hyperactivation of mTOR signalling should result in prevention of TFEB translocating to the nucleus where it is active. However, there is conflicting evidence of this in the literature in the context of TSC. This present study shows that despite high mTORC1 activity, the localisation of TFEB is predominantly nuclear. Of interest, this has also been shown for a mouse model of BHD-associated kidney cancer in a paper by Napolitano et al., indicating that TFEB may be a driver of tumourigenesis in both TSC and BHD. This is the opposite of what you would expect and so it is important to understand why this happens.

The authors made use of multiple different models to examine TFEB activity in cells lacking TSC2. In a mouse model of TSC which develops kidney cysts they found a 3-fold increase in the number of lysosomes in the tumours compared to adjacent healthy tissue, indicating an increase in TFEB activity in tumours. They also demonstrated an increase of TFEB with a predominantly nuclear localisation in cells lacking TSC2 in vitro. They confirmed that the nuclear TFEB was active in these cells and that this activity led to an increase in cell proliferation, which is required for tumourigenesis.

As FLCN has been shown to be important for TFEB regulation, Alesi et al., next looked at a combined effect of FLCN and TSC2. They depleted TSC2 and FLCN either alone or in combination in vitro and as expected, saw a significant increase in TFEB nuclear localisation and activity when either TSC2 or FLCN were depleted alone. This effect was further enhanced when both TSC2 and FLCN were depleted. The ability of FLCN to regulate TFEB activity is mediated by the proteins RAGC and RAGD which activate mTORC1. The authors demonstrated an increase in the expression of RAGC and RAGD in TSC2 deficient cells, as well as in FLCN-deficient cells and cells lacking both TSC2 and FLCN. They suggested that this could represent an additional mechanism for sustained mTORC1 activity in TSC2 and/or FLCN-depleted cells. The authors stated that the combined loss of TSC2 and FLCN resulting in an even stronger nuclear localisation and thus activity of TFEB implies that there is a pathogenic link between TSC and BHD and that TFEB may represent a therapeutic target for both these rare conditions.

At the BHD Foundation and Myrovlytis Trust we found this paper exciting. The rarity and complexity of conditions such as BHD and TSC present many research challenges. Identification of common pathways that may be targeted therapeutically against multiple conditions is an extremely attractive approach. Further research needs to be performed to investigate if TFEB can be a therapeutic target for alleviating kidney disease in both TSC and BHD.


1.        Alesi N, Akl EW, Khabibullin D, Liu HJ, Nidhiry AS, Garner ER, et al. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nat Commun. 2021;12(1).

Folliculin: Functions Independent of mTOR and AMPK

Ramirez Reyes et al., recently provided an in-depth review of the functions of folliculin (FLCN). We previously published a blog piece based on this review discussing the role FLCN plays in the mTOR signalling pathway. Following on from this, we now focus on other pathways in which FLCN is involved and discuss the relevance to Birt-Hogg-Dubé Syndrome (BHD).


FLCN has been identified as a negative regulator of ribosomal RNA synthesis and thus loss of FLCN can lead to an increase in translation through increased levels of ribosomes which are required for the hyperproliferative state of cancer cells. FLCN has also been linked to the upregulation of two microRNAs in cystic lesions of primary spontaneous pneumothorax in BHD patients. One of these has been shown to induce apoptosis, and the other is involved in mesenchymal to epithelial transition in lung fibroblasts which may be able to at least partly explain the development of lung lesions found in BHD.

FLCN and EGFR Signalling

A role for FLCN in epidermal growth factor receptor (EGFR) signalling has been demonstrated. Cell growth and mechanisms preventing apoptosis, which are hallmarks of cancer, are examples of events that occur downstream of EGFR signalling. Loss of FLCN in BHD-derived kidney tumours has been shown to enhance EGFR activation and therefore could lead to the hallmarks of cancer described.

FLCN and the Cell Cycle

Loss of FLCN leads to acceleration of progression through the G2/M phase of the cell cycle which results in increased cell proliferation. The mechanism by which FLCN controls this is unknown, but it has been hypothesised that it may be through the regulation of the oncogene cyclin D1. It is well established that activation of mTORC1 leads to an increase in cyclin D1 expression which may contribute to BHD-related tumorigenesis.

