Director's Blog
Highlights of the NF Forum and a Discussion of Newly Published Clinical Care Guidelines for NF1
NF Forum
In early May, I travelled to Atlanta to participate in the NF Forum, a bi-annual event sponsored by the Children’s Tumor Foundation (CTF). Held in different cities across the U.S. each year, the NF Forum is a national patient education and family gathering that features NF experts from around the country providing a series of keynote presentations, panels, and sessions on a variety of NF topics such as research advances and current clinical issues. The event included a meeting for clinic coordinators, physicians, genetic counselors, and other healthcare professionals, as well as a series of talks aimed at the NF patient community. I presented a talk on advances in NF treatment and provided an update on our research program’s current cutaneous neurofibroma clinical trial using an investigational drug. The NF Forum is important for disseminating the most current information about NF and also provides NF patients and their families an opportunity to network and learn from one another.
Clinical Care Guidelines for Adults with NF1
The American College of Medical Genetics and Genomics (ACMG) has recently spearheaded an effort to produce suggestions for clinical practice for adults with NF1. As part of this effort, the ACMG convened a panel of clinical experts to review current practice and published papers, and to use these to formulate guidelines for care of adults with NF1. Concluding many months of work, these guidelines were recently published in the journal Genetics in Medicineand are officially sponsored by the American College of Medical Genetics and Genomics (https://www.nature.com/articles/gim201828). These consensus guidelines were written for the professional community, specifically general practitioners and other healthcare professionals providing care to adult patients with NF1. Pediatric guidelines for NF1 produced by the American Academy of Pediatrics (AAP) have been available for many years. The American College of Medical Genetics and Genomics and the AAP have recently partnered in an effort to write updated pediatric guidelines, which are still in process.
There are two major types of guidelines: evidence-based and consensus guidelines. Evidence-based guidelines are considered more authoritative and are developed through a formal process that involves gathering published, peer-reviewed results of clinical research and reviewing evidence about why a certain approach or treatment is or is not effective. Evidence-based guidelines carry a great deal of weight, especially with insurance carriers. However, for NF1, our panel didn’t feel that evidence-based guidelines were an option at this point in time. The primary reason is that there have been very few large, randomized clinical trials for management of NF1 due to the relatively small numbers of individuals with the condition and the significant variability in symptoms and complications. It is easier to conduct large clinical trials for common conditions such as diabetes and cardiovascular disease. Another obstacle is that a thorough review of evidence is a time-consuming and expensive process, beyond the reach of the organizations sponsoring the guideline development at this time.
Consensus guidelines, like those written for NF1, are developed by convening a group of clinical experts who provide their opinions based on clinical experience as well as a review of evidence from the literature. These guidelines summarize current knowledge of clinical care and propose an approach to diagnosis and management. Because the consensus guidelines for NF1 are intended for general practitioners, they provide guidance in identifying specific problems but don’t address treatment, which would be managed by a specialist. For example, the guidelines address the identification of patients showing signs of a malignant tumor, but they don’t specify how to treat the malignant tumor.
Guidelines for Malignant Peripheral Nerve Sheath Tumors
In the next few months, I’ll try to discuss some of the recommendations of the adult guideline panel, and, when it is available, the pediatric guidelines. To start, I’ll cover one of the issues addressed in the clinical care guidelines, the occurrence of malignant peripheral nerve sheath tumors (MPNST). These malignancies occur in about 10% of people with NF1 and represent one of the few life-threatening complications of the condition. MPNSTs occur mostly in teens and young adults with NF1. Malignant peripheral nerve sheath tumors usually arise from pre-existing plexiform or nodular neurofibromas. Atypical neurofibromas, which have distinctive clinical and pathological features, may be a precursor to the development of an MPNST and appear as homogenous nodules that, if superficial, have a firm consistency when palpated.
Because MPNSTs are very difficult to treat, the focus is on early diagnosis. The clinical care guidelines for NF1 indicate a possible diagnosis based on any one of the following: persistent unexplained pain; rapid growth of a tumor; a change in a tumor from soft to hard; and the use of PET scanning to determine increased uptake of the radioactive tracer. The use of whole body MRI may be of value as a screening tool in helping to identify atypical neurofibromas so they can be followed or surgically removed to prevent their progression to MPNSTs. However, the utility of this approach requires further study at this time.
