Highlights of CDMRP Meetings

At the beginning of March, I spent a day in Washington, DC, meeting with congressional legislative aids to discuss the importance of continued NF research funding for the Congressionally Directed Medical Research Programs (CDMRP).  The CDMRP was established in 1992 to support novel approaches in biomedical research to benefit the American public and the military.  The program is funded by the Department of Defense (DoD) through the annual Defense Appropriations Act.  However, funds for the program are not included in the DoD’s annual budget and must instead be renewed each year during the congressional budget approval cycle based on response to requests by consumer advocates and those affected by the condition. Our primary purpose in meeting with congressional aids was to explain the relevance and impact of NF research and the need for a continued investment that will lead to breakthrough treatments and improvements in patient care.

In addition to neurofibromatosis research, a wide range of biomedical research projects are funded by the CDMRP, including breast and ovarian cancer, autism, multiple sclerosis, and spinal cord injury, to name only a few.  We emphasized during our meetings that NF research has implications for bone and wound healing, medical issues important to the military.  Also, we discussed the fact that NF genetics research is yielding information that is applicable to several other areas of medicine. For example, it has been established that the NF1 gene is one of the most commonly altered genes in cancer.  Some may wonder if these research projects could be funded through the National Institutes of Health (NIH), the nation’s largest government-funded medical research agency.  While the NIH does fund important basic and translational research relevant to NF, it’s difficult for the NIH to direct funding to a specific condition, as the CDMRP has the flexibility to do. In fact, a hallmark of the CDMRP is filling critical research gaps by funding high-impact projects that would be not be feasible for other agencies. For example, the NF Clinical Trials Consortium –  funded by a grant that integrates research at more than 17 sites coordinated by UAB – was developed 10 years ago in response to a funding need identified by the CDMRP for NF-related clinical trials.  In this way, the CDMRP complements the work of the NIH by filling a critical niche.  We found the congressional aids with whom we met to be supportive of continued NF funding for the CDMRP primarily because the program has a substantial return on investment. It also has the unique capability to leverage funds for high-impact research that might not otherwise receive needed support.

NF Neck Examination

Continuing our discussion about what to expect during an NF exam, I’d like to discuss issues that may be identified during a neck examination.  The most common feature we look for on the neck is neurofibromas, benign nerve sheath tumors that appear on or under the skin. In children, neurofibromas can be sometimes difficult to distinguish from lymph nodes, which can usually be palpated in the neck; however, an experienced NF clinician can usually make this distinction.

Plexiform neurofibromas, which involve large branches of multiple nerves, can cause significant problems in the neck. In some people, they grow aggressively and can compress the airway and other structures in the neck.  While it is possible for plexiform neurofibromas to encase the carotid artery and jugular vein, usually the blood flow is unimpaired.

Another problem associated with plexiform neurofibromas in the neck is possible compression of the spinal nerves as they exit the spinal cord, causing pain or weakness in one or both arms.  For this reason, an NF exam should include monitoring of patients for pain and neurologic function in the arms.  It’s also possible for plexiform neurofibromas to grow into the vertebral foramen, the gap between vertebral bones where nerve roots connect to the spinal cord.  Surgical removal is the only treatment option for plexiform neurofibromas, which can be difficult in the neck due to the risk of damage to vessels and nerves that could cause serious bleeding and other problems. Because of these significant risks, we reserve surgery for critical cases in which important structures in the neck are affected.  

Some people with NF develop narrowing of the major arteries, which commonly occurs in one or both kidneys. The reduced blood flow caused by the narrowing signals the kidneys to release hormones that result in high blood pressure, which is a significant health risk.  During each NF exam, blood pressure is closely monitored to ensure this problem isn’t developing.  Narrowing can also occur in one or both of the carotid arteries, the major arteries in the neck supplying blood flow to the brain. As this condition gradually develops, collateral blood vessels are formed to compensate for reduced blood flow to the brain. Although most people with carotid artery narrowing don’t experience significant symptoms, certain conditions, such as dehydration, significantly increase the risk of stroke in these individuals. We don’t routinely perform imaging tests to screen for this issue, although we’re alert to any symptoms a patient may be experiencing that could indicate this problem.  When this problem is recognized we usually recommend starting a mild blood thinner, typically baby aspirin.  In symptomatic cases, there are surgical approaches that can restore blood flow to the brain.

