Dr Maurice van Steensel and Karen

BHD Researcher Interview: Dr Maurice van Steensel, a dermatologist at the Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, The Netherlands. Dr van Steensel works on congenital dermatological disorders.

1. How did you get interested in BHD research?

I have been interested in molecular genetics, in particular of the hereditary skin disorders, for a long time and am one of the few dermatologists in the world specializing in these disorders. So my department is a referral center for rare disorders and “funny” disorders. And my interest in BHD arose from a chance meeting with someone who had something “funny”. One day, back in 2006, a patient with small facial tumours came into my outpatient clinic to have something done about those annoying bumps. I took a good look and then a biopsy and so found out that my patient had fibrofolliculomas. I had never seen those before and became really curious – hair follicle tumors to the dermatologist are a sign of underlying disorders, often cancer syndromes, but fibrofolliculomas were not on my radar at the time. A little searching then made it quite obvious that he had to have Birt-Hogg-Dubé syndrome and sure enough further screening showed renal cysts. We next sequenced his FLCN gene and found a novel mutation. A bit of reading then quite quickly showed that very little was known about BHD and FLCN’s function and that was when I decided to invest extra time and effort and see whether we could have a stab at building a new research line – here was a promising new field! So we did some initial work to try and work out whether FLCN behaves like a typical tumour suppressor in skin, which we found it doesn’t. So that was pretty surprising and we did not really know where to go from there until I had a casual conversation with my colleague and friend Michel van Geel who is a molecular geneticist. While talking about the phenotype and then hit upon the close similarity between BHD and tuberous sclerosis. We then hit upon the idea that FLCN might be involved in mTOR and HIF signalling. I wrote a grant proposal around that idea and got funded so I could hire a PhD student. A second grant then brought in a post-doc for two years. These initial investments allowed us to build the infrastructure and get the preliminary data needed to go after larger funds which we got fairly recently when I was awarded a major grant from the Dutch Cancer Society to hire a post-doc and a PhD student and fund my own salary so I could spend more time on BHD. The Myrovlytis Trust meanwhile had agreed to fund a clinical researcher for two years to work out clinical management of BHD and conduct the first translational trial. So now we have a group of five people doing nothing but BHD! I’m a lucky man.

2. What are you currently working on?

We spent a lot of time getting up to speed – tooling up, building up our infrastructure and defining our goals for the next five years. Our research is now focused on pretty basic stuff – we have become quite interested in how FLCN responds to various inputs from the outside world and are looking at things like phosphorylation of FLCN after activation of (presumed) upstream inputs. We have started a close collaboration with Andrew Tee in Cardiff and together with his group we are looking at BHD tumorigenesis in a number of systems that we think are relevant to the patients. We also have someone who is working to create three-dimensional tissue culture systems in which to check cell growth of BHD mutant cells and there is a new PhD student who is examining epigenetic changes in hair follicle tumors, including fibrofolliculomas. On the clinical side the Myrovlytis Trust has funded a clinical researcher for us who is setting up a trial of topical rapamycin for fibrofolliculomas – we’re very excited about that. Together with our friends from Birmingham and Amsterdam she is also starting to explore other aspects of BHD, such as the behaviour and biology of metastasizing renal cancers that patients can develop, with a particular view to the type of treatment that patients with metastatic cancer might require. Finally, we act as a referral center for patients and provide FLCN mutation analysis as a free service to researchers and physicians. So, we’re pretty busy!

3. What would help current research (equipment, technique etc.)?

I think the consortium [European BHD Consortium] is pretty much on the right track – we have structural biology support and zebrafish models. Still needed are decent fruit fly models and people interested in/experienced with yeast because I think that some aspects of FLCN function may be more tractable in that organism. Rodent models are good but not for understanding the skin phenotype because they do not develop skin tumors. So I would like to have a rodent (mouse/rat) that does develop skin tumors, I have some thoughts about how to go about it but nothing really definitive yet. What’s also very important is to keep up the work on the clinical side- we have just started to define the research questions d have  a lot of work ahead of  us to improve patient care.  Finally, it would be good to have access to high-throughput gear for examining protein-protein interactions.

4. What recent developments in the field have interested you most?

Top on my list is the recent elucidation of the crystal structure of FLCN’s C-terminus. That has given us a LOT of new ideas. Number two would be the Consortium’s first set of guidelines for clinical management, because these will help us to systematically study the clinical behaviour of BHD and to prospectively work out optimal patient management. The mouse data that have been published recently have also given me much to think about.

5. Do you have a favourite research paper?

Not a single one but a load of them. But if I do have to choose, my favourite BHD paper would be the 2007 paper by van Slegtenhorst et al looking at the S. Pombe ortholog of FLCN. It kind of contradicts much of the ideas that for a long time influenced much of the experimental work that was done in BHD and is now providing new inspiration for my group. My favourite biology paper of all time is the Watson& Crick paper – not for its contents per se but for the way it manages to condense a paradigm shift into a single page and end with a masterful understatement.

6. What are your short/long term goals?

My short-term goal is to get a clear sense of where to go with elucidating FLCN’s role in health and disease – there are conflicting insights at the moment. Working on that now. The long-term goal is to understand how FLCN mutations cause BHD and to be able to translate that insight into a drug-screening program and thence into the clinic. Even further down the road I want to understand why the skin tumours in BHD do not become malignant whereas the kidney tumours do. This is a mystery that contains a profound lesson about malignancy. To understand it, I think, will be to understand cancer.