FLCN and Autophagy

Autophagy is the process by which cellular molecules are broken down and recycled to provide energy and the building blocks to maintain cellular homeostasis under conditions of stress or starvation. It has been reported that loss of FLCN in cells leads to AMPK-mediated induction of autophagy. This results in an inhibition of apoptosis and increased ATP levels which may confer an energetic advantage in tumours lacking FLCN which would support tumour progression under conditions of stress.

FLCN and Glycogen Metabolism

There is increasing evidence of a key role for glycogen in carcinogenesis and accumulation of glycogen has been observed in many cancer types, including renal tumours from BHD patients. A loss of FLCN has been shown to increase the expression of genes involved in glycogen synthesis. Breakdown of glycogen is also a driver of cancer cell proliferation and survival in models of glioblastoma, breast cancer and colon cancer and has shown to be important in the first steps of metastasis.

The role FLCN plays in cells is exceptionally complex and it not yet fully understood. It is complicated further by conflicting evidence in the literature of what FLCN does depending on the model used. Development of better models to study FLCN in the context of BHD would enable a more precise understanding of how a lack of FLCN contributes to the symptoms observed in BHD. This includes models for all the manifestations of BHD (skin, kidney and lung), better platforms for testing drugs on a large scale, inclusion of computational analysis to look at networks rather than single proteins or pathways. Without this deep knowledge of FLCN biology, development of new therapies is extremely difficult, which is why the BHD Foundation and Myrovlytis Trust are committed to funding research to develop these models so that they can be used to inform the development of treatments for BHD.


1.        Reyes JMJR, Cuesta R, Pause A. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways. Front Cell Dev Biol. 2021;

Extracardiac Rhabdomyomas in BHD

Rhabdomyomas are rare cancers formed from striated muscle. Although they are usually benign, meaning they do not spread elsewhere in the body, they can negatively impact the structures around them so must be monitored. There are two main types of rhabdomyoma, cardiac (found in the heart) and extracardiac (found elsewhere in the body), which is further split into three subtypes: adult, fetal and genital. Although rare, there have been a few cases of cardiac and adult rhabdomyoma reported in patients with Birt-Hogg-Dubé syndrome (BHD), however, there is not enough evidence to determine whether these are incidental findings or are characteristic of BHD. A recent research letter by Bajwa et al., discusses a patient with BHD who was found to have multiple extracardiac rhabdomyomas and explores whether they could be linked (1).

The letter describes a 63-year-old man, with known BHD, who presented with ‘fullness’ under the chin. He had an ultrasound and CT of his head and neck which showed multiple soft masses in his neck. A biopsy was taken whereby multiple extracardiac rhabdomyomas were found. The DNA of the tumours was sequenced and demonstrated loss of heterozygosity for the folliculin gene. This is what happens in BHD-related kidney cancer, where the second copy of folliculin acquires a mutation or is lost, which leads to the formation of tumours. This is not the case in the fibrofolliculomas or lung cysts seen in BHD where mutation in a single copy of folliculin is sufficient.

Bajwa et al., explored the literature and this case to further understand whether there may be a link between BHD and rhabdomyomas. Firstly, it must be noted that it is rare to get multiple extracardiac rhabdomyomas, with only 33 cases having been reported in the literature; this suggests a genetic cause. Folliculin was shown to be mutated in the case of the 63-year-old and although BHD was not diagnosed in any of the other cases, one patient was said to have undefined skin papules, which were not investigated further (2). This suggests it could be the result of BHD.

In addition to multiple cases of rhabdomyoma being recorded in the literature, one study  using a rat model of BHD showed that 12% of rats  developed rhabdomyomas (3).

At the BHD foundation we were really interested by this case report which appears to be the first piece of evidence demonstrating that loss of heterozygosity of folliculin can drive the growth of rhabdomyomas. This case study, and the limited other reports of rhabdomyomas in BHD, provides a stronger link between rhabdomyomas and BHD and warrants further investigation. A database or patient registry which collects information regarding BHD and infrequent manifestations would further consolidate these associations.