In previous blogs, I’ve referred to the leading-edge work conducted in the UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D.  Viewed in the medical and scientific communities as the gold standard for NF genetic testing, the laboratory has identified mutations in more than 8,000 unrelated NF1 patients and has identified more than 3,000 NF1 mutations.  A recent UAB School of Medicine web site article highlights the groundbreaking work of Dr. Messiaen and her colleagues in determining correlations between specific NF1 mutations and symptoms of the disorder (http://www.uab.edu/medicine/news/latest/item/956-uab-researchers-work-to-unravel-the-complex-genetic-disease-neurofibromatosis-type-1).  Using the database of more than 3,000 different NF1 mutations and a catalogue of phenotypes (symptoms) in NF1 patients, Dr. Messiaen led a team of 74 researchers and clinicians from 58 centers (from 24 U.S. states and 8 non-U.S. countries) in identifying only the third genotype/phenotype correlation ever found for NF1.  The details of this and other recent investigations conducted by Dr. Messiaen’s team were published last year in the journals Human Mutation (http://www.ncbi.nlm.nih.gov/pubmed/26178382) and The American                                                           Journal of Human Genetics (http://www.ncbi.nlm.nih.gov/pubmed/26189818).                                                               

This finding is significant in giving patients and clinicians a better understanding of the expected course of the disease, including the symptoms that are likely to be most prominent, with a specific type of NF1 mutation. As we’ve discussed previously, there is broad clinical variability in the expression of NF among individual patients, and the course of the disease is often difficult to predict.  This uncertainty can be anxiety-provoking and unsettling for families of children facing a diagnosis of NF1.  Dr. Messiaen’s continued efforts in developing, utilizing and expanding the laboratory’s extensive mutation database to identify additional genotype/phenotype correlations will help to explain the causes of variability of expressions of NF and provide a greater degree of clarity and predictability for patients and clinicians about the expected course of the disease. 

Our NF research program is continuing to accelerate the development of new animal models of NF mutations. Recently, we have been in discussions with various groups about developing models of individual mutations.  Our goal remains to create models that allow us to test or develop new drugs that will restore function to the mutated gene or gene product. We will soon have completed our first mouse model preclinical trial of one new approach to therapy, and expect to launch others in the upcoming months.

I’d like to continue our discussion, featured in the previous few blogs, briefly reviewing specific NF features and symptoms clinicians may identify during a patient examination.  When conducting an exam of the head, the most obvious NF-related feature is often the presence of neurofibromas, soft benign tumors that develop on or under the skin. These are not usually seen in young children but typically appear during adolescence and continue to develop throughout life. Because skin neurofibromas are harmless, the primary concern may be cosmetic in individuals who have a significant distribution of neurofibromas on the face and neck. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.

Another tumor that can occur on the face is a plexiform neurofibroma, a type of tumor that involves multiple branches of small or large nerves.  Some children with NF1 develop a plexiform neurofibroma behind an eye, which may show up as a swelling of the upper eyelid in the early years of life.  These can grow rapidly in childhood and cause significant disfigurement and interference with vision.  Approximately 2% to 3% of people with NF1 develop orbital plexiform neurofibromas.  Treatment involves surgical removal when possible, although surgery is complex and challenging due to the location of these tumors and the involvement of cranial nerves. Because recurrence after surgical removal is common, close follow-up with an experienced NF clinician as well as an ophthalmologist and plastic surgeon is important.

In some cases, distinctive facial features may be present in people with NF.  An example of a feature that may be noted by a clinician is palpebral fissures – the longitudinal opening between the eyelids – which slant downward from the midline to the lateral area. While many people with NF share this feature, it doesn’t appear in everyone with NF.  There also may be slight drooping of the upper eyelids.  Other NF features on the head include scalp neurofibromas, which can become painful and sometimes bleed, usually in adults.  Also, some people with NF retain a soft spot on the head, usually behind the left ear, that doesn’t completely close during the normal process of skull bone fusion that begins in early childhood. While this feature is uncommon, it may be noted by an experienced clinician during an  examination.  It is a benign feature that usually does not require treatment.

