June 2012

Professor Stéphane Richard and Sophie

BHD Researcher Interview: Professor Stéphane Richard is a leading authority on rare hereditary renal disorders. He is Professor at the École Pratique des Hautes Études and Director of the Laboratory of Oncogenetics at the Faculté de Médecine Paris-Sud and the Institut Gustave Roussy (INSERM U753). Professor Richard also directs PREDIR, the French National Expert Centre for rare renal cancer syndromes funded by INCa (Institut National du Cancer).

1. How did you get interested in BHD research?

I have been interested in both the fundamental and clinical aspects of inherited predispositions to renal cell cancer (RCC) since 1990. I was first in charge of French families affected with von Hippel-Lindau disease and organized a national network with Colleagues from all involved medical specialities and especially Urologists, Nephrologists and Uroradiologists like Prof. Arnaud Méjean, Prof. Jean-Michel Corréas and Prof. Dominique Joly. We progressively extended the network to other syndromes including Birt-Hogg-Dubé (BHD), then hereditary leiomyomatosis and renal cell carcinoma (HLRCC), hereditary papillary renal carcinoma (HPRC) and familial non-VHL clear-cell renal cell carcinoma (FcRCC).

I met the first BHD family in 1998 and we published the second molecular paper on BHD in 2002 with the team of Prof. Bin TEH (Van Andel Institute, Grand Rapids, USA), including four French families with FLCN germline mutations identified by Dr Sophie Giraud who introduced genetic testing immediately after the discovery of the gene. This work described for the first time the existence of potential phenocopies and also a close segregation between FLCN mutation and occurrence of colonic polyps (an association also described by Prof. Eamonn Maher but not found in US families) in a large French family with 10 affected members.

A close collaboration with Dermatologists including Dr Didier Bessis and Prof. Marie-Françoise Avril and Pneumologists was then established, and we showed in 2006 that BHD can be revealed by an isolated pneumothorax in infancy.

The French National Cancer Institute (”INCa”) and the Department of Health decided to create a few number of Expert National Center for Rare Cancers in 2009 and the PREDIR Center (www.predir.org) dedicated to all predispositions to kidney cancer was one of the first recognized and sponsored.

To date, there are about 40 BHD families followed in France including more than 120 clinically affected people but a number of patients are certainly not yet diagnosed.

2. What are you currently working on?

The Oncogenetics EPHE Lab works mainly on functional characterization of germline mutations in the main genes of RCC predispositions, searching for new potential genes and also molecular analysis of renal tumor.  Dr Sophie Gad who previously described somatic FLCN mutation in sporadic chromophobe RCC in 2007 and Dr S. Couvé are currently working on a number of novel missense FLCN mutations identified by our two genetic testing Labs (Dr Sophie Giraud in Lyon and Dr Nadem Soufir in Paris) in patients with demonstrative clinical BHD or in patients with sporadic renal tumors.

As this type of mutations is very rare in BHD (most mutations leading to truncated proteins), it is imperative to demonstrate they are really pathogenic. We previously eliminated potential polymorphisms and our project is to functionally characterize all variants in order to demonstrate their deleterious character, thanks to a generous grant recently obtained from the Myrovlytis Trust. Briefly, we will reintroduce the FLCN sequence containing the missense variants in a FLCN-/- cell line derived from a renal cancer from a BHD patient and will measure the impact of missense variants at both protein and cellular levels. We think that this project can also lead to gain insights into the relationships between FLCN missense mutations and folliculin function.

On a clinical point of view, Prof. Arnaud Méjean has a very large experience of conservative renal surgery and Prof Jean-Michel Corréas has recently successfully introduced the use of radiofrequency ablation for renal tumors when possible, as it was previously made for VHL disease.

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

We have collected a number of frozen RCC of different histological subtype from BHD patients and we think that exome sequencing would be useful for characterization of molecular events occurring after FLCN inactivation but this technique is not yet available in our Institution.

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

Of course, the demonstration that FLCN is mainly (but not exclusively) involved in the regulation of mTOR pathway was exciting as specific inhibitors already exist and are well-known. Such mTOR-inhibitors are now used in metastatic sporadic RCC refractory to inhibitors of VEGF receptors signaling and could be useful in BHD patients. On the other hand, a clinical trial evaluating topical rapamycin for cutaneous lesions of BHD is in progress under the direction of Prof. Maurice Van Steensel in Maastricht.

5. Do you have a favourite research paper?

I was very impressed by the paper from Baba et al. (2008) reporting on the development of a FLCN kidney-specific knockout model in mice. This is a great contribution to future understanding of renal tumorigenesis and evaluation of targeted therapies.

