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Schwannomatosis is the rarest form of neurofibromatosis (NF), affecting an estimated 1:40,000 people, and it causes tumors to grow on peripheral nerves as well as severe and unmanageable pain.  It has also been the most mysterious form of NF, both in terms of accurate clinical diagnosis and in terms of understanding its biology and genetics.

In 2005, the Children's Tumor Foundation spearheaded the publication of the first diagnostic criteria for schwannomatosis.  In those initial critieria, it was stated that if a person had one or two vestibular schwannomas  (tumors on the 8th cranial nerve in the brain) then this would exclude a diagnosis of schwannomatosis and indicate a diagnosis of NF2.  In 2007,  the first candidate gene for schwannomatosis - INI1/SmarcB1/Snf5 - was identified, and though this gene does not appear to be universally involved in all cases of schwannomatosis, it has aided in the diagnosis of the disorder and in researching its molecular basis. 

Now a team led by Dr. D. Gareth Evans (University of Manchester) reports in the American Journal of Medical Genetics on two people each presenting with a unilateral (single) vestibular tumor as well as peripheral nerve tumors but for whom a diagnosis of NF2 has been eliminated through clinical or genetic evaluation.  This is an important finding, and suggests that there may be other cases elsewhere that have previously been diagnosed as NF2 that are in fact schwannomatosis.

The Children's Tumor Foundation has made significant contributions to advancing schwannomatosis research through grant funding, including establishing the first Schwannomatosis International Database, as well as organizing a series of International Schwannomatosis Workshops to spur collaboration.  In December, we'll be announcing some newly funded schwannomatosis research projects and unveiling future plans for our continued commitment to advancing this research area.

                As neurofibromatosis clinical trials increase in number, the clinicians leading them are keen to design the trials to be as effective and meaningful as possible. A key part of this effort is developing the right trial endpoints - measures and metrics that can be used to determine if a drug or intervention is effective or not.  To tackle this area, a team of neurofibromatosis clinicians and researchers has formed  a working group called Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS). Spearheaded by Dr. Scott Plotkin (MGH) and Dr. Brigitte Widemann (NCI) and first convened in June at the Children’s Tumor Foundation 2011 NF Conference, around 30 leading NF clinicans and researchers participating in the REiNS met in Boston to continue their planning and discussions.

                Past endpoints for neurofibromatosis clinical trials have included changes in maximum tumor dimension on MRI scans or changes in cognitive function on neuropsychological assessment (for learning disabilities).  Looking ahead, more advanced endpoints under discussion (and already being piloted in some cases) include volumetric tumor analysis and whole body MRIs; and the use of biomarkers – biological indicators in the blood or other body fluids to determine if a drug is working. REiNS members have organized into groups to focus on different measures and plan to meet every few months to continue advancing this project.

                The Children’s Tumor Foundation is delighted to be investing in endpoint development through our Clinical Research Awards program.  Currently our funded projects include developing a computerized test for more accurate assessment of learning disabilities trials; identifying a blood biomarker of NF1 status; and developing measures of response for optic pathway glioma trials. We will be announcing more funded awards in early 2012. 

                Clinicians or researchers interested in participating in REiNS can contact Vanessa Merker at MGH: vmerker@partners.org. 

The following was written by CTF Chief Scientific Officer Dr. Kim Hunter-Schaedle:

Earlier this week the Children’s Tumor Foundation hosted a workshop/think tank convening 25 international researchers and clinicians to review recent progress in schwannomatosis research and clinical management, and set priorities to advance future progress. The meeting was planned and chaired by Dr. Scott Plotkin (Harvard/MGH), Dr. Marco Giovannini (House Research Institute) and Dr. Gareth Evans (University of Manchester) and included updates on genetics, cell biology, surgical intervention and the potential of advancing to clinical drug therapies for schwannomatosis, the rarest form of neurofibromatosis affecting an estimated 1:40,000 persons.

In part through CTF funded projects, significant progress has been made since the gene SMARCB1 (also known as INI-1) was in 2007 identified as a causal factor in inherited schwannomatosis.  Researchers have further unraveled the genetics of schwannomatosis, and learned that while SMARCB1 is important in inherited cases of schwannomatosis, this disease onset also involves the NF2 gene; and that in spontaneous (non-inherited) cases, SMARCB1 is not necessarily involved but that there are as yet unidentified genes involved.   The first mouse models of schwannomatosis tumors and pain are now developed and being used to study tumor and pain biology and test drug therapies.  And an international schwannomatosis database is established to collect information on schwannomatosis patients worldwide and facilitate future research projects and clinical trials.

At the workshop a series of priorities for the future was identified. There is a need to identify the additional genes and genetic modifiers that may be involved in interacting with the SMARCB1 or NF2 genes to lead to schwannomatosis. There is a need to develop more refined mouse models that represent schwannomatosis seen in humans as closely as possible, so that these can be used to study biology and tumor growth/pain and to test candidate drug treatments.  The biology and mechanisms of pain - which is such a central and poorly understood element of schwannomatosis - need to be unraveled and understood.  In terms of candidate drug therapies, it is rational to look at those drugs that are showing promise in mouse models of NF2 tumors, and see if they have impact on the tumors in mouse models of schwannomatosis.