With the beginning of a new year, I’d like to follow the time-honored tradition of outlining a few key New Year’s resolutions for the UAB NF Program in 2016 that will continue to build on our commitment to excellence in patient care, research, and education. First, we continue our important mission of finding and developing new, life-changing therapies for people with NF by expanding and enhancing our program’s innovative research efforts during the upcoming year.  As part of this effort, we are actively recruiting an additional faculty member to join our drug discovery initiatives.  Also, we continue to make significant progress in animal model development that will allow us to test the effectiveness of potential NF medications more quickly and efficiently.  To accomplish this objective, a graduate student in our program has developed new animal models with NF features that develop more rapidly than previous animal models that have neurofibromas, which are often slow-growing. We believe these new models hold promise in allowing for more expeditious drug testing efforts that will enable us to test more medications more quickly.

Also, as part of our ongoing drug discovery efforts in 2016, we continue to test the effectiveness of potential new drug therapies for NF1 using specialized types of cells derived from individuals with the NF1 gene mutation, called induced pluripotent stem (iPS) cells. Using cells from a biopsy taken from either skin or a neurofibroma of a patient with NF1, we can create iPS cells by manipulations that cause them to behave like undifferentiated cells. These patient-specific cell lines can be used to test the effectiveness of potential new drug therapies for NF1. An additional research goal for this year is to launch a clinical trial for skin neurofibromas in 2016. We are currently following patients and collecting data on the growth and progression of their neurofibromas, which is a necessary step before the clinical trial can begin.

In a recent blog post, I mentioned that we have plans to remake a video that was produced while I was Boston more than 10 years ago featuring a counseling session with a family regarding the new diagnosis of NF1 in a child (called “Understanding NF1,” available at (www.understandingnf1.org). Based on that post, we received a response from a family interested in participating and the project is now moving forward.  Our Community Advisory Board, which held their initial meeting last October, will meet this spring with the overall objective of providing valuable input and direction regarding patient information, education, support, and coordination of care in our NF Clinic.  Based on feedback from the Board, we are currently developing several projects for new approaches to patient education. Also, the Community Advisory Board will play a key role in helping to organize this year’s NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included.

In continuing our discussion from last month’s blog regarding important issues NF clinicians are focused on during a patient evaluation, I’d like to briefly review what we look for on the skin during an NF clinic visit.  While NF1 includes many features, the appearance of multiple flat, brown spots called café-au-lait spots is the most common sign. These spots, which have flat margins and distinct borders, commonly appear in the first few months of life and may continue to increase in number through age two, though they often fade in adulthood. The coloring of café-au-lait spots is typically at least a shade darker than the general pigmentation of the skin.  Anyone can have one or two café-au-lait spots without having NF1; however, most people with NF have at least six and most have many more. It’s important to understand that the presence of this feature only suggests the possibility of NF1. Legius Syndrome is another condition that causes café-au-lait spots, although this is a benign condition that does not cause the development of tumors and is much more rare than NF1

Freckling in the skin fold regions is another common NF1 feature that we look for during an exam.  This distinctive freckling appears between three and five years of age and most commonly occurs in the groin region, under the arms, at the base of the neck, and under the breasts in women. Unlike typical freckling that occurs on sun-exposed areas of the skin, NF-related freckling manifests as many freckles in the region, as if paint were spattered from a brush. In addition to freckling, we also look for neurofibromas, soft benign tumors that develop under the skin. Although we occasionally see these in young children, the more visible neurofibromas appear later in childhood or adolescence and continue to develop throughout life, especially during pregnancy in women. While the size of neurofibromas can vary, the average size is that of a pencil eraser, though some can be larger or smaller. Skin neurofibromas are generally harmless, although they can be a significant cosmetic concern for individuals who have many neurofibromas distributed over large areas of the body such as the face, neck, and arms.  In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.

Another skin condition that can be detected during an NF exam is a type of lesion called nevus anemicus, which can be associated with NF1.  These lesions appear as a flat white patch on the skin, often on the chest or back.  They are irregular in shape and sharply marginated.  Usually present at birth or early childhood, the lesions seem to be caused by the incomplete formation of blood vessels in the skin and are harmless. Lastly, we sometimes see children with skin nodules called xanthogranulomas that occur more frequently in people with NF1. These appear as small, yellowish-orange bumps on the skin, especially at the hairline, in infants or very young children. Because xanthogranulomas regress spontaneously, they don’t require any special treatment. An experienced NF clinician can provide information and guidance about the clinical significance of the various skin conditions detected during an examination.