The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome

The symptoms of Birt-Hogg-Dubé syndrome (BHD) have been widely described in Europe and the United States (USA) with approximately 90% of individuals developing skin lesions, 30% developing kidney cancer, 80% developing lung cysts and 25% developing pneumothoraces. However, studies looking at BHD in the East Asian population suggest a difference in prevalence of these characteristics. Guo et al., published a study to provide further information about the clinical characteristics of BHD in the East Asian population to aid diagnosis and ensure early intervention (1).

Guo et al., reviewed the current literature on BHD in Japan, China and Korea and enrolled 166 patients from these papers for their study. In addition, they gathered data from 10 BHD patients from Xiangya Hospital in China. The patients’ age, sex, BHD symptoms, genetics and family history were recorded and analysed. They found that skin lesions were less common in the East Asian BHD population with only 36.7% patients recorded to have them, though the most common lesions were fibrofolliculomas and trichodiscomas as seen in the European/USA population. Prevalence of kidney cancer were also lower with 7.2% of patents developing kidney cancer. However, there were more incidences of lung cysts (87.3%) and pneumothoraces (74.7%) in the East Asian BHD population.

The reason for these differences in characteristics is not clear. Interestingly Guo et al., found no significant difference in folliculin mutations found in the East Asian BHD population compared with other countries.  This supports research by Schmidt et al., which found no link between folliculin mutations and BHD characteristics and suggests difference in characteristics may be the result of other genetic or environmental factors(2). Guo et al., also suggest that the reduced incidences of skin lesions could be due to misdiagnosis, highlighting that there are differences in medical habits in different countries which could contribute to the difference in BHD characteristics being diagnosed.

Altogether this study suggests BHD will present differently in the East Asian population, with the biggest difference seen in prevalence of pneumothoraces (25% of cases in the Europe/USA population compared with 74.7% in the East Asian population).  This is important as a pneumothorax is more likely to be the only characteristic of BHD in the East Asian population and therefore it is essential that clinicians consider the diagnosis of BHD in patients who have spontaneous pneumothoraces in the absence of any other BHD characteristics.    

1.          Guo T, Shen Q, Ouyang R, Song M, Zong D, Shi Z, et al. The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome. Ann Transl Med [Internet]. 2020 Nov [cited 2021 May 12];8(21):1436–1436. Available from: http://dx.doi.org/10.21037/atm-20-1129

2.          Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-Mutation Spectrum and Phenotype Analysis of a Large Cohort of Families with Birt-Hogg-Dubé Syndrome. Vol. 76, Am. J. Hum. Genet. 2005.


Announcing the 2021 BHD Symposium

The Myrovlytis Trust/ BHD Foundation is delighted to announce the relaunch of our annual BHD Symposium, bringing together researchers and clinicians worldwide to discuss the latest developments in the BHD world. Although the event is aimed at researchers and clinicians, we welcome everyone from the BHD community and will also be holding a patient and family focused session the following day. Details and registration for the patient/family focused event to be announced soon.

The 2021 Symposium will take place on October 21st 2021, and will be held virtually. We anticipate returning to in-person symposia from 2022.

Register to secure your attendance at the 2021 BHD Research Symposium here.

Emails will be sent to researchers with further details regarding presenting at the meeting. We are busy organising the day and are looking forward to working with you all as we restart our research efforts.

Folliculin Regulates Iron Homeostasis

Birt-Hogg-Dubé syndrome (BHD) is caused by a mutation in a gene called Folliculin (FLCN). FLCN is involved in numerous cellular process throughout the body including cell growth and proliferation, stress resistance, and autophagy (controlled cell death), however we still have a lot to uncover. An interesting study by Wang et al., suggests FLCN is also involved in iron homeostasis(1).

FLCN was recently found to be involved in the Rab11a pathway, which transports and recycles proteins within a cell(2). During this research they incidentally found that FLCN also bound to Transferrin Receptor 1 (TfR1) a protein involved in iron homeostasis. Iron is a mineral that the body requires to stay healthy. It is involved in oxygen delivery, energy production and DNA metabolism. Too little or too much iron can result in harmful side effects and therefore the body has mechanisms in place to ensure iron levels are tightly controlled including TfR1. TfR1 sits on the surface of cells, acting as a sentry, waiting to bind passing iron and bring it into the cell cytoplasm. Once the iron is released within the cytoplasm, TfR1 is recycled and returns to its role as sentry. If iron levels are low, Hypoxic-Inducible Factor (HIF) proteins, increase the transcription of TfR1 to recruit more to the cell surface and increase iron levels.