1.          Bajwa DS, Cook S, Winn R, Winship IM, McQueen A, Husain A, et al. Multifocal extracardiac rhabdomyomas: Extending the phenotype of Birt‐Hogg‐Dubé syndrome. Br J Dermatol. 2021 May 28;

2.          Khalaf MG, Haddad R, Akiki M, Khazen J, Melkane AE. Multifocal adult rhabdomyoma of the head and neck: case report and systematic review of the literature. Vol. 50, International Journal of Oral and Maxillofacial Surgery. Churchill Livingstone; 2021. p. 327–34.

3.          Bondavalli D, White SM, Steer A, Pflaumer A, Winship I. Is cardiac rhabdomyoma a feature of Birt Hogg Dubé syndrome? Am J Med Genet Part A [Internet]. 2015 Apr 1 [cited 2021 Jul 8];167(4):802–4. Available from:

Folliculin: A Regulator of mTOR Signaling

Birt-Hogg-Dubé Syndrome (BHD) is caused by mutations in the gene folliculin (FLCN). If we can fully understand how FLCN functions in the cell, we can start to develop novel therapies which will restore signalling when FLCN is mutated. Although this seems like a simple task, research has shown that FLCN is involved in a lot of different cellular processes and the pathways involved are actually very complex.

We know that FLCN forms a complex with two other proteins, named folliculin interacting protein 1 (FNIP1) and FNIP2 respectively, and many studies have shown that the FLCN/FNIP complex acts to modulate the activity of mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK). Ramirez Reyes et al., provide a comprehensive review of the known functions of FLCN (1). This blog post will focus on the role of FLCN in mTORC1 signalling. Future blog posts will focus on FLCN and AMPK signalling, and other roles of FLCN discussed in by the authors.

What is mTOR signalling and why is it important?

mTOR signalling is a master regulator of cell metabolism, growth, proliferation, and survival. In cancer cells, these pathways are manipulated to create a favourable environment for cancer progression. Cellular metabolism needs to be increased in order to promote cellular growth and proliferation, and survival of these cells is critical for the growing tumour. It is therefore no surprise that mTOR signalling is often affected in not just cancer but many other diseases including metabolic syndromes and neurodevelopmental disorders. In fact, hyperactivation of mTORC1 signalling has been found in over 80% of cancers. Targeting this pathway is very attractive for anticancer therapy, as restoration of aberrant mTOR signalling in cancer cells can slow or inhibit tumour development.

What is the role of mTOR in BHD?

The role of mTOR in BHD is controversial and there have been conflicting reports in the literature of the effect of the loss of FLCN on mTOR signalling. In some cell lines which have reduced FLCN, mTOR activation is reduced (i.e. less cell growth and proliferation). However, in BHD-derived kidney tumours, FLCN has been shown to have the opposite effect and lead to hyperactivation of mTOR.

To further understand how hyperactivation of mTOR contributes to cancer progression it is important to look at the downstream factors that are activated by this pathway. Two of these factors are the transcription factors TFEB and TFE3 (transcription factor binding to IGHM enhancer B or 3). TFEB and TFE3 are known to regulate the expression of genes involved in a wide range of cellular processes including lysosome biogenesis and autophagy which are both important in the recycling of cellular components and cancer progression. Activation of TFEB and TFE3, and therefore transcription of target genes, has been demonstrated in several cancers.

It has been shown that FLCN prevents the translocation of TFEB and TFE3 to the nucleus and consequently prevents transcription of target genes. Loss of FLCN therefore leads to constitutive activation of TFEB and TFE3 and transcription of target genes. Moreover, a paper published in 2020 by Napolitano et al., demonstrates that depletion of TFEB in a mouse kidney model of BHD completely rescues the disease phenotype (2).

