A New Specialist Joins the NF Clinic Team, Upcoming NF Symposium at UAB, and Understanding RAS Disorders and their Relationship to NF

As I mentioned in the previous blog, we are pleased to announce the addition of Dr. Ashley Cannon, a genetic counselor and clinical researcher, to our team of specialists in the UAB NF Clinic.  With a unique and diverse background that includes a Ph.D. in neuroscience and a degree in genetic counseling (completed at UAB), Dr. Cannon brings a range of capabilities that will further enhance both patient care and clinical research.  She will play an integral role in seeing patients in the clinic, helping to identify the needs of individual patients, organizing genetic testing, and providing genetic counseling. In addition, Dr. Cannon will serve a key role in coordinating clinical trials and research studies conducted in the NF research program.  I have also asked her to begin the process of establishing our community advisory board, which will be comprised of NF patients and family members who will provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets their needs.

Currently, Dr. Cannon is assisting with final preparations for the upcoming Neurofibromatosis Symposium to be held at the Finley Conference Center in the Kaul Human Genetics Building on Saturday, August 29th.  Co-sponsored by UAB and the Children’s Tumor Foundation (CTF), this half-day, free event is designed to provide NF patients and their families with information about a range of NF-related topics including:  an overview of neurofibromatosis; updates on clinical trials and other research advances; genetic counseling and the NF registry; pain management; a patient and family roundtable discussion; advocacy, fundraising, and upcoming events in the NF community; and a question-and-answer session.  Breakfast, lunch, and childcare will be provided for the convenience of our families.  While there is no cost to attend, reservations should be made by August 24th by emailing acannon@uab.edu. This is an invaluable opportunity for NF patients and families – especially those facing a new diagnosis – to gain information, support, and answers to questions about neurofibromatosis. Each year, we look forward to serving NF patients and their families through this important forum that not only provides key information about NF but also offers the opportunity for NF families to gain understanding and strength through sharing their experiences, challenges, and concerns.

Neurofibromatosis Symposium: Family Day 2015

Saturday, August 29th, 2015


08:00-08:30am                       Register/Breakfast

08:30-10:00am                       Welcome/NF 101/Updates – Dr. Bruce Korf                                            

10:00-10:30am                       Break

10:30-11:00am                       Clinical Trials Update – Dr. Alyssa Reddy

11:00-11:30am                       Research Studies – Ashley Turner

11:30-12:00pm                       Counseling Issues/Registry – Ashley Cannon

12:00-12:30pm                       Pain Management – Dr. James Weisberg

12:30-01:30pm                       Lunch / Patient and Family Roundtable

01:30-02:00pm                       Advocacy, Fundraising, Upcoming Events – Renie Moss

On July 17th- 19th, I attended the 4th International RASopathies Symposium in Seattle, Washington.  The RASopathies are a group of medical genetic syndromes, including NF1, that have in common the fact that their underlying genetic alterations occur in a critical cellular signaling pathway called the RAS/MAPK pathway.  Neurofibromatosis type 1 is caused by a genetic alteration in the gene that encodes for neurofibromin, a protein regulating activity of the RAS signaling pathway that also has a role in cell growth and division. As in NF1, the RAS pathway can be disturbed in a host of other syndromes including Noonan syndrome, cardiofaciocutaneous (CFC) syndrome, Legius syndrome, and Costello syndrome. All RASopathy syndromes affect multiple systems of the body; features such as cardiac disease, growth deficits, facial characteristics, bone and skin abnormalities, and learning and behavior problems are common. However, as with NF1, the presence and severity of these features varies widely among affected individuals.

The purpose of the RASopathies Symposium is to bring together scientists, clinicians, researchers, and affected families to facilitate a collaborative discussion focused on future research, development of therapies, and best clinical practices for RAS/MAPK pathway syndromes.  Because NF1 was the first RASopathy to be identified, we in the NF scientific community are much further along than the other related syndromes in our capability to develop clinical trials focused on mechanism-based therapies. This is due in part to the fact that we’ve known about NF1 for a longer period of time and also because it is easier to define what success would look like in an NF patient.  It is encouraging that the development of mechanism-based therapies that inhibit the over-activated RAS pathway and other RAS-connected pathways opens new avenues of therapeutic intervention for the many complications of the RAS disorders. Because neurofibromatosis has been a beacon in the realm of mechanism-based therapeutics, other RAS disorders are looking to the NF scientific community for examples in the development of effective treatments; we’re certainly hopeful that we can share valuable information based on our experience with NF and that this shared knowledge will facilitate research that will benefit those with the various RAS disorders.     