Highlights of NF Symposium and a Discussion of the Frequency of NF Clinic Visits
Re-Cap of Successful NF Symposium
Another successful and informative UAB NF Symposium, also known as NF Family Day, was held earlier this month in the Bradley Lecture Center of the Children’s Harbor Building. Co-sponsored by UAB and the Children’s Tumor Foundation (CTF), this half-day, free event provided an opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics from clinical experts. We were pleased to host more than 70 attendees from several states, including as far away as Colorado. A special program of activities was provided for the children in attendance by NF Clinic staff as well as students in the UAB Genetic Counseling and Biomedical Sciences Programs. For the first time, this year’s event featured a keynote speaker from outside the UAB community, New York University neuro-oncologist Kaleb Yohay, M.D., who gave a presentation about the role of alternative medicine in the management of NF. This topic is of great interest to many of our patients, who often ask about the possible benefits of alternative medicine treatments. While alternative medicine is not known to be effective in shrinking tumors or slowing their growth, in some cases there could be some benefits in managing symptoms of NF that can impact quality of life. UAB Professor of Pediatrics and Director of Neuro-Oncology Alyssa Reddy, M.D., provided an update of NF-related clinical trials currently in progress, and I gave a presentation about recommended clinical management for all three forms of neurofibromatosis. In addition to serving as a forum for educating NF patients, families, and the community about important NF-related topics, the event also provides a means for establishing a connection with other NF families who are sharing the same journey. Several NF patients and family members shared how they came to be diagnosed and their personal experiences of managing care for themselves or loved ones.
Frequency of NF Clinic Visits
Next, I’d like to address a question that patients frequently ask, which is how often should an individual with NF be seen in a specialty NF clinic? I generally recommend that children be seen in clinic on a regular basis, usually once a year. The rationale for recommending clinic visits for children annually is to help in the identification of any NF-related problems during a period of rapid change as a child develops. In early childhood, there is uncertainty about how NF will evolve, with the potential for the development of complications such as optic glioma, scoliosis, and bone dysplasia. For this reason, I recommend that children should be seen once a year by both an NF specialist and a pediatric ophthalmologist. Of course, if there are recognized problems, it may be appropriate to see a child more than once a year; that should be decided by the physician, together with the family.
Annual review in an NF Clinic can also be recommended for adults with NF. Again, the exact frequency of visits depends on the nature of the clinical problems facing the individual. Some have active problems that require more frequent follow-up; others have been stable for a long period of time, with little change from year-to-year. In the latter instance, one can debate whether annual follow-up is really necessary. I can’t say that a rigid annual schedule is critical for all adults with NF1 if nothing is changing clinically. There are, however, advantages to regular follow-up. First, sometime these visits provide an opportunity to review symptoms that may have been present for a while, but weren’t severe enough to warrant a special visit. Probably most of these are not medically significant, but sometimes complaints such as pain require further investigation to rule out problems such as malignant change of a neurofibroma. We do occasionally see people with NF after a gap of many years who have developed significant complications that ideally would have been identified earlier. A second reason to consider annual follow-up is to stay up-to-date on new advances in the field. For example, we now have access to clinical trials and even prescription medications that didn’t exist even a few years ago. The field is changing rapidly, and there is value to staying in touch, as something that couldn’t be treated years ago may well be treatable going forward. A third reason is to provide updated education on NF, including things to look for that might be a sign of progression of the condition. NF can be a complicated condition, so hearing about the major signs repeatedly over a period of years can be helpful. Finally, regular – not too frequent, but regular – visits provide a way to stay in touch with the medical team, so that they are familiar with a person’s history if problems do eventually arise.
Our goal is to help patients to be more proactive about their own care and encourage them to stay in touch with their NF care team through tools such as the UAB patient portal when concerns arise. Also, we’re currently working to develop an educational app that will help patients better understand their condition and signs of potential problems. The key for successfully managing NF is to remain vigilant about potential problems as much as possible.