FLCN is an essential modulator of these metabolic processes, however the conflicting evidence in the literature means there are still many questions to be answered to fully understand the interplay between FLCN and mTOR signalling. Further research into understanding the role FLCN plays in mTOR signalling will increase our knowledge of tumour progression and facilitate the identification of potential novel therapies. In addition to running the BHD Foundation to provide advocacy and support, the Myrovlytis Trust are committed to uncovering the role of FLCN and developing new therapies through funding research and bringing the research community together to tackle these important questions.


1.        Reyes JMJR, Cuesta R, Pause A. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways. Front Cell Dev Biol. 2021;

2.        Napolitano G, Di Malta C, Esposito A, de Araujo MEG, Pece S, Bertalot G, et al. A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome. Nature [Internet]. 2020 Sep 24 [cited 2021 May 18];585(7826):597–602. Available from:

Cassandra’s BHD Story: Pneumothorax

Today is World Pneumothorax Day. Familial pneumothorax accounts for around 10% of all spontaneous pneumothoraces. Of those that can be diagnosed with a genetic cause, BHD is the most common diagnosis but is often not thought about in the clinic. The BHD Foundation would like to change this and raise awareness of BHD and pneumothorax.

We also spoke to Cassandra a member of the BHD community about her BHD diagnosis and pneumothoraces. Cassandra explained how recurrent pneumothoraces resulted in surgery and key things to consider in the recovery process. She also discussed how she would approach discussing BHD with her daughter and the importance of information. You can watch her interview below. A transcript is also available here.  

Findacure Drug Repurposing for Rare Diseases Conference 2021

The team from the Myrovlytis Trust/BHD Foundation attended the drug repurposing for rare diseases conference (14-15th June 2021) organised by findacure. Findacure aim to build a strong, supportive and collaborative rare disease community to transform the lives of people affected by rare diseases. This conference aimed to bring together industry, patient groups, researchers and clinicians and get them thinking about how we can use drug repurposing in the rare disease field.

Of the 7000 recognised rare diseases, only 400 have licensed treatments. Finding new treatments for all these conditions would take 500 years at the current rate of drug development. There is a clear, urgent need for new treatments and drug repurposing is one way to accelerate this.

Day 1 Highlights

Rick Thompson, CEO of findacure highlighted the advantages of drug repurposing:

A series of short talks from Dr Rona Smith (University of Cambridge), Dr John Liddicoat (University of Cambridge) and Professor Indi Banerjee (Manchester University) showcased examples of drug repurposing and what is needed to drive forward a drug repurposing project. It is more common for clinicians and researchers to pursue this type of project as there can be little financial incentive for industry. However, the cost of developing a new treatment should be weighed against the cost of lifetime healthcare for patients.

Two parallel sessions featured 5 minute ‘lightning talks’ from a range of speakers from patients, clinicians and industry. They focused on the importance of advocacy and raising awareness of rare diseases and discussed the challenges of doing this.

In a session hosted by LifeArc, the headline sponsor of the conference, the challenges of creating collaboration between patient groups and industry was highlighted, from initiating a discussion through to intellectual property rights. However, there are clear benefits of involving industry – they often have greater resources than a smaller rare disease charity, with expertise in the regulatory affairs aspect of getting a drug to market. To help navigate collaboration with industry, LifeArc recently published a report entitled “Repurposing medicines: the opportunity and the challenges”.

Day 2 Highlights

The second day of the conference concentrated on drug repurposing in action. Talks from industry featured George Drakakis (CEO of Purposeful) and Kelly Gray (open innovation manager at Astrazeneca); both considered how patient groups and researchers can collaborate with industry to advance drug repurposing projects. Pulse Infoframe led a discussion on the need for quality data and how this can increase interest from industry to form partnerships. Patient data is vital for all stages of drug repurposing, from pre-clinical through to approval. A patient registry, or a large patient dataset with quality data can be invaluable in clinical trials, in which recruiting enough patients can be difficult due to the rarity of the disease.

Medical student Catriona Chaplin gave an overview of her winning essay for the student voice essay competition. She explained that rare diseases aren’t often a focus of medical training, and through spending time with patients of rare diseases learned that this lack of awareness of rare diseases has a significant impact on both a patient’s life and the healthcare treatment they receive. Catriona also highlighted the fact that patients are in fact often the ‘expert’ in their own rare disease and that doctors need to listen and work in partnership with their patients to ensure the best care.