6. What are your short/long-term goals?

Renal carcinoma is the most potential threatening complication of BHD in spite it is very less frequent than in VHL disease (20% in our series). Of course we would like to understand why BHD patients are predisposed or not to the development of renal tumors in the same family (modifier genes?). In addition, a very intriguing and unique feature is the occurrence of various types of renal tumors (chromophobe RCC, oncocytomas, hybrid tumors but also sometimes papillary RCC, clear-cell RCC or mixed patterns) and we would like to better characterize them at molecular level. We also wish to investigate if the occurrence of extra-renal tumors that have been described in some patients is really linked to BHD or is only a coincidence.

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

I think the role of FLCN will be more and more understood and the discovery of all partners and physiological functions may lead to effective specific targeted therapies in the next ten years.

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

Unfortunately, I don’t have enough time any more for reading (except for medical and scientific journals) but, as many French people, I like very much “The Count of Monte Cristo” by Alexandre Dumas that is one of our most famous novels.

There are a number of films I love including great classics like ”Gone with the Wind”, ”North By Northwest” but also the sagas “The Godfather” and “Star wars”.

I like many styles of music but my favourite one is the blues with great guitarists like B.B. King or Eric Clapton (my son is a very good guitarist and would dream to enter the Berklee College of Music in Boston…). One great pleasure would be to go to New Orleans for the Zydeco festival, a unique style of music that combines blues, Cajun and Creole music with French lyrics.

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

I wished to be a great sportsman and hoped to attend the Olympic games (“discus throw”) but I stayed only to a national level. I was certainly more “gifted” for Medicine and I think I am now more useful!

10. Where do you see yourself in 10 years?

I will be close to retirement…but I hope to be still active in cancer research in participating in non-profit organizations and patients associations.

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

Certainly the sentence of my past boss Prof. J.F. Foncin (a great neurogeneticist) “don’t pay them any attention and go on!” when I wanted to work on rare cancer predispositions in 1989, after some great physicians told me: “these affections are without interest…”.

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

Marie Curie, the great French physicist and chemist who obtained two Nobel Prizes.


BHD Personal Story: Sophie is from France and was diagnosed with BHD earlier this year. Sophie’s interview in available in both French and English.

1. Quand et comment avez-vous reçu le diagnostic? / When and how did you first get diagnosed?

J’ai eu confirmation des tests génétiques en janvier 2012. J’ai été reçu par le conseiller en génétique, le docteur en génétique ainsi que par la psychologue.

I had confirmation from the genetic tests in January 2012. I have been seen by the genetic counselor, the clinical geneticist as well as by the psychologist.

2. Quels symptômes ont indiqué le diagnostic du syndrome de BHD? / What symptoms prompted the BHD diagnosis?

Quelques symptômes dermatologiques et une énorme fragilité dentaire (mes dents cassent comme du verre)

A few dermatological symptoms and severe dental weakness (my teeth break like glass).

3. Comment avez-vous réagi à l’annonce du diagnostic ? / What impact did the diagnosis have on you?

En fait, je m’était tellement préparé psychologiquement à la possibilité d’être atteint de BHD que je n’ai pas été surprise. De plus, j’avais bien constaté des changements de ma peau et étudié via internet les symptômes de la maladie.

L’arbre généalogique des maladies familiales m’a fait voir tellement de similitudes et d’évidences !!!

In fact, I had prepared myself so much psychologically for the possibility that I might have BHD that I was not surprised. Additionally, I had closely observed the changes in my skin and studied the symptoms of the condition online.

The family tree showing hereditary diseases made me see so many similarities and so much evidence!!!

4. Avez-vous parlé du syndrome de BHD aux membres de votre famille? / Have you explained BHD to family members?

Oui, avec mon mari, ma mère, mon frère et ma sœur qui n’avaient pas encore consulté. Le BHD vient de la branche paternelle et mon père est décédé il y a 7 ans d’un cancer rénal métastasé. Toute la famille a fait corps autours de moi !

Par contre, je n’ai dit que le minimum à mes enfants (16 et 14 ans). Je n’ai jamais prononcé le mot cancer devant eux !

Yes, with my husband, my mother, my brother and my sister who have not yet gone to a doctor. BHD comes from the paternal side and my father passed away 7 years ago from metastasized renal cancer. The whole family has gathered around me!

On the other hand, I haven’t said anything more than the minimum to my children (16 and 14 years old). I haven’t ever said the word ‘cancer’ in front of them!

5. Quels effets pensez-vous le diagnostic a eus sur votre famille? / What implications do you think the diagnosis has had on your family?

La peur, je crois a fait place à l’incrédulité…

Fear I think has given place to disbelief…

6. Où avez-vous cherché pour avoir plus d’infos sur le syndrome de BHD? / Where did you go for more information on BHD syndrome?