Understanding Possible Explanations for Isolated Features of NF

Frequently I receive questions, through both e-mails and individuals who are referred to my office, regarding patients who have one isolated feature of NF but do not have a confirmed diagnosis of neurofibromatosis. These isolated features most often occur in the form of either plexiform neurofibromas or optic gliomas, although they sometimes may include dermal neurofibromas or bone dysplasia.  It is important to know that isolated features of NF can occasionally been seen in both children and adults who do not actually have the condition.  I’d like to give a brief overview of how we evaluate patients with only one isolated feature of NF in the absence of other symptoms and provide some possible explanations of why this phenomenon may occur.

Some individuals develop plexiform neurofibromas – tumors that involve multiple branches of large nerves – in one isolated area of the body, such as the spine, with no other features of NF. The age of presentation varies, but it usually begins from the teenage years into adulthood, as the symptoms of a plexiform neurofibroma do not become apparent until adolescence.  Isolated optic gliomas, tumors of the optic nerve, can also occur in children and adults who have no other features of NF. Unlike isolated plexiform neurofibromas, optic gliomas that occur in individuals who do not have NF are typically more aggressive tumors than those found in people who have neurofibromatosis.  Some individuals also develop isolated dermal neurofibromas or bone dysplasia in the absence of other NF features and with no confirmed diagnosis of neurofibromatosis.

When we see someone in our clinic with an isolated feature of NF, we provide a comprehensive evaluation to make certain that subtle features of the condition are not present. In some cases, if possible, we obtain a tissue sample of the tumor, although this is often difficult due to the location of tumors, such as plexiform neurofibromas deep inside the body.  Sometimes we obtain a blood sample for genetic testing; however, a negative result does not necessarily confirm that an individual does not have NF. 

There are at least three possible explanations for the occurrence of isolated NF features in some individuals.  The first is mosaicism, caused by a mutation in the NF1 gene that occurs early in embryonic development and that only affects certain cells in the body.  As a result,  individuals with mosaicism have features of NF1 that are limited to only one part of their body, such as neurofibromas or café-au-lait spots in a certain region. The only method of confirming mosaicism is to biopsy the lesion and do genetic testing on the tissue.  A second possible explanation for the occurrence of isolated features of NF is that there could be other, still unknown mechanisms that cause tumors that occur in people with NF to also occur in individuals who do not have the condition. 

A third possible explanation is related to the specific “two-hit” genetic mechanism that causes the development of tumors in people with NF1.  All persons have two copies of the gene, one inherited from each parent.  In individuals with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the mutated gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development.  This represents the “first-hit” genetic mutation.  For a neurofibroma to develop in someone with NF1, a random genetic mutation must occur to the other copy of the NF1 gene in the tissue that will become the neurofibroma, café-au-lait spot, or other lesion; this is referred to as the “second-hit” mutation.  Although an extremely rare occurrence, it is also possible for some individuals to acquire two random NF mutations, affecting each inherited copy of the NF1 gene, in a cell that could become a neurofibroma or other lesion.  This two-hit mutation – similar to lightning striking twice in the same place – could result in the development of an isolated feature of NF in the absence of other signs of the condition.

On another topic, there are two things to report regarding the UAB NF Program.  First, Dr. Ashley Cannon has joined the program as genetic counselor and clinical research coordinator.  Dr. Cannon has unique training both as a neuroscientist and genetic counselor; she will be seeing patients with me in clinic and also involved in many of our research studies and clinical trials.  Second, we will be hosting our annual NF Symposium this summer on Saturday, August 29.  As in the past, the focus will be on educating patients and families about NF and highlighting research progress.  We have assembled a group of speakers both from UAB and from the Children’s Tumor Foundation who will participate.  If interested in knowing more about the symposium please contact Dr. Cannon at acannon@uab.edu. We look forward to seeing as many families as possible at this event!

