Noteworthy Milestones of 2016

The end of 2016 provides a time to reflect on significant milestones for the UAB NF Program during the previous year and an opportunity to look ahead to new goals in the areas of patient care, education, and research for 2017.  A significant accomplishment achieved this year is the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District, recently completed as part of a reorganization into adult and pediatric clinics located in the Kirklin Clinic at UAB and the downtown Children’s Hospital of Alabama, respectively. The clinics that have been held in the new locations thus far have gone smoothly, and patients have provided positive feedback about the improved facilities and logistics, particularly more convenient parking.  An important benefit for our patients is that the new locations allow more streamlined integration with the range of other medical specialties involved in the multidisciplinary care we provide and enable imaging, blood draws, and consultations with other specialists to occur in the same location. Our previous clinic space in the Hugh Kaul Human Genetics building has been closed and will be reconfigured for another purpose yet to be determined. We’re pleased that our patients are benefitting from the convenience and integration of care that the new clinic locations provide.

In the area of patient education and support, our program co-sponsored, with the Children’s Tumor Foundation (CTF), another highly successful NF Symposium on August 27th.  The event, also known as NF Family Day, was held for the first time at the Children’s Harbor Building at Children’s of Alabama and provided an opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics presented by clinical experts. We were also pleased to again support the 3rd Annual Alabama NF Walk held on October 16th in Veteran’s Park in Hoover. The NF Walk is held in cities across the nation as an important fundraising event 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 Alabama NF Walk, launched for the first time in our area only three years ago, raised more than $40,000 and registered more than 300 participants.

Our research program continued to advance robust basic and preclinical research as well as  clinical trials focused on finding and developing life-changing therapies for people with NF. Earlier this year, our NF Program Genetics Counselor, Ashley Cannon, MS, PhD, CGC, was named a 2016 recipient of the prestigious Francis S. Collins Scholars Program Award, which is designed to attract the highest level of talent to the field of NF research by providing salary and research support to advance a clinical translational research study that will lead to improved treatment options for NF1.  The first individual in our program to have received this significant honor, Ashley has been working on a clinical study for cutaneous neurofibromas utilizing eight years of patient data, representing the largest existing data set of cutaneous neurofibromas. The results of the study are in the final stages of review and will be submitted for publication in the near future. Our entire NF clinic team is proud of Ashley for receiving the Collins Scholar distinction and her outstanding work in NF research.

The capabilities of our renowned and dedicated research team were further enhanced with the addition of two new faculty members this year.  Deeann Wallis, PhD, joined our drug discovery initiative to identify compounds that may lead to effective therapies for NF. Her research involves developing assays that are used to test cultured cells with compounds that could restore function of the NF gene using the RAS pathway. Our program’s partnership with Southern Research Institute provides access to a vast chemical compound library and the use of high-throughput screening, an important drug discovery method that uses robotic automation to quickly evaluate the biochemical activity of a large number of compounds that may have potential in restoring gene function.  Additionally, Dr. Wallis is testing the effectiveness of potential new drug therapies for NF1 using induced pluripotent stem (iPS) cells derived from individuals with the NF1 gene mutation. These specialized types of cells are reprogrammed from an adult cell and can develop into virtually any type of cell in the body, allowing the creation of disease-specific stem cells that can be used to test drug effectiveness. Also, computational biologist Andre Leier, PhD, joined our research team this year with a focus on developing mathematical models of the RAS signaling process. Dr. Leier’s efforts will further our understanding of the genetic mechanisms involved in NF so that drug therapies can be developed to restore function to mutated genes.

In other research initiatives this year, our efforts to produce mouse models of specific types of NF mutations continues to progress. These models are useful in allowing our genetic scientists to study the NF disease process as well as the effectiveness of new drug treatments.  Animal model development represents an area of significant commitment in our research program that will continue to expand in 2017 and beyond. In the area of clinical trials, we are hoping to launch a clinical trial for cutaneous neurofibromas in the upcoming year.

New Goals for the Year Ahead

Our commitment to supporting clinical trials continues with our role as the coordinating center for the NF Clinical Trials Consortium, a collaborative group of 18 medical centers across the country and in Australia dedicated to conducting clinical trials of the most promising drug therapies for all forms of NF. We have submitted a five-year funding renewal request to the U.S. Department of Defense and are hopeful that funding will be renewed. During our recent Consortium steering committee meeting, several new clinical trials were proposed for the upcoming year. There are two clinical trials for next year that are not dependent on Consortium funding, including a cutaneous neurofibroma trial that will be launched in early 2017.