Wang et al., investigated the relationship between TfR1 and FLCN using human kidney cancer cells in vitro. They found that FLCN increased the binding of TfR1 and Rab11a and suggested that FLCN may act as a scaffold to facilitate transportation. They then knocked down FLCN, reducing its expression in the kidney cancer cells.  This caused a reduction in TfR1 recycling and therefore less TfR1 was present on the cell surface to capture iron, leading to iron deficiency. Additionally Wang et al., hypothesized that the increase in HIF, which has been suggested to be linked with tumor formation in BHD(3), may be caused by iron deficiency. They discovered that HIF proteins increased in the FLCN knockdown cells and that this increase could be reversed with iron supplementation, supporting the idea that it is linked with iron deficiency.  Lastly, Wang et al., used an animal model for BHD in the fruit fly Drosophila and found that an iron rich diet reversed the BHD phenotype.

Altogether Wang et al., demonstrated that FLCN is involved in iron homeostasis in kidney cancer cells and provide further evidence that folliculin is involved in multiple cellular processes. Future studies are required in other cell types and animal models to determine if iron homeostasis is a conserved function of FLCN throughout the body and whether proteins involved in iron homeostasis could be targeted therapeutically to inhibit HIF activation and therefore tumour growth in BHD.

References

1.          Wang X, Wu H, Zhao L, Liu Z, Qi M, Jin Y, et al. FLCN regulates transferrin receptor 1 transport and iron homeostasis. JBC [Internet] 2021 [cited 2021 May 5]; Available from: https://doi.org/10.1016/j.jbc.2021.100426

2.         Zhao L, Ji X, Zhang X, Li L, Jin Y, Liu W. FLCN is a novel Rab11A-interacting protein that is involved in the Rab11A-mediated recycling transport [Internet]. Vol. 131, Journal of Cell Science. Company of Biologists Ltd; 2018 [cited 2021 May 7]. Available from: https://pubmed.ncbi.nlm.nih.gov/30446510/

3.          Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, et al. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene [Internet]. 2011 Mar 10 [cited 2021 May 6];30(10):1159–73. Available from: /pmc/articles/PMC3787473/

No evidence for increased prevalence of colon cancer in Birt-Hogg-Dubé syndrome

Jim was diagnosed with Birt-Hogg-Dubé syndrome (BHD) in 2005. He has a medical history of pneumothoraces (the first of which occurred at the age of 13), fibrofolliculomas and a family history of colon cancer. His mother, also believed to be a carrier of the mutated folliculin gene, was diagnosed with colon cancer in her 60’s.  Many people wonder whether BHD is associated with colon cancer and whether BHD patients such as Jim should be screened regularly.

There have been multiple cases of colon cancer reported in BHD patients, however a link between the two has never been established. Previous studies have not included a large enough number of patients to be able to make conclusions. A recent study in the Netherlands compared a cohort of 399 BHD patients with 382 family members who did not have a folliculin mutation, to try and answer this question and to ensure patients with BHD are receiving the correct screening(1).   

We spoke to Dr Arjan Houweling and MD Irma van de Beek at Amsterdam University Medical Centre about their research.

What prompted you to initiate this research?
Patients with an inherited form of cancer are often interested in the risk for other types of cancer. Patients with Birt-Hogg-Dubé syndrome are at a significantly increased risk for kidney cancer, but less information is available about other types of cancer. In one of the earliest publications on BHD, one of the patients also suffered from colon polyps(2). Colon polyps are benign, but can be a precursor for colon cancer. Following that early publication, many patients with both BHD and colon cancer have been reported. However, it was not clear whether these occurred together accidentally or whether they were really related to each other. This can only be assessed by studying larger groups of patients with BHD. One study from 2002 by Zbar and colleagues did not find significantly more colon polyps and colon cancer in patients with BHD compared to family members without BHD (3). However, even after publication of this study clinicians apparently were still not completely convinced, since colon screening for BHD patients was still advised in several guidelines. We hoped to gather more information about risks for colon polyps and colon cancer in patients with BHD, so we could adjust our guidelines if necessary.

