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. 

As the year draws to a close, I’d like to provide a brief update on the NF Program’s research progress in the important area of animal model development. Animal models allow scientists to study the process of specific diseases and often serve as an important foundation of drug research before clinical trials can begin in humans. Our research program is continuing work on a mouse model we developed with a specific type of gene mutation, called a premature stop mutation, that is responsible for ~20% of NF1 cases.  A mouse clinical trial is currently in progress with the objective of determining whether certain medications are effective in overcoming the stop mutation by either shrinking existing tumors in the mice or delaying or preventing tumor growth. In addition to the premature stop mutation model, we have also expanded the number of mutations for which we’re developing animal models, with an overall goal of establishing a library of animal models that can be used to test the efficacy of potential medications. We’re using the new gene editing approach called the CRISPR/Cas9 system, which allows investigators to “edit” the genome and quickly introduce mutations into these model systems.  Although the results of our research initiatives can’t be released until they have been peer-reviewed and published (and a set of papers are now in preparation), it’s important to know that significant progress is being made in the development of animal models that are allowing us to test new drug therapies that hold promise in restoring function to genes with specific types of mutations.

In other developments, we are anticipating that by early 2016, the NF Clinic will be separated into adult and pediatric clinics located at two distinct sites: the adult clinic will be located in the Kirklin Clinic at UAB, while the pediatric clinic will be at the downtown Children’s Hospital of Alabama location. Both of these facilities provide more convenient patient parking than our current NF Clinic location in the Hugh Kaul Human Genetics building. Most importantly, the new locations will allow for a more seamless integration with the range of other medical specialties involved in the multidisciplinary approach to care that we provide to our NF patients.

Lastly, I’d like to briefly discuss some of the important issues that we, as NF clinicians, are focused on during a patient evaluation by highlighting three main points: the value of NF patients being followed by NF specialists; the purpose of annual follow-up exams; and a brief explanation of what NF clinicians are looking for during an NF exam.  First, we understand that most patients have a primary care physician and we try to work together with these providers.  Primary care physicians play an integral role in the healthcare continuum by providing recommended screenings, risk assessments, and vaccinations, for example. Our goal as NF clinicians is to serve as consultants by providing support and assistance.  NF is a progressive disorder, and an NF clinician has experience in detecting changes in NF patients before significant problems develop and in recognizing NF-related problems when they do occur. We occasionally see patients with NF-related problems whose diagnosis was delayed, which can make the problem more difficult to manage.

Once a patient is established in an NF Clinic, exams at one-year intervals are a convenient and useful benchmark for clinicians to stay in touch with patients and detect any NF-related problems that may be developing. Also, the state of knowledge in the NF field changes significantly from year to year, especially with the progress in clinical trials and other research, and we want our patients to benefit from new treatment advances or opportunities to participate in research.  The emphasis of annual exams varies depending on many factors, including the age of the patient, the type of NF involved, and the complications the patient is currently experiencing. As NF clinicians, we follow people with all forms of NF at all ages, from birth to advanced age; the problems a clinician looks for in an NF patient vary with all these factors.  For example, we keep a close watch on the formation of optic nerve tumors in children with NF1 because they are more common in pediatric patients, while we’re not as concerned about this issue in adults. In general, an annual exam focuses on keeping track of known problems, identifying new signs or symptoms, and anticipating likely future issues.  In an NF clinic, exams are performed by experts who can detect problems early and customize care to the needs of individual patients and their life stage. 

I’m pleased to report that the 2nd annual Alabama NF Walk, held on October 18th in Veterans Park in Hoover, was a huge success both in terms of fundraising and attendance. The purpose of the event is to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults.  This year’s NF Walk raised more than $73,000 and registered more than 400 participants, a significant accomplishment for this important event that was launched in our area only one year ago by Birmingham resident Renie Moss, a dedicated patient advocate and mother of two children with NF.  Through the tireless efforts of the Moss family, as well as other Birmingham families who have been affected by NF, the Alabama NF Walk has become a significant fundraising event in our area that supports critical NF research focused on the development of breakthrough treatments.

As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the newly formed NF Community Advisory Board held its first meeting at the Kaul Human Genetics Building last month.  Comprised of NF patients and family members, the primary purpose of the Board is to provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets the needs of our community.  Due to the collective expertise and experience of our NF Clinic specialists and staff, I’m confident that our patients are receiving the highest level of NF care available.  However, we also want to ensure that our patients have the best possible experience in our Clinic with respect to patient information, education, support, and coordination of care. The Board, which will meet three or four times a year, will maintain an emphasis on community outreach and education regarding NF and the clinical and research programs available at UAB.  In addition, the Board will serve an integral role in helping to organize the NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included. Other goals for the group include identifying any needs that are currently not being addressed by our NF program and offering advice to our program leadership to help make the NF Clinic as strong and responsive as possible. Also, the Board will explore the development of smart phone and tablet apps to assist patients in documenting and storing information about their own care that can also be shared with clinicians to expedite communication and enhance patient care.  These and other initiatives will serve to improve our patients’ experience in the Clinic and ensure that our NF program continues to maintain our commitment to meeting patients’ needs in every area.

One final point:  More than 10 years ago, while I was still in Boston, we produced a video of a counseling session with a family regarding the new diagnosis of NF1 in a child.  It can be viewed online at www.understandingnf1.org.  We have gotten a lot of good feedback about the video over the years, as many families have found it helpful to understand the many issues that arise with a new diagnosis of NF1.  A lot has happened in NF research – genetic testing and clinical trials, for example – since the video was done, and therefore I’d like to redo it and include this new information.  The couple who were featured in the video actually do have a child with NF1, though this was not really their first time hearing about it.  It works best to have a couple with a young child who has been diagnosed in the relatively recent past.  If anyone reading this would like to consider working with us on this, please let me know (bkorf@uabmc.edu).