Very importantly, now that we have a patient database, there is a need to plan clinical research studies to better understand schwannomatosis, such as understanding how individual patients condition has progressed following surgery, especially multiple surgeries; identifying whether there are blood-based or other biomarkers of schwannomatosis; and developing a pain survey for patients to better define the type and range of pain seen in schwannomatosis.; and looking ahead, prospective studies monitoring patients from time of diagnosis ongoing such as by whole body MRI. It is considered to be premature to consider clinical trials for schwannomatosis as we don’t have sufficient knowledge to do this; but that for patients in states of extreme crisis, there is the potential to begin testing drugs such as bevacizumab (Avastin) that have shown promise in NF2 patients.

Finally the clinical diagnostic guidelines for schwannomatosis were published in 2005 and the group reviewed these and made some recommendations to update these based on new genetics and clinical knowledge.

As a follow up to this workshop CTF will be spearheading the publication of a meeting report summarizing the latest update and recommendations for schwannomatosis. Also – in the next month – CTF will be releasing a Request for Applications to fund further schwannomatosis research.  After this great meeting we look forward to seeing further research progress.

On June 27th-28th the Children's Tumor Foundation is convening a Schwannomatosis Workshop (think tank) in Los Angeles. International expert researchers and clinicians will review the most recent findings in schwannomatosis research and clinical care, share progress and chart the future path to improving care and finding effective treatments for schwannomatosis.  I look forward to reporting the outcome of  the next 2 days of meetings. Below is a preview to set the stage.

I'll be staying in LA for the remainder of the week to attend the Acoustic Neuroma 2011 Meeting which includes a lot of NF2-relevant presentations, and will be reporting on that later in the week too. 
Schwannomatosis is the most rare form of neurofibromatosis affecting an estimated 1:40,000 persons. It causes the growth of multiple peripheral nerve tunors called schwannomas, and in addition it causes chronic, severe and unmanageable pain. There are no treatments for this. For a long time schwannomatosis was not well understood and in fact the first guidelines for its clinical diagnosis were not published until 2005.  A breakthrough came in 2007 with the publication of the first candidate schwannomatosis gene, INI-1/SmarcB1/Snf5. This gene has emerged to be a key player in schwannomatosis but interestingly there may also be involvement of the NF2 gene in the onset and progression of schwannomatosis. Schwannomatosis research faces added challenges as there are so few patients, so to accelerate progress CTF has brought this community of researchers and clinicians together since 2007 for a series of think tanks and they have shared and collaborated extensively with each other. CTF has been a major force in advancing schwannomatosis research in the past 4 years since the candidate gene was identified. In addition to hosting the think tanks, CTF has invested more than $700,000 in schwannomatosis research in this period. Projects we have funded include the creation of a schwannomatosis patient database now up and running;  the creation of the first 2 mouse models of schwannomatosis, both of which are now  being utilized for preclinical drug testing to reduce tumor growth and pain; and further genetics studies. Look for updates from the schwannomatosis think tank in the next day or so!

Ed note: During May, NF Awareness Month, we will be posting stories of individuals and families living with and overcoming the challenges of NF.  If you'd like your story to be featured please email ggleeson@ctf.org with an article of approximately 500 words, and your picture (or your family's picture). If you like this story please share it with your friends and family via email, Facebook, Twitter etc.  To help spread awareness this month we are also introducing the tagline "Help make NF Not Forever'" and the Twitter hashtag #NotForever, together we can do wonderful things to promote NF awareness and research, thank you for your commitment to the cause. 

Hi my name is Aaron, I am going to talk about my experiences living with NF.

I was diagnosed with NF when I was about 3 years old. The way NF affects me is mainly from scoliosis, my spine has two curves. I had a spinal fusion when I was 8 on the upper curvature. I have several neurofibromas on my chest and back, but they don’t really cause problems, apart from a large plexiform on the side of my trunk. I am also dyslexic, so needless to say primary School was an interesting experience! 

The problems I have experienced with NF are both medical and personal.

Since the spinal fusion I hadn’t had any issues with NF until 2004 when I started to experience chronic lower back pain. I went to my GP who prescribed some meds for me, but the pain didn’t go away. Fearing there could have been a change in my scoliosis and the fact I hadn’t seen him for over 10 years I decided to see my orthopaedic surgeon.  He concluded that there were no new issues with the scoliosis and that because of the curvature I would be more prone to back pain.

Then I went to a neurologist because I hadn’t seen one since I was a teenager. I had an MRI which showed no Neurofibromas on my spine.

I was then referred to a new doctor.  He said that eventually the lower back would need surgery too but it would be 20 or 30 years down the line. He suggested that pain management was the best solution. The pain specialist recommended an epidural injection containing a slow release pain medication.

Today between the injections and Meds the pain level is under control, unless I’m up dancing half the night.

On a personal level NF has affected me too.

Even though anti-discrimination laws exist in my experience some employers still don’t treat people with medical problems the same as “normal” people.

I have gone for lots of interviews in the past for jobs that I could do. I am not saying every job I have never gotten was only because I have NF. But some employers only see the small guy with the hump on his back and not the potential I would bring to their business.

Another aspect in which NF has affected me is the difficulty in meeting a partner or the way people stare at me.

We live in a very materialistic world where image and look are more important than honesty and integrity.

I’m not going say that “Being Different” doesn’t leave me feeling a little blue at times.

There are times when I wonder what my life would have been like if I didn’t have NF.

What job would I be doing?

Where in the world would I be living?

Would I still be single?

These are all questions that I will never have the answers to.  I came to terms with having NF a long time ago, I just wonder sometimes. 

When I look in the mirror I like the person I see and I think most the world does too.

Having NF hasn’t stopped me doing some of the things I love.

I believe there is a plan for everyone and I have faith that things will be alright in the end.