A Focus on Improving Our Patients’ Experience and the Relationship Between Atypical Neurofibromas and Malignant Peripheral Nerve Sheath Tumors
Identifying Areas for Improving Patients’ Clinic Experience
A primary focus of our NF Clinic this year is conducting a careful evaluation of our internal systems to identify areas for improvement. To that end, we have begun a series of internal discussions about process improvements in the clinic with the goal of making the experience of our patients as positive as possible. While we feel that our clinic provides the highest level of care comparable to or better than specialty clinics anywhere in the world, we’re continually interested in identifying areas where we can improve the experience of our patients. Providing comprehensive care for NF patients involves multiple appointments with many specialists as well as coordination of a variety of laboratory and imaging tests. In addition, obtaining insurance preauthorizations requires significant behind-the-scenes work from our staff.
Because of this complexity of care, our ongoing focus is to provide the most streamlined and stress-free experience possible for our patients – and we know that we have to go some distance to achieve this goal. We feel that helping patients to become more engaged in their care is an important way to give them more control and enhance their overall experience. One way we’re doing this is to encourage patients to use the online UAB Patient Portal, which allows secure messaging of clinical information for pediatric and adult patients. This important tool helps to streamline care by expediting and increasing communication between patients and the clinical care team. Although we send electronic invitations to all patients for the portal, not everyone registers to use it because the invitation is sometimes not recognized or the instructions aren’t well understood. We’re focused on increasing usage of the online patient portal system by walking patients through the portal registration process while they are in clinic, as we feel all of our patients can benefit from this care management tool. Additionally, we’re attempting to minimize the number of no-show appointments in our clinic through appointment verifications and other measures. When a patient doesn’t arrive for an appointment, this represents a slot we could have offered to someone else who was hoping to be seen sooner. We welcome comments regarding additional ways we can improve our patients’ experience, and we look forward to maintaining our commitment to providing the highest level of patient-centered care.
Atypical Neurofibromas and Malignant Peripheral Nerve Sheath Tumors
Next, I’d like to address the issue of atypical neurofibromas and their potential to become malignant peripheral nerve sheath tumors (MPNST), probably the most feared complication of NF1. Occurring in about 10% of people with NF1, the malignant peripheral nerve sheath tumor can develop from a pre-existing plexiform neurofibroma. Diagnosis usually requires imaging, and in some cases use of a radioactive tracer (PET scan), and, ultimately, surgical biopsy of the tumor. Surgical resection is the most effective treatment, as these tumors are not sensitive to standard chemotherapy or radiation. The best way to prevent serious complications resulting from these tumors is to identify them as early as possible and consider surgical resection if this can be done safely.
Atypical neurofibromas, which have distinctive clinical and pathological features, may be a precursor to the development of a malignant peripheral nerve sheath tumor. They usually appear as homogenous nodules that, when palpated, have a firm consistency that is unlike plexiform neurofibromas, which are usually soft or spongy to the touch. Biopsies of atypical neurofibromas tend to show densely packed cells and may show dividing cells, whereas non-malignant neurofibromas typically are less dense. There is evidence that atypical neurofibromas may be early precursors to a malignant peripheral nerve sheath tumors, so vigilance is important, which may include biopsy or surgical resection. Whole body MRI is beginning to emerge as a method that may be helpful in identifying atypical neurofibromas, and we are exploring the utilization of whole body MRI for this purpose.
New Role as UAB Medicine’s Chief Genomics Officer, Upcoming NF Family Day, and Newly Identified Mutation/Phenotype Correlation in NF
New Role as Chief Genomics Officer and Continued Role as Director of NF Program
Along with the significant growth our program has experienced over the past 15 years, the field of genomic medicine has continued to evolve since the completion of the Human Genome Project in 2003 that successfully sequenced the complete human genome. Since that time, our understanding of the role of genes in health and disease has greatly expanded, leading to the rapid growth of genomic medicine to provide individualized clinical care to patients. Genomic medicine uses an individual’s genetic profile to guide decisions about prevention, diagnosis, and treatment. UAB Medicine has committed to advancing research into genomic medicine through two initiatives aimed at collecting health data from participants to determine the impact of lifestyle, environment, and genomic profiles on a variety of health conditions. UAB has launched the Alabama Genomic Health Initiative (https://www.uabmedicine.org/aghi) in collaboration with HudsonAlpha Institute for Biotechnology. We have been actively involved in recruiting participants in support of this initiative’s goal to enroll 10,000 individuals in our state over the next five years to determine how genomic information correlates with health status and risk of disease. We are also the hub of a regional network as part of the NIH All of Us research program (https://allofus.nih.gov), which ultimately will recruit 1 million volunteers across the country. Local enrollment in this program will begin soon.