One of the major strengths of the rare disease community is the involvement of and engagement with patients. A highlight of this conference was that rare diseases were spoken about from various perspectives, from industry, scientific and clinical through to patient groups and patients themselves. This really enforced the importance of collaboration and bringing together different groups and resources to drive the identification of new routes to treatment.

Take Home Messages

  1. Collaboration, collaboration, collaboration! Establishing a solid network between different groups from patients, through to researchers and clinicians, industry partners and regulatory agencies is critical to the success of a drug repurposing projects. Patient charities can be the central point of collaboration and work to bring everyone together.
  2. Projects should be patient focused. Patients need to be at the centre of research and their voice needs to be heard throughout the drug repurposing process.
  3. Clinical trial design needs to be innovative. There are additional challenges when conducting clinical trials for a rare disease, and a multiplatform approach is often the best method. This can involve testing the same drug on multiple, related diseases or testing multiple drugs on the same disease.
  4. Patient registries are important in providing quality data for researchers and clinicians, establishing industry partnerships and clinical trial design.
  5. Raising awareness of rare diseases is vital to improve patient’s lives and the treatment they receive. Rare diseases need to be thought of as more than just the physical symptoms and care should be approached holistically.

The Myrovlytis Trust/BHD Foundation team would like to thank Findacure for organising such an engaging and thought-provoking meeting that has had an impact on us and will drive our thought processes as we move forward with various initiatives. We are looking forward to what the future brings for dug repurposing in rare diseases!

COVID-19 and Pneumothorax – an Observational Study

A recent letter in the European Respiratory Journal by Marciniak et al., has provided an update on pneumothorax in COVID-19 (1). The authors analysed data from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK). This encompassed the first and second wave of COVID-19 in the UK and enrolled 131,679 patients over the age of 18 admitted to hospital with COVID-19. Overall, 0.97% had a pneumothorax at some point during their hospital admission, which is in line with their previous estimate of 0.91% (2). The incidence of pneumothorax was not statistically different between the first and second waves, however there was a marked difference in the incidence between groups of patients who received different levels of respiratory support. Of patients requiring no oxygen, 0.16% had a pneumothorax, this increased to 0.56% for patients requiring oxygen support, 0.96% for patients requiring non-invasive respiratory support and 6.1% for patients who required invasive ventilation.

The authors also analysed whether receiving dexamethasone treatment impacted the incidence of pneumothorax, as a small study from Italy had suggested that there was an increased incidence of pneumothorax in patients who had received dexamethasone  (3). Importantly, Marciniak et al., found no association of dexamethasone with increased risk of pneumothorax. There was however an increased risk of pneumothorax for those with ‘chronic pulmonary disease’ (e.g. chronic obstructive pulmonary disease) in non-critical care wards, but this didn’t translate to critical care patients.

The most serious finding from this study was that having a pneumothorax with COVID-19 was associated with a worse prognosis, and an increased mortality rate. However, there are several limitations to the study which the authors discussed. Importantly, it was not known if the pneumothorax occurred after ventilation, or if the pneumothorax resulted in the need for ventilation and so the authors were unable to determine if the incidence of pneumothorax in ventilated patients reflects the severity of the disease or is a result of medical intervention.

The authors state that the risk factors identified for pneumothorax in COVID-19 are smoking, male sex, chronic pulmonary disease and invasive ventilation. They do not discuss people who are already at risk of pneumothorax and what this means for them. At the BHD Foundation, we felt this was an important study to share with the BHD community but we fully understand that this information may cause concern and anxiety. We have therefore contacted the lead author of the paper, Professor Stefan Marciniak to ask him some specific questions about the work and what it means for BHD patients.