We also plan to continue our preclinical research efforts in the coming year. Several members of our NF clinic team attended a meeting in Detroit recently with scientific leaders from all over the world representing many genetic conditions, including cystic fibrosis and muscular dystrophy. We discussed drug development efforts aimed at restoring function to mutated genes and have developed collaborations with many of these leaders so that we can adapt these approaches to NF research.  Also, we continue to support NF research efforts beyond those of our program. In my role this year as chair of the strategic planning committee for the Children’s Tumor Foundation (CTF), I recently chaired a retreat in Virginia focused on planning future CTF research goals. 

In the area of patient education and support, an important goal for our clinic in the upcoming year is to increase patient engagement. We are working with a group at UAB to develop a smart phone app that will allow patients to become more involved in several aspects of their care as well as enhance their interaction and experience with the clinic.  We are also actively planning the next NF Symposium, or NF Family Day, scheduled for August of 2017.  In conjunction with Children’s Harbor, we’re exploring the possibility of using an off-campus location for an overnight retreat with our NF families.  Also, we’re looking forward to supporting another successful Alabama NF Walk in October as part of CTF’s ongoing efforts to raise funds for critical research aimed at finding and developing effective treatments for NF.

Relocation of Adult and Pediatric NF Clinics

I’d like to provide an update of a development mentioned in a previous blog regarding the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District. The relocation, which has recently been completed, originated earlier this year with the reorganization of the NF Clinic into adult and pediatric clinics.  The adult clinic is located in the Kirklin Clinic at UAB, while the pediatric clinic is at the downtown Children’s Hospital of Alabama location.  Both of these facilities provide our patients with more convenient parking than our previous NF Clinic location in the Hugh Kaul Human Genetics building.  Also, the new locations will enable improved integration with the range of other medical specialties involved in the multidisciplinary care we provide while allowing our patients to remain in one physical location for blood draws, imaging, or consultations with other specialists. Although our previous clinic location allowed us to see adults and children in the same visit, we now see adults at the Kirklin Clinic location on Mondays and children at the Children’s Hospital facility on Thursdays; at the Kirklin location, patients must be 16 or older, while patients in the children’s clinic must be 18 or younger. Because we understand that these split clinic days could be an inconvenience for some patients, we can certainly arrange to see members of the same family on the same day if needed, by prior request on a case-by-case basis.  Overall, we believe that our patients and families will benefit from the convenience and integration of care that our adult and pediatric clinics provide.

Increased Breast Cancer Risk in Women with NF1

Next, I want to review information concerning the increased risk of breast cancer in women with NF1. In recent years, it has become clear that women with NF1 are at an increased risk for breast cancer, with the risk being two to three time higher in women with NF1 than in those in the general population.  Also, these cancers occur at a younger age and tend to be more aggressive in women with NF1 than those that occur in women in the general population. The nature and composition of the cancers, however, are not different. 

In many women who have been diagnosed with breast cancer, a genetic panel of tests is performed to detect mutations that might be associated with the cancer.  The NF1 gene is now being tested as part of this panel, as well as other genes including BRCA1 and BRCA2.  However, it’s important to note that the increased risk of breast cancer in women with NF1 is not associated with mutations in the BRCA1 or BRCA2 genes.

The reason for the increased risk of breast cancer in women with NF1 is not completely understood. We know that cancer is the result of the accumulation of genetic alterations that cause cells to behave abnormally. The NF1 gene has been shown to have mutated in many common cancers, which might indicate that the NF1 mutation puts an individual one step closer to developing other cancers.

Some women diagnosed with breast cancer have been referred to our clinic because of an unexpected NF1 mutation detected in the genetic testing panel.  There are a few possible explanations for this finding, including that the individual has NF1 and was never diagnosed because the clinical features went unnoticed. Another possibility is that the individual has a mosaic form of NF1 that is detected in the blood but may not be clinically evident. Lastly, genetic variants are sometimes found in testing that are different from the normal gene variations. These are known as variants of unknown significance, and it can be a challenge to know what to do with this information. Often, when these patients are evaluated, they are not found to have NF1.

Breast Cancer Screening Recommendations

The increased risk of breast cancer in women with NF1 raises questions about screening recommendations. The National Comprehensive Cancer Network (NCCN), an organization that issues screening guidelines for various cancers, recommends that women with NF1 should be screened for breast cancer at an earlier age than the general population, beginning at age 30. In addition, the NCCN states that some consideration should be given to the use of breast MRI from age 30 to age 50.  After this, the guidelines shift back to that of the general population. We are now recommending these screening standards to the patients we see in our clinic with the goal of achieving an early diagnosis for improved outcomes.