In support of UAB Medicine’s commitment to implement precision medicine across all clinical programs, I have recently been appointed to the new role of Chief Genomics Officer for UAB Medicine, with the responsibility for establishing clinical programs in genomic medicine across the UAB Health System. This role also involves providing training and education to clinicians in the use of clinical tools to enable the use of genomic information in making diagnosis and treatment decisions. Because of this new role, I’ve stepped away from my position as Chairman of the Department of Genetics, as relinquishing the administrative responsibilities involved in that position will allow more time for me to focus on these new initiatives. I’ll continue to serve as a professor in the Department of Genetics and will also continue in concurrent positions as Associate Director for Rare Diseases in the UAB Hugh Kaul Precision Medicine Institute and as Co-Director of the UAB-Hudson/Alpha Center for Genomic Medicine. From the perspective of the NF Program, nothing changes, as I’ll continue to direct the program, with ongoing involvement in clinical trials and research initiatives in developing genomic therapies. Also, I will continue to see patients in the NF Clinic with a continued commitment to maintaining the highest standards of clinical care.
2018 NF Symposium/NF Family Day Coming in April
The annual UAB NF Symposium, also known as NF Family Day, is scheduled for Saturday, April 7th, in the Bradley Lecture Center of the Children’s Harbor Building. This year’s keynote speaker will be New York University neuro-oncologist Kaleb Yohay, M.D., who will give a presentation about the role of alternative medicine in the treatment of NF. This annual event serves as a forum for NF patients and families to hear a series of presentations about a range of NF-related topics from clinical experts and also provides a means for establishing connections with other NF families. Event registration information is coming soon; for more information, please contact Ashley Cannon at ashleycannon@uabmc.edu or Renie Moss and rpmoss@uab.edu.
Newly Identified NF Mutation/Phenotype Correlation
Previously, I’ve discussed the ongoing efforts of the UAB Medical Genomics Laboratory to determine correlations between physical manifestations of NF (phenotype) and specific mutations in the NF1 gene (genotype). More than 3,000 mutations have been identified in the NF1 gene, and there are a few examples in which a specific mutation can be correlated to certain NF symptoms. The January issue of the American Journal of Human Genetics (Am J Hum Genet. 2018 Jan 4;102(1):69-87. doi: 10.1016/j.ajhg.2017.12.001. Epub 2017 Dec 28.) features a paper from the UAB group and multiple collaborators, led by Dr. Ludwine Messiaen, that identifies a cluster of mutations in the NF1 gene that are associated with a relatively severe set of NF complications. This represents an example of a correlation between specific mutations and certain manifestations of NF. It is known that most NF mutations turn off the gene, thereby destroying its function; there is no particular phenotype associated with these mutations, except the typical features of NF. However, there are a handful of mutations where there is some ability to predict the phenotype. Identifying a correlation between a mutation and phenotype can be clinically valuable because certain complications can be anticipated with the potential of managing the condition more effectively. Also, a correlation provides information about how the gene works and may lead to answers regarding why some mutations result in a large burden of internal tumors but not many cutaneous neurofibromas, such as the mutations described in the recently published paper. With more than 3,000 NF gene mutations representing the largest repository in the world, the UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., is in the best position for determining additional mutation/phenotype correlations. In 2016, using the repository of mutations and a catalogue of phenotypes (symptoms) in NF1 patients, Dr. Messiaen and her colleagues identified only the third genotype/phenotype correlation so far found for NF1. Some of these newly identified mutations are being reproduced in animal models, such as mice, rats and pigs, to observe the manifestations of NF correlated with these mutations. Also, we are developing a cell culture system that will help us to determine the way specific mutations alter function within the cell. These studies will help us to classify the ability of specific mutations to cause NF1, and also will provide a system to test new approaches to treatment.