As an expert on pneumothorax what have you seen in your clinic during the Covid-19 pandemic?
In my pneumothorax clinic I have over 500 individuals who previously suffered pneumothoraces from a variety of causes including cystic lung diseases. None appears to have suffered a recurrence due to COVID-19, although I don’t know how many contracted the illness. Having a family history of pneumothorax does increase the risk of recurrence (although this is not specific to BHD patients as the numbers are too small to confirm this). Overall, lifetime recurrence risk for pneumothorax is about 45% for all patients, and seems similar for BHD; however, it’s uncommon for a recurrence to be attributable to infection or strenuous activity.

How does BHD compare to other cystic lung diseases in terms of risk of severe Covid-19/worse prognosis?
Most of my patients with BHD have largely normal lung tissue on CT, so I don’t consider them to have “significant underlying lung disease”. I haven’t advised my pneumothorax patients to shield unless they have significant underlying lung disease e.g. at least moderate COPD.

Do BHD patients who have more significant lung manifestations have an increased risk of worse prognosis?
This is a very difficult question because there aren’t longitudinal studies in which patients have been followed for many years with a diagnosis of BHD. Surprisingly, it isn’t clear if cysts (the most common feature of BHD in the lung) change over one’s life. It is relatively uncommon for BHD patients to have very severe cystic lung disease, although I have seen this rarely in older patients, so it isn’t possible to give a definitive answer.

Are BHD patients who have had an intervention for pneumothoraces (e.g. pleurodesis) more vulnerable to infection with SARS-CoV-2?

Again, I don’t have data to support or refute this, but I can’t think of a plausible mechanism by which prior surgery would render someone more vulnerable. On the contrary, pleurodesis should make COVID-19 pneumothorax less likely.

Finally, what would your advice be to anyone who may be more vulnerable to infection or worse prognosis upon infection? 

Vaccination is safe and highly effective. I would strongly recommend that anyone at risk of COVID-19 should accept vaccination if offered.  There is much disinformation about vaccines on social media and the internet, so if people are hesitant or worried, they should discuss the pros and cons of vaccination with their doctor or read the NHS information pages:

We thank Stefan for his time in answering our questions and hope that this reassures the BHD community.  If you do have any further questions regarding this study then please email us at Additionally, Stefan will be discussing BHD and pneumothorax in our next

Meet the Experts session which is happening this Wednesday 23rd June. You can sign up for the event here, and a recording of the session will be posted on our website afterwards.

1.          Marciniak SJ, Farrell J, Rostron A, Smith I, Openshaw PJM, Baillie JK, et al. COVID-19 Pneumothorax in the United Kingdom: a prospective observational study using the ISARIC WHO clinical characterisation protocol. Eur Respir J [Internet]. 2021 Jun 3 [cited 2021 Jun 17];2100929. Available from:
2.          Martinelli AW, Ingle T, Newman J, Nadeem I, Jackson K, Lane ND, et al. COVID-19 and pneumothorax: A multicentre retrospective case series. Eur Respir J [Internet]. 2020 Sep 9 [cited 2021 Jun 17];56(5). Available from:
3.          Palumbo D, Campochiaro C, Belletti A, Marinosci A, Dagna L, Zangrillo A, et al. Pneumothorax/pneumomediastinum in non-intubated COVID-19 patients: Differences between first and second Italian pandemic wave [Internet]. Vol. 88, European Journal of Internal Medicine. Elsevier B.V.; 2021 [cited 2021 Jun 17]. p. 144–6. Available from:

Worldwide LAM Awareness Month

June is Worldwide LAM Awareness Month which aims to raise awareness and educate people about Lymphangioleiomyomatosis (LAM). LAM is a rare disease caused by mutations in the tuberous sclerosis genes. It affects the lungs, kidneys and lymphatic system and almost exclusively affects women. Recognising the symptoms of LAM is important in order for patients to access the treatment they need early. The most common presenting symptom of LAM is worsening shortness of breath and a history of recurrent pneumothoraces. Additionally, patients can experience bloating due to fluid around their lungs and stomach (from the disruption of their lymphatic system) and angiomyolipomas, which are a type of benign tumour that can cause pain and bleeding. Although there is no cure for LAM, the progression of the disease can be slowed by a drug called Sirolimus (Rapamycin).  