7. How do you see the field developing in the next ten years?

We’ll probably make some real progress towards understanding BHD and be able to rationally look for/design medical interventions to prevent malignancies and to treat the outward manifestations. I’m also looking forward to some deep insights into the basics – how the network that FLCN is in functions to manage cell growth and proliferation. There’s some real biological subtlety there and I am going to thoroughly enjoy learning how it works. That, in turn, will help us to understand some other processes that are still mysterious – one being why people with BHD develop hair follicle tumours in their faces. Nobody knows or understands and that applies to related disorders such as tuberous sclerosis, too. There are profound lessons to be learnt and I think that we will learn some of them in the next ten years.

8. What’s your favourite book/film/music?

My favourite film is Paul Schrader’s Mishima and my fave book is the Ancestor’s tale, by Richard Dawkins. I am a musical omnivore so I find it difficult to give a definite favourite there, but if there has to be one it’s probably la Sonnerie de Sainte-Geneviève, a work by the French composer Marin Marais.

9. What did you want to be when you were younger?

A geneticist, so I did not end up too far from my childhood dreams – I count myself lucky.

10. Where do you see yourself in 10 years?

Hopefully leading a couple of thriving research groups working on the absolute cutting edge of my favourite themes. Not sure whether it’s going to be in Maastricht, I’ve had some interesting offers lately. But, generally, doing much the same as I am doing now but on a larger scale and hopefully with a very strong sense of direction.

11. What’s the best advice you’ve been given?

Don’t look back.

12. Do you have a scientific hero, dead or alive?

No real heroes but I do very much like Richard Dawkins for his rationality and passion for all there is to know and experience about life and the living.

[bhdlikes]

 

BHD Personal Story: Karen, who is from New Zealand.

1.   When did you first get diagnosed?

I was diagnosed with BHDS about two years ago.

2.   What symptoms prompted the BHD diagnosis?

I had pneumothoracies on both lungs and a family history of spontaneous pneumothorax (SPs) so enrolled in Dr Christine Garcia’s study of Familial spontaneous pneumothorax. Although my test results could not be disclosed to me, it was recommended that I discuss the link between SPs and BHDS with my family doctor. He then referred me to a dermatologist who confirmed the BHD diagnosis

3.   What impact did the diagnosis have on you?

It was a shock initially, especially reading about the increased risk of renal cancer. On the positive side, it was actually good to know why my family were having lung collapses when so many of us did not fit the usual profile for pneumothorax at all.

4.   Have you explained BHD to family members?

Yes, I explained the BHD to my immediate family, I have done online research, so I also sent copies of the information to my family. Spreading the information hasn’t been easy, my mother’s siblings were told and some did not want to inform their children until their own diagnosis was confirmed. This meant some family members knew and some didn’t. It was very difficult to manage and caused some ill feelings at the time. With all seven of them receiving positive test results, this is no longer an issue.

5.   What implications do you think it has it had on your family?

The full implications to my family are still uncertain as we have not all been screened yet. Those of us who have been diagnosed are undergoing renal and lung scans. Most of us are concerned about how widespread the syndrome is within our family. Of the nine screened so far we have had no negative results.

6.   Where did you go for more information on BHD Syndrome?

I have obtained most of my information from the internet. BHD is not well known within the general medical profession in New Zealand, and I have often found myself taking the educator role when speaking with doctors. I now go to BHD appointments armed with fact sheets.

7.   Do you have advice for people who are looking for a diagnosis?

I think if you are concerned that you have BHD it is best to seek diagnosis as quickly as possible. Although not a lot can be done about preventing symptoms, it is reassuring to have regular screening, then any treatment can be undertaken quickly.

8.   Has it affected you as a parent?  E.g. telling your children, starting a family, genetic counselling.

I have children in their early twenties, they have not yet sought diagnosis. I do worry about how it will affect them if they have BHD, will they consider the options when starting a family, will they experience collapsed lungs, will my beautiful daughter end up with fibrofolliculomas. There is a degree of guilt attached to passing something like this on to your children, and that is difficult.

9.   Do you have tips and advice for caregivers?

Be open and honest with your children, don’t over dramatise the syndrome, and help them work towards informed choices for their own health.

10. What are your current symptoms?

I have fibrofolliculomas on my face and upper torso. I also have lung cysts.

11.  What treatment are you having, and have you had?

I am not being treated currently. I have had pleurodesis and partial pleurectomies on both lungs.

12.  How did you find a doctor?

I do not have a doctor that looks after my BHD conditions, the general medical section of the local hospital has ensured that I have seen any specialist needed, and they are responsible for arranging regular renal screening for me.

13.   What has been your experience of the healthcare system and healthcare professionals?

One of the difficulties for me has been that in New Zealand the healthcare system is quite departmentalised with different specialists treating each aspect of the syndrome. But because BHD affects an unusual group of specialtities, renal, cardiothoracic and dermatology, there hasn’t been what I would see as a holistic approach to managing my health.

As I said earlier, BHD is not well known among healthcare professionals, however there is a greater awareness among younger professionals.

14.   Has BHD had any health insurance implications for you?

New Zealand has a public healthcare system, so I am able to get all the treatment I need free. However we can also top up our medical cover with private health insurance, this would no longer an option for me as my premiums would be loaded. The New Zealand public health system is renowned for having long waiting lists, but I have always had immediate treatment when I needed it.

15.   What are your thoughts for the future?

I am optimistic that my family will continue to have no incidence of renal tumours.

I am resigned to the fact that my face lumps will continue to get worse, but hopeful that in the future a way will be found to stop the symptoms of BHD.

16.   What advice would you give to someone who has just been diagnosed with BHD?

It probably isn’t as bad as you think at first. Find out everything you can about BHD and take good care of your general health and well being.

[bhdlikes]