Some patients are concerned that neurofibromas in the breast may be confused with breast tumors during imaging. Although neurofibromas can develop in the skin of the breast, they are clinically distinguishable from tumors in breast tissue. However, it is important for radiologists to know the NF history when reading imaging results for these patients.

Highlights of 3rd Annual Alabama NF Walk

The 3rd annual Alabama NF Walk, held on October 16th in Veteran’s Park in Hoover, proved to be another highly successful event that raised both awareness of NF in our community and critical funds for NF-related research. Held in cities across the nation, the NF Walk is an important fundraising event 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. Launched only three years ago in our local area, this year’s Alabama NF Walk raised more than $40,000 and registered more than 300 participants.  In addition to raising awareness of NF among people in our community, the event also provided an opportunity for NF patients and families to enroll in the NF Registry, established by CTF in 2012; the purpose of the NF Registry is to notify NF patients who may be eligible for clinical trials or other research studies and to determine the frequency of NF characteristics.  Several newly diagnosed patients and their families in attendance expressed their gratitude for the hope and support they received as a result of coming together as an NF community, which is an important and meaningful benefit of this special fundraising event.

Cognitive Function and Learning Difficulties

I’d like to focus our discussion this month on developmental issues and cognitive function in individuals with NF.  Neurofibromatosis type 1 is associated with an increased risk of learning disabilities as well as a constellation of other symptoms that can impede school performance, including attention-deficit/hyperactivity disorder (ADHD), delayed language development, immature behavior, and low muscle tone. Sometimes cognitive problems are severe and evident early in life; however, sometimes these problems don’t appear until children have reached school age.  It is estimated that 50% of children with NF1 have some type of learning problem, although this statistic may be an underestimate of the prevalence of learning issues in children with NF1. I find that the more one looks for learning problems in children with NF, the more these problems are identified.

We therefore keep a watchful eye out for learning difficulties among children with NF1. Although we don’t always perform formal developmental assessments, we do focus on developmental issues and evaluate whether a child’s development is in the normal range of what is expected for his or her age.  Also, we educate families about the prevalence of learning disabilities in children with NF1 and arrange an evaluation with a neuropsychologist for a formal developmental assessment if needed.  Some parents have found that developmental assessments administered by schools can be difficult to obtain. Families considering formal evaluations for their child with NF should seek out an experienced professional, usually a neuropsychologist with experience in administering developmental assessments, who is familiar with resources in the community and can also advocate effectively for their child.

It’s important to note that learning problems are also common among the general population. Because there is not a specific profile of learning issues unique to NF, there is not a specific management plan that is unique for those with NF1. Learning problems are managed using the same methods as for individuals who don’t have NF. Effective management of learning difficulties involves providing a supportive educational environment with a focus on early intervention to address specific issues such as delayed language development. The same management approach applies to children with ADHD, although these children may also benefit from the use of stimulant medication to help control symptoms.

Regarding other developmental issues in children with NF1, the low muscle tone that occurs in some children tends to improve over time. It may, however, evolve into less overall coordination in adolescence and adulthood.  The lax muscle tone may cause some children with NF, even those of normal weight, to have a protuberant belly. This is a common occurrence, however, and not a cause for concern.

Questions sometimes arise as to whether parents should tell a teacher that their child has NF. The concern is that providing this information may cause a teacher to assume that the child has a learning disability. If learning issues are occurring, however, early intervention and support can lead to better outcomes for the child. Without this critical support, children are at risk for performing below their academic capabilities, which may lead to more limited opportunities in adulthood. Another consideration is that when parents don’t inform the teacher that their child has NF they are not in control of the information acquired and assumptions the teacher may form about their child. Most parents find that sharing information and recruiting the teacher as an ally is a helpful step in ensuring their child’s academic success. The Children’s Tumor Foundation offers a brochure designed specifically for educators that can be helpful in sharing information about NF ( or 1-800-323-7938).

While there are no medications that are effective in improving learning disabilities, there was hope that statin drugs may improve learning based on studies a few years ago using mouse models. However, three subsequent clinical trials showed no beneficial effect of statin drugs on learning.  Possible reasons that statins showed improved learning in mice but not humans include the fact that mice are inherently different than humans and the measures for learning are also different. Also, the dosage administered to mice in the studies may have been higher than is safe for humans. Based on the findings of the clinical trials and the risks associated with statins, the use of these medications for learning disabilities is not a recommended approach to treatment.