A Re-Cap of the Year’s Endeavors and a Preview of Plans for 2018
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!
Highlights of American Society of Human Genetics Meeting, Alabama NF Walk, and a Discussion of Muscle Involvement in NF1
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.
Recognizing Problems That Require Further Evaluation in 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.
Headache
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.
Department of Defense NF Research Program Grant Proposals and a Review of Pain in the Context of NF
Pain Related to NF1
In this month’s post, I think it would be helpful to discuss the issue of pain in the context of NF, other than headaches, which have been covered previously. Individuals with neurofibromatosis type 1, the most common form of NF, can sometimes experience pain related to the presence of neurofibromas, benign tumors that can grow on nerves throughout the body. While neurofibromas are not typically painful, some people have pain associated with these tumors that may take a variety of forms. Cutaneous neurofibromas, which appear on the surface of the skin, can sometimes result in pain due to an event that causes pressure on the tumor, such as hair brushing. These tumors can also become infected, which can be painful. Subcutaneous neurofibromas, occurring under the skin, can be nodular and are usually pea-sized to marble-sized. Though not typically painful most of the time, they can be tender to the touch or pressure such as hair brushing or lying down. Subcutaneous neurofibromas on the scalp can also serve as trigger points for headaches by internally pressing on nerves and surrounding structures, causing pain.
Plexiform neurofibromas occur deep inside the body and are usually not painful unless causing pressure on internal structures. There are instances in which they can press on nerve roots, resulting in significant pain. Some individuals with NF1 develop a condition call dural ecstasia in which there is a ballooning of the membranes surrounding the spinal cord that can put pressure on surrounding nerves, resulting in pain in the lower back or legs. This can be a very difficult condition to treat surgically, and may result in chronic pain.
Some adults with NF1 may also experience exquisite pain with pressure applied at the tips of fingers and toes due to the presence of glomus tumors that occur under the nail beds. Fortunately, this pain can be eliminated by removing these tumors surgically; however, many adults don’t associate this pain with NF and therefore don’t seek treatment. It’s important for patients and clinicians to be alert to this type of pain so that surgery can be performed if needed.
Malignant peripheral nerve sheath tumors, which occur in 10% of people with NF1, cause a nagging, unremitting pain that becomes worse over time. It’s important to recognize this type of pain so that an imaging study, such as an MRI and PET scan, can be performed to identify the tumor and recognize its malignant potential. For this reason, people with NF should be alert to any unexplained and persistent pain.
Pain Related to NF2 and Schwannomatosis
Chronic pain can occur in individuals with neurofibromatosis type 2 due to nerve root compression by one of the two types of tumors associated with the condition, meningiomas and schwannomas.
People with schwannomatosis, the third distinct type of NF, usually experience excruciating pain, which is a hallmark of the condition. Surgical removal of schwannomas usually relieves pain, although surgery is not always feasible due to the location of the tumors. Interestingly, the pain tends to be out of proportion with the number and size of tumors. Small tumors can be surprisingly painful, which may indicate there is something inherent in the tumor that causes pain.
Pain Management and Signs to Seek Treatment
In mild instances of NF-related pain, over-the-counter medications, such as Ibuprofen, are usually indicated and can be effective. Pain due to nerve compression or dysfunction sometimes responds to the medicine gabapentin or other similar medications. Also, pain management programs can be helpful in dealing with chronic pain for which there is not a treatment option available. These programs have extensive experience in helping patients achieve symptom relief while avoiding addictive drugs when possible.
In conclusion, it’s important for individuals with NF to understand the signs of when to seek treatment for pain, including: chronic or nagging pain that gets worse over time; neurofibromas that become noticeably larger; pain with pressure applied to the tips of fingers and toes; and localized pain, which may be an indication of nerve root compression.