What did you find out?
We compared data from the Dutch national pathology database between two groups: 399 patients with BHD and 382 of their family members without BHD. There was no significant difference between the number of colon cancers that had occurred in both groups. There were significantly more patients with BHD who had had removal of colon polyps. We did anticipate this, since a part of the BHD patients was advised to undergo colon surveillance based on their BHD diagnosis, while their family members without BHD do not undergo colon surveillance. Since colon polyps are common in middle- and older-aged individuals, it was to be expected that more BHD patients had colon polyps removed. Analyzing these polyps in more detail, there was no significant difference between the two groups in the median number of polyps per individual, the location of the polyps, the subtype of the polyps and the number of advanced polyps.

Our study had some limitations. We anonymized all patient records, therefore we could not be sure whether all extra detected polyps in patients with BHD were actually the result of extra colon surveillance. Furthermore, the removal of colon polyps may prevent the development of colon cancer. The extra surveillance in patients with BHD might therefore have led to a lower number of BHD patients with colon cancer. Despite these limitations, we believe that our data are a clear indication that the risk for colon polyps and cancer in patients with BHD is low, in line with the observations by Zbar et al(3).

What message would you give to BHD patients who are concerned about developing colon cancer.
There is no evidence for an increased risk for colon polyps or colon cancer in BHD. Even if the risk is increased, it is probably only slightly increased and does not need extra surveillance based on current knowledge. Most countries offer population screening for colon cancer, which should be sufficient for patients with BHD.

Altogether this study suggests that the risk of developing colorectal cancer if you have BHD is not significantly different from the general population and that additional colon screening is not required.

The BHD Foundation sincerely thanks Dr Arjan Houweling and MD Irma van de Beek for taking part in this interview and sharing their insights on the study. In addition, thank you to Jim Laycock, member of the BHD community for sharing his background and contributing to this blog.

Read the freely available research article here.

References

1.          van de Beek I, Glykofridis IE, Wolthuis RMF, Gille HJJP, Johannesma PC, Meijers-Heijboer HEJ, et al. No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dubé syndrome. Br J Cancer [Internet]. 2020 Feb 18 [cited 2021 Apr 27];122(4):590–4. Available from: https://doi.org/10.1038/s41416-019-0693-1

2.          Hornstein OP, Knickenberg M. Perifollicular fibromatosis cutis with polyps of the colon-a cutaneo-intestinal syndrome sui generis. Arch Dermatological Res [Internet]. 1975 Jan [cited 2021 Apr 27];253(2):161–75. Available from: https://pubmed.ncbi.nlm.nih.gov/1200700/

3.          Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax pneurnothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev [Internet]. 2002 Apr 1 [cited 2021 Apr 27];11(4):393–400. Available from: http://intl-cebp.aacrjournals.org/cgi/content/full/11/4/393

Is Kidney Cancer Curable?

We attended The European International Kidney Cancer 2021 virtual meeting in April, providing insights into clinical developments in renal cancer. The meeting was fascinating, and of note was the remarkable pace of research yielding new insights into treatments.

The keynote address was given by Dr David McDermott, Chief, Division of Medical Oncology at the Beth Israel Deaconess Medical Center. Dr McDermott challenged the audience to think about advanced renal cancer as a curable neoplasm.

To move into an era where we think in this way, Dr McDermott suggested that we need to treat patients who are predicted to respond well to therapy in a more aggressive manner. This will require new ways of predicting response to treatment, the discovery of new biomarkers and targets as well as new trials. We will also need to explore the end of point of trials in a more nuanced manner, and start thinking about “treatment free survival” as an output. This final point is key for patients – the difference between a continuous therapy with all the associated side effects versus a treatment that ends and provides a treatment free survival benefit is huge.

We are in a period where the potential of immunotherapies and combined treatments are close to being realised, and it was incredible to witness the change in approach and the grand challenge of curing kidney cancers and supporting patients to live treatment-free lives addressed.

Diagnosing Skin Bumps

Although everyone experiences Birt-Hogg-Dubé syndrome (BHD) differently, a common feature that people share is that healthcare professionals often have not heard of the condition. An article by Dazé et al not only described a case of BHD but designed a quiz, based on the case, as an education tool for healthcare professionals.