Due to its similarities with BHD, researchers often study both conditions. We talked to Professor Elizabeth (Lisa) Henske, Director of the Center for LAM Research and Clinical Care, Brigham and Women’s Hospital, about her work in LAM and how this translates to the BHD community. Her lab’s discovery of Tuberous Sclerosis Complex 2 (TSC2) resulted in the first FDA approved drug for LAM.

Could you tell me about your discovery of the TSC2 mutation and what that meant for patients? 

LAM occurs in two forms:  in women with tuberous sclerosis complex (TSC) and in women who do not have TSC (referred to as sporadic LAM).  The Henske Lab discovered that sporadic LAM is caused by mutations in the TSC2 gene.  A few years later, it was discovered that the TSC proteins inhibit the mTOR pathway (a pathway involved in cell growth), and Dr. Vera Krymskaya demonstrated that the mTOR pathway is hyperactive in LAM cells.   Together, these discoveries paved the way for a pivotal clinical trial led by Dr. Frank McCormack, which was published in the New England Journal of Medicine in 2011.  This trial proved that treatment with sirolimus (Rapamycin), an oral inhibitor of the mTOR pathway, stabilizes lung function in women with LAM.  In my own clinical practice, I can see the tremendous benefit of sirolimus in so many women with LAM, allowing them to work, care for their families, travel, exercise, and live a life that is close to “normal.” 

What research is currently being done into LAM? 

Some of our most urgent research questions include:

1) why does LAM affect almost exclusively women?
2) can we use treatments that block estrogen’s actions to treat LAM? 
3) how does the immune system promote the growth of LAM cells?
4) why do LAM cells cause cystic destruction of the lungs? 

We are excited to be working with Dr. Wei Shi, a leading developmental biologist at Los Angeles Children’s Hospital, to understand how both LAM and BHD lead to cystic lung disease. 

What difficulties have you come across in researching LAM? 

With any rare disease, access to tissue samples (for example, lung and kidney samples) is absolutely essential to progress.  We have been very fortunate that The LAM Foundation (based on Cincinnati OH) has helped make samples available for research.  We are also lucky to have an exceptionally collaborative and connected LAM research community, including many dedicated scientists and physicians who are committed to curing LAM.  Dr. Joel Moss, who leads the LAM program at the National Institutes of Health, has had an especially positive impact on these collaborative efforts.

From your experience what are the main differences/similarities between the symptoms of BHD and LAM? 

There are important similarities and also important differences between BHD and LAM.  The similarities include the risk of lung collapse (pneumothorax) and the risk of kidney tumors (renal cell carcinoma in BHD and angiomyolipomas in LAM).  One important difference is that in BHD, it is unusual for shortness of breath to develop.  In LAM, many women develop shortness of breath, and some become dependent on oxygen therapy, especially if the LAM is not treated early in the disease.  Another difference is that LAM affects almost exclusively women, while cystic lung disease in BHD occurs in both men and women.

What can the BHD community learn from the research into LAM? 

LAM research has brought together a highly collaborative group of clinicians and scientists.  The scientists are diverse in their background and approaches, including biochemists, developmental biologists, cancer biologists, cell biologists, geneticists, and more.  This allows LAM to be studied from many different angles.  Regular scientific and clinical meetings allowing new data to be discussed and ideas to be shared have propelled LAM research breakthroughs. 

What can we do to raise awareness about rare conditions such as LAM and BHD?

One of the best ways to raise awareness is to make clinically relevant discoveries.  In LAM and TSC, breakthroughs have consistently boosted awareness among both scientists and clinicians.  This has a “positive feedback” effect, with more awareness leading to even more progress. 

The BHD Foundation sincerely thanks Professor Elizabeth (Lisa) Henske for taking part in this interview and sharing her insights on LAM and BHD. If you a researcher working on BHD we would love to hear about your research. Please contact us at

To find out how you can get involved with LAM awareness month visit the LAM Foundations webpage. The LAM Foundation is a wonderful resource for both clinicians and members of the LAM community and they have several useful resources for raising awareness about LAM. Their centres of clinical excellence also support BHD patients.