Orphanet et votre site !!

Orphanet and your site !!

7. Avez-vous du conseil pour des personnes qui sont en recherche d’un diagnostic? / Do you have advice for people who are looking for a diagnosis?

Carpe diem

8. Si vous avez des enfants, le syndrome de BHD a-t-il eu des effets sur vous en tant que parent ? Par exemple : parler de BHD aux enfants, fonder une famille, le conseil génétique. / If you have children, has BHD affected you as a parent?  E.g. telling your children, starting a family, genetic counselling.

Le plus difficile à vivre pour une maman de 2 enfants adolescents. Un énorme sentiment de culpabilité…la peur pour eux. En France aucune possibilité de faire diagnostiquer les enfants avant leur majorité. De fait, je vis avec la peur au ventre jusqu’à leurs 18 ans !!

This is the most difficult thing to live with for a mother of 2 teenage children. A huge sense of guilt…fear for them. In France, there is no possibility of testing children as long as they are minors. And so, I live with fear in the pit of my stomach until they are 18!

9. Avez-vous du conseil pour des aides-soignants? / Do you have any tips and advice for caregivers?

Rester humain.

To stay human.

10. Quels sont vos symptômes maintenant? / What are your current symptoms?

Simplement des symptômes cutanés.

Only the skin symptoms.

11. Quels traitements recevez-vous? Quels traitements avez-vous reçus? / What treatment are you having, and have you had?

Je passe des analyses de tous genres : IRM poumons + reins. Radio pulmonaire. Coloscopie. Dermatologue, endocrinologue…tous les résultats seront envoyés au généticien qui suit mon dossier. Ce suivi sera annuel.

I’m going through all sorts of tests : lung and kidney MRI. Chest x-ray. Colonoscopy. The dermatologist, endocrinologist…all the results will be sent to the clinical geneticist who will follow my case. This follow-up will be annual.

12. Comment avez-vous trouvé un médecin? / How did you find a doctor?

Je suis passé par mon médecin traitant qui m’a fait un courrier pour un généticien de ma région. Je suis son premier BHD. Tout comme les autres médecins rencontrés. Le second généticien qui a mis en place le suivi médical m’a dit que je suis son second cas.

I went through my GP who referred me to a geneticist in my region. I am his first BHD. Just like the other doctors I’ve met. The second geneticist who arranged my medical follow-up told me that I am his second case.

13. D’après votre expérience, comment avez-vous trouvé le système de santé et les professionnels de la santé? / What has been your experience of the healthcare system and healthcare professionals?

Je rencontre de nombreux spécialistes et sur le nombre, un seul connaissait un cas similaire. Les internes de médecine viennent souvent frapper à la porte des médecins que je consulte pour voir « la dame qui a le BHD ». Cette maladie rare attire les curieux et je me prête gentiment au jeu.

I meet many specialists and among them, only one knew a similar case. The residents often come knocking on the doors of the doctors I see, to have a look at “the lady who has BHD”. This rare disease attracts the curious and I kindly take part in the game.

14. Le diagnostic de BHD a-t-il eu des effets sur votre assurance maladie? / Has BHD had any health insurance implications for you?

Le système de santé français est formidable : Mon médecin généraliste a fait une demande de prise en charge à 100% pour tous les actes médicaux liés au BHD. J’ai été convoqué par un médecin conseil car j’étais son premier cas BHD. Nous avons beaucoup parlé et il s’était renseigné sur cette maladie. Tous les frais liés à cette maladie sont donc pris en charge. Quel soulagement.

The French health system is great : my GP asked for 100% coverage of all the medical procedures linked to BHD. I had been called by a medical consultant because I was his first BHD case. We talked a lot and he learned about this disease. So all the costs linked with this disease are covered. What a relief.

15. Que pensez-vous de l’avenir? / What are your thoughts for the future?

Je ne crains pas l’avenir et me dis que je gagnerai toutes les batailles car je suis quelqu’un d’optimiste. J’ai seulement peur pour mes enfants et j’espère que la science fera d’immenses progrès.

I don’t fear the future and I tell myself that I will win all the battles because I am an optimist. I only fear for my children and I hope that science will make tremendous progress.

16. Quels conseils donneriez-vous à quelqu’un qui vient de recevoir le diagnostic du syndrome de BHD? / What advice would you give to someone who has just been diagnosed with BHD?

Ne pas rester seul avec ses questions ! Trouver comme moi du réconfort auprès de site comme le votre. Et encore une fois rester optimiste !!

To not remain alone with their questions! To find comfort, like me, in a site like yours! And one more time, to stay optimistic!