Highlights in Patient Care and Education and Plans for Upcoming Year

As the year draws to a close, I’d like to highlight significant accomplishments and events in the UAB NF Program during 2017 and provide a preview of plans for the upcoming year in patient care, education, and research.  It has been more than a year since the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District as part of a reorganization into adult and pediatric clinics, and the change continues to reap benefits.  Patients seem to be pleased with the new facilities and improved logistics, including more convenient parking. The most significant benefit for our patients is the streamlined, integrated care that is provided in the new clinic locations that enable imaging, lab tests, and consultations with a range of specialists to occur in one location. We’re pleased that our patients are benefitting from this new structure and that our hopes seem to have been realized for improved convenience and integration of care. 

As part of our ongoing commitment to patient education and support, our program co-sponsored, with the Children’s Tumor Foundation (CTF), another successful NF Symposium at the Children’s Harbor Building at Children’s of Alabama in August. Also known as NF Family Day, this annual event serves as a forum for NF patients and families to hear a series of presentations on a range of NF topics from clinical experts as well as  provides a meaningful opportunity for NF families to connect with others sharing the same journey. Our program was also pleased to again support the 4th Annual Alabama NF Walk held last month in Veteran’s Park in Hoover. 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.

Another highlight for our program this year was our participation in the Rare Disease Genomics Symposium, held in March at UAB, which is an event designed to share information about the role of genomics in the diagnosis and treatment of rare diseases with healthcare practitioners who are non-genetic specialists. While the event was not specific to neurofibromatosis, NF1 is a rare disorder that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders.  The Symposium serves as an important forum for increasing awareness of rare disorders and educating faculty and clinicians at UAB and in the community about the role of genomic medicine in the diagnosis and management of rare diseases.  This year’s Symposium featured a panel discussion led by parents of children with rare diseases as well as an art exhibit showcasing works that depict people with genetic conditions in a humanistic way.  Next year, the Symposium will be a two-day event with the first day designed for professionals and the second day focused on families.

In addition to lending our continued support to the NF Symposium, NF Walk, and Rare Disease Genomics Symposium during the upcoming year, we also plan to increase patient engagement through continuing work begun this year on the development of a smart phone app.  This app will allow patients to become more involved in several aspects of their care and enhance their interaction and experience with the clinic.

Re-Cap of 2017 Research Initiatives and a Preview of 2018

The UAB NF Research program has been actively engaged in basic and preclinical research as well as clinical trials focused on identifying and developing effective therapies for people with NF. Our primary research focus is the development of therapeutics targeted at specific mutations. The UAB Medical Genomics Laboratory is a world leader in genetic testing and medical diagnosis of NF, performing the most scientifically reliable, leading-edge genetic testing currently available for the diagnosis and characterization of mutations for NF1, NF2, and schwannomatosis, with the highest volume of NF genetic testing in the world. The Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene.  This research could provide a framework for determining the extent to which complications of NF are predictable.

Continuing our efforts in the development of animal models, we have developed several additional mouse models with specific NF mutations, some of which have been identified in our own patients. This offers the possibility of a personalized medicine approach to treatment that will remain an increased area of focus for our program in the upcoming year. These models enable our scientists to study the NF disease process as well as the effectiveness of potential drug treatments. Also in the area of preclinical research, we have developed a method of expressing the NF1 gene in a cellular system. This was accomplished by deleting the normal NF1 genes in these cells and replacing them with a mutated gene, allowing us to investigate the effects of a mutation on cells. A scientific poster summarizing our development of this model won first prize at the annual NF Conference last June.  We expect that the model system will yield further information about the NF disease process that will help guide the development of targeted therapeutics.

Additionally, we are conducting a clinical trial targeting cutaneous neurofibromas using the investigational drug called selumetinib. Cutaneous neurofibromas, which are common in adults with NF1, are benign tumors on or in the skin. This trial is actively recruiting study participants, and more information regarding the trial can be found at: www.clinicaltrials.gov (study number NCT02839720).

In support of our continued focus on the development of genome-guided therapies, we have also responded to several RFAs for research funding focused on genome-guided therapeutics with an emphasis on identifying approaches that will allow function to be restored to a non-functional gene or gene product. Our research program was the first to concentrate in this area several years ago, and now this approach is gaining increased attention from others in the scientific community.