The article describes a 54-year-old man with a 10-year history of white- and skin-coloured papules across his face and neck. Biopsies from the papules revealed them to be trichodiscomas, which are benign skin lesions similar to fibrofolliculomas – the difference being these are skin coloured rather than white. This finding led to imaging of his abdomen and pelvis, which showed lung cysts and bilateral kidney cysts.  Genetic testing confirmed he had a mutation in his folliculin gene, and hence a diagnosis of BHD was obtained.

The quiz takes this scenario and asks three questions. Firstly, it asks for a diagnosis based on this case.  Secondly it asks about the cancer associated with the syndrome and finally it asks about the histology of fibrofolliculomas. Although short this article allows healthcare professionals to work through a case of BHD and pinpoint exactly the features of BHD to aid future diagnosis.  

Read the freely available article (Includes photos) and take the quiz!

References

Dazé R, Fronek L, Moon S, Farsi M, Miller R. Masquerading case of a lumpy bumpy face. JAAD Case Rep. Oct 2020 16;6(12):1261-1263. doi: 10.1016/j.jdcr.2020.10.014.

Watch the First ‘Meet the Experts’ Event Now!

This week we held our first ‘Meet the Experts’ virtual event with genetic counsellor Lindsay Middelton. Almost 50 people joined from all over the world to ask questions and hear about genetic counselling and Birt-Hogg-Dubé syndrome.  At the next event we will be talking about pneumothoraces and the date will be announced very soon.

Click here to watch the first ‘Meet the Experts’ event.   

Meet a BHD Expert

We are excited to announce that we are hosting our first Meet the Experts virtual event on Thursday 22nd April at 7:30 pm BST (British Summer Time). Lindsay Middelton has over 25 years of experience in counselling and genetic assessment of patients with familial renal cancers including Birt–Hogg–Dubé syndrome. She will be sharing her experiences and answering your questions about BHD and genetic counselling.

Sign up now for the event!

If you are unable to attend the event, we will be recording it and posting it on our webpage.

March Newsletter

Last week we sent out our March 2021 BHD newsletter and it’s not too late to read it. We discuss the highlights from this month, upcoming events, and the latest science news with a focus on Folliculin, the gene which is mutated in Birt-Hogg-Dubé syndrome.

Read it now

If you would like to receive future newsletters please email contact@bhdsyndrome.org with the subject line “Subscribe to Newsletter”.

Birt-Hogg-Dubé symptoms in Smith-Magenis syndrome

Smith-Magenis Syndrome (SMS) is a neurodevelopmental condition most commonly caused by a deletion of an area called 17p11.2 on chromosome 17. The gene which predominantly causes the neurodevelopmental symptoms exhibited in SMS is called Retinoic Acid Induced 1 (RAI1), however in most cases of SMS multiple genes on this region of chromosome 17 are affected including Folliculin (FLCN). Variants in Folliculin including deletions cause Birt-Hogg-Dubé syndrome (BHD). Interestingly there have been very few reports of BHD symptoms occurring in SMS. A recent study by Finucane et al., collected data from 117 SMS patients asking if they had any of the three core symptoms associated with BHD: fibrofolliculomas, pneumothorax and kidney cancer. Five people reported pneumothoraces and two reported fibrofolliculoma. Four of the pneumothoraces occurred in childhood, three being under the age of 4. This differs to individuals with BHD syndrome, who most commonly develop their first spontaneous pneumothoraces in their 20’s or 30’s.  It must be noted that unexpectedly one of the participants who developed a pneumothorax only had a mutation in their RAI1 gene and not Folliculin . It remains to be determined if this was an unrelated spontaneous event or if there is a relationship between RAI1 and Folliculin.

Although more research is required to fully understand the relationship between BHD and SMS, this study suggests that patients with SMS may be at greater risk of manifesting symptoms of BHD and it is important for families to be aware of the association so that they can recognize symptoms of BHD early. 

PRISM is a nonprofit, advocacy, education, and support organization for individuals with SMS and their families. They provide advice on their website regarding BHD and recommendations for kidney screening.  

References

Finucane B, Savatt JM, Shimelis H, Girirajan S, Myers SM. Birt-Hogg-Dubé symptoms in Smith-Magenis syndrome include pediatric-onset pneumothorax. Am J Med Genet A 2021. doi: 10.1002/ajmg.a.62159.