Responding to E-mailed Questions from Patients and Reviewing Diagnostic Criteria for Café-Au-Lait Spots and Groin Freckling

On an almost daily basis, I receive e-mails from people in all parts of the U.S. and other countries asking clinical questions about NF.  Most of the time, individuals who e-mail me have run across my name on social networking sites, such as a discussion board or a chat room devoted to the topic of NF.  There is a robust network of NF-related discussion forums on the Internet, and they can serve as a valuable resource for patients and families in locating specialists who can provide a definitive diagnosis and treatment plan. In this blog, I’d like to address the general principles I follow in replying to patients’ questions via e-mail. 

Because most of the people who contact me have questions about clinical features that might indicate NF – or they have already received a diagnosis and need a plan of treatment – my primary goal is to connect them with a qualified specialist in their area whenever possible, and I always stress in my response the importance of identifying a trusted clinician in the region.  Fortunately, specialists can be found relatively easily in most major U.S. cities.  For patients and families seeking assistance in locating a specialist, the Children’s Tumor Foundation (www.ctf.org) web site features a patient information tab that provides a list of specialists within the U.S.

However, finding a qualified NF specialist often can be challenging, especially for people in other countries.  In many regions of the U.S., and in many other countries, there is not ready access to NF specialists, and some physicians with the clinical knowledge to make an NF diagnosis may lack experience in managing complications and developing a treatment plan.  For these reasons, NF-related discussion boards and chat rooms have proven to be a valuable resource for patients and families seeking information and guidance.

Because I understand the importance of helping people gain access to accurate information about NF, I’m always glad to respond to any e-mailed questions I receive and consider it a privilege to communicate with patients who have NF-related concerns. However, I can’t provide specific medical advice to people whom I have not personally examined and whose records I have not reviewed.  Many people who e-mail me often attach photos, for example of café-au-lait spots, usually taken with a cell phone. Most of these photos are difficult to interpret, and it’s important not to give advice based on the limited information provided in an e-mail or photo. Instead, I focus on providing general information about NF that is not specific to their situation – perhaps about the value of genetic testing or a review of different treatment approaches.

Regarding the numerous e-mailed questions I receive asking if a child with café-au-lait spots has NF, the majority describe children in whom a diagnosis of NF is not obvious.  Parents of these children are usually distraught about the possibility of NF based on the presence café-au-lait spots, which may have been noticed by a pediatrician or other clinician.  Frequently, I have the impression that most are healthy children with a few spots that don’t fulfill the diagnostic criteria requiring six or more café-au-lait spots.  It is important to note that the vast majority of people with NF1 have this number of café-au-lait spots or more.  Sometimes, infants can develop café-au-lait spots, but café-au-lait spots usually begin to appear in the first few weeks of life.  By two years of age, a child with NF will have at least six café-au-lait spots, if they ever will.  It’s important to note that a young child with six or more café-au-lait spots that are clear usually will have NF1 that can be confirmed with genetic testing.  In my clinical experience, many children with between one and three spots usually don’t have NF.

There are some people with variant forms of NF who have fewer than six café-au-lait spots.  Some of these individuals develop internal neurofibromas, but have few visible on the skin.  Legius Syndrome is another condition that causes café-au-lait spots, although these individuals do not develop tumors; this is a benign condition that is much more rare than NF1, and genetic testing is required to confirm it.  Also, there are other conditions that can produce café-au-lait spots, though most are rare.  It should also be noted that some healthy people can have up to six spots with no other symptoms.

Freckling in the groin and under the arms is another feature used to confirm an NF1 diagnosis. While some parents may worry based on the presence of a few small freckles in these regions, it’s important to note that NF-related freckling appears between three and five years of age.  Instead of a few tiny freckles in these regions, there are usually many freckles in the region, as if paint were spattered from a paint brush.  Also, a café-au-lait spot that happens to appear under the arm or in the groin does not count as a skin fold freckle.

Because NF-related features such as café-au-lait spots and groin and underarm freckling are sometimes over-interpreted and often a source of unnecessary anxiety, it’s important to identify an experienced clinician who can make a recommendation about diagnosis and the use of genetic testing for NF based on the presence of specific clinical criteria. My continued objective in responding to e-mailed questions is to provide patients with accurate information about NF and assist them in identifying an experienced, trusted clinician who can provide additional information and guidance.