Finally, last year we applied for renewal of our Department of Defense grant to fund the NF Clinical Trials Consortium.  This grant was approved, and the Consortium is now into its third five-year funding cycle.  We are in process of developing multiple new clinical trials for all forms of NF, including NF1, NF2, and schwannomatosis, and expect to be announcing the launch of the first trials very soon in the new year.

In summary, this has been a very busy year in the UAB NF Program, and next year promises to be at least as active.  I am grateful to our many supporters, and to the patients and families we serve for their confidence in our care.  I wish everyone a very restful and happy holiday season and look forward to reporting on our progress in the New Year! 
American Society of Human Genetics Meeting and Alabama NF Walk

Last month, several colleagues from UAB attended the American Society of Human Genetics meeting in Orlando (ASHG). The ASHG is the primary worldwide professional membership organization for human genetics with the mission of advancing genetics research by promoting the exchange of research findings at annual meetings, advocating for research support, and enhancing genetics education for current and future professionals in the field.  Several faculty members from the UAB NF research program gave poster presentations at the meeting, including NF Program Genetic Counselor Ashley Cannon, PhD, MS, CGC, and Associate Professor of Genetics Deeann Wallis-Schultz, PhD, as well as several other members of our research team. These presentations served as an opportunity to bring attention to our role as a national leader in advancing innovative NF research initiatives.

Our program was again pleased to support the 4th Annual Alabama NF Walk, which occurred on November 5th in Veteran’s Park in Hoover. Held in cities across the nation, the walk serves as a key 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 walk raised over $30,000 and gathered individuals and families from Alabama as well as surrounding states. To learn more about the Alabama Walk visit: https://join.ctf.org/hoover/events/2017-alabama-nf-walk/e130144.

Muscle Involvement in NF1  

An area of interest that we haven’t discussed previously is whether there is a direct involvement of muscle in NF1.  The primary manifestation of NF1 involves nerves affected by the growth of tumors. Because nerves control muscles, one might expect some muscle weakness due to impairment of a nerve by neurofibroma growth.  For example, a plexiform neurofibroma located on a spinal nerve could result in weakness of muscle innervated by that nerve.

There is, however, evidence now that there can be muscle involvement that is not related to a nerve sheath tumor.  Many children with NF1 exhibit low muscle tone, which usually becomes apparent between the ages of 2 and 5. Low muscle tone results in muscles that feel looser or more lax than normal, although muscle strength is typically within normal limits. Some children with low muscle tone tire more easily as a result of the condition. Also, the bellies of some children may protrude and give the appearance of a potbelly. This protrusion is due to abdominal and spinal muscles that are laxer than normal, not as a result of being overweight in most cases.  Low muscle tone should not affect one side more than the other, and the problem usually gradually improves by adolescence. However, these individuals retain relatively poor coordination compared to their peers.

For a long time it was assumed that low muscle tone in children with NF1 could be due to a central nervous system problem related to neurological pathways to the muscles. In recent years, increased attention to this issue has resulted in studies of muscles in individuals with NF1, which have shown some abnormalities of the function of muscle cells themselves. These findings suggest that something may be occurring in muscle cells, although it is not known in what ways the NF1 gene is affecting the muscle.

Parents of children affected by low muscle tone often ask if anything can be done to improve the condition. Physical therapy is often the recommended approach for improving the muscle tone and strength. It is a safe and useful way to define the current level of muscle function and provide opportunities to gain strength and improve overall coordination when a child is young. There are ongoing studies focused on developing more specific treatments for low muscle tone. While these are promising for the future, physical therapy is the only current option for improvement of motor function, though in many children this improves only very gradually over a period of years.
This month, I’d like to address an issue that often arises in the minds of parents whose children have been newly diagnosed with NF1. These parents often ask when they should be concerned about an issue or symptom that they notice in their child. I don’t think parents should assume the task of being their child’s doctor and become hypervigilant about every potential issue. Instead, parents have the important role and responsibility of nurturing and caring for their child. However, it’s natural for parents to experience anxiety about possible complications of NF1, and we do want parents to be alert to any potentially serious complication that may develop. The key is in separating everyday aches and pains from important symptoms, and the central question becomes:  What are the complications that, if detected early, would allow for better outcomes for children with NF1?

Optic Glioma

A tumor of the optic pathway, or optic glioma, occurs in approximately 15% of children with NF1. These tumors usually occur early in life, between the ages of 18 to 24 months. While more than half of children with optic glioma have no symptoms, some children experience vision loss, usually between the ages of 2 to 6 years. Because very young children don’t complain of vision loss, the early presentation of these problems can be subtle. Some signs of possible visual impairment include: tripping over objects or having difficultly navigating physical obstacles; becoming fearful of walking down stairs; and holding objects closer than normal or sitting closer to a screen, such as a television or computer. While we recommend yearly eye exams for children with NF1, parents who recognize these possible signs of vision loss should make an appointment for an evaluation with an NF specialist or pediatric ophthalmologist.

Physical Growth

A physical feature that is common for children with NF1 is that head size tends to be larger than average. However, a sign of concern would be if the size of the head crossed percentile lines as it grew or became noticeably larger in a relatively short period of time. Also, vomiting and lethargy could be a sign of obstructive hydrocephalus, a condition of increased brain fluid pressure that is rare, but more common in people with NF1 and usually occurs in childhood or young adulthood.

Also regarding physical growth, some degree of short stature is common among children with NF1. Slow weight gain is also common, although falling off the growth curve or crossing percentile lines are a cause for concern that requires further evaluation. In some cases, a brain stem tumor or optic glioma can affect the functioning of the hypothalamus where appetite is controlled, resulting in weight loss.

Plexiform Neurofibromas

These tumors, which occur deep in the body and involve large branches of multiple nerves, are usually noticed in the first year of life. They appear as a painless soft tissue swelling of the arm, leg, or around one or both eyes or on the face. Plexiform neurofibromas are believed to be congenital in most cases, although they are not easy to see at birth. Swelling of the upper eyelid in the early years of life could be a sign of a plexiform neurofibroma around the eye, which can grow rapidly in childhood and cause significant disfigurement and interference with vision.  Enlargement of an arm or leg can also be an early sign of plexiform neurofibroma.   

Bone Dysplasia

This problem is an abnormality of a long bone, usually involving the tibia in the leg but also sometimes affecting the fibula as well as bones in the arms. Bone dysplasia sometimes presents as bowing of a leg in infancy, although this can be difficult to detect early because most infants have some normal leg bowing. By the time a child can stand, one can usually determine if dysplasia is present. An X-ray is performed to confirm the problem, and the child is referred to an orthopedist for treatment with a leg brace to prevent fracture. If a fracture does occur, it can be difficult to treat, which makes early detection of this problem important.

Developmental and Cognitive Issues

Some children with NF1 exhibit low muscle tone, which results in muscles that are less firm and seem weaker than normal.   This problem tends to improve over time, but it may evolve into some degree of poor coordination in adolescence and adulthood. Also, learning problems are present in approximately 50% of children with NF1, although this issue may not become apparent until the child has reached school age.  Children with NF1 may exhibit problems in maintaining attention, hyperactive behavior, and social immaturity.  In some, speech articulation may be affected.  Sudden onset developmental delay is not common in children with NF1.  If a child is failing to reach developmental milestones or displays signs of learning or cognitive problems, this is a cause for concern and further evaluation. 


I have mentioned the occurrence of headaches in children with NF1 in previous blogs.  Most typically these occur intermittently and may be associated with nausea, stomach aches, and vomiting.  These signs are suggestive of migraine, which seems to be more common in children with NF1 than in the general population.  Another cause of headaches in children with NF1 is Chiari malformation, in which the base of the brain extends below the foramen magnum, which is the space in the skull where the spinal cord connects to the brainstem.  This is also more common in children with NF1 than in the general population.  Many parents of children with NF1 and headaches worry that the headaches could be a sign of brain tumor.  For a brain tumor to cause headaches it requires that the tumor cause increased fluid pressure in the brain.  If this does happen, the headaches are usually severe, may wake the child from sleep, and are associated with severe vomiting.  A careful physical exam would reveal increased pressure on the optic nerve visible in an eye exam, and would be followed up with an MRI scan.  Fortunately, I find that this is an uncommon cause of headaches in children with NF1.