Highlights of the 2017 NF Conference, NF Clinical Trials Consortium Update, and Frequently Asked Questions about Clinical Trials
Last month, nearly a dozen colleagues from UAB attended the 2017 NF Conference in Washington, DC. This international conference, organized by the Children’s Tumor Foundation, began in the 1980s with the original purpose of promoting the sharing of data to assist in mapping and the ultimate identification of the NF genes. When these goals were accomplished for NF1 and NF2, the meeting gradually evolved to an annual international research conference. The event now serves as the global flagship scientific forum where more than 300 participants from a range of scientific and clinical backgrounds gather annually to build consensus and foster collaboration for advancing basic, translational, and clinical research focused on improving outcomes for all forms of NF. The four-day conference features a series of poster presentations summarizing research, invited lectures, and platform presentations. Many of the speakers are from outside the NF field, broadening the scientific input into the study of NF.
While I’m not certain whether our UAB group was the largest contingent at the meeting, we were certainly among the largest groups in attendance. Several of us from UAB gave talks from the platform and most had poster presentations. A poster developed by Bob Kesterson, PhD, a professor of genetics and research scientist in our program, won the prize for best poster at the conference. Dr. Kesterson’s poster demonstrated how complementary DNA (cDNA) is now being used to provide a tool for assessing whether a mutation affects the function of the NF1 gene. This approach will be useful in determining whether some variants of unknown significance in the NF1 gene are actually disease-causing. It will also be used to determine whether skipping some part of the gene that contains a mutation will be tolerated (see last month’s blog on exon skipping). Dr. Kesterson was invited to give a brief talk on his research, and his award and recognition was an honor for him and our program. As I discussed in last month’s blog, there is an increasing focus within the NF scientific community on the development of genomic-guided therapies that will restore function to mutated genes. While this approach is already being used to develop potential treatments for other diseases such as cystic fibrosis and muscular dystrophy, it is receiving greater focus and attention from other scientific communities, including NF. We at UAB are recognized as the pioneering group in genomic-guided therapeutics within the context of NF, and we look forward to continuing our role as a leader in developing initiatives that will advance this promising avenue of potential treatment for NF.
NF Clinical Trials Consortium and Commonly asked Questions
Every six months, the NF Clinical Trials Consortium Steering Committee meets to discuss plans for upcoming clinical trials. Our most recent meeting was held in December in Baltimore with staff members from the Department of Defense (DoD) in attendance. This was the first steering committee meeting held since we learned of renewed funding, and we are preparing to launch the next round of clinical trials. Persons with NF often inquire about which clinical trials are available and if they can participate. Sponsored by the US government, the Web site www.clinicaltrials.gov provides information about all clinical trials categorized by condition. The federal government requires trials to be registered and to include detailed information on the site about eligibility criteria, site location, primary outcome measures, and other information.
In the past, clinical trials were not always forthcoming about outcome information, especially if the trial did not prove to be effective. Now it is mandated that outcome information be posted on the site for trials that have been completed.
We also receive occasional questions regarding the preliminary outcome of a clinical trial that is ongoing. We’re unable to provide any information about the preliminary findings of a clinical trial until the final data have been received. Typically, the investigators are not privy to the data because there is concern about possibly biasing the study. We therefore can’t answer the question of “What are you seeing so far?” A Data Safety Monitoring Board appointed to oversee a trial reviews the data for the ongoing study. In some cases, the trial is so effective that it is discontinued early. In other cases, the board may have data to indicate that the trial is not working or that side effects are too serious, and they will stop the trial. Another frequent question from patients is whether they can participate in a trial at a distance, or even from outside the country, instead of at the site where the trial is being conducted. Depending on the trial design, sometimes this is possible, though most times challenges exist that may not make it possible. If a medication is part of a trial, it is required that participants receive the medication at the site of the trial. Also, there are often routine screening tests that must be performed on site. Because it is sometimes possible to participate in a clinical trial from another location, it’s best to contact the staff conducting a particular trial to learn about participation requirements. Contact information is provided on clinicaltrials.gov.
Development of Genome-Guided Therapeutics for NF Based on Genetic Mutation Subsets
Neurofibromatosis type 1 is caused by a change in the genetic sequence in the NF1 gene, a large and complicated gene that contains a code for making a protein called neurofibromin. All individuals have two copies of this gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered due to either inheriting the altered gene from a parent, or acquiring a new genetic mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development (this results in segmental NF). For someone to develop NF1, a random genetic mutation must occur to the second 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. All individuals – with or without NF1 -- probably have some acquired mutations, which are random errors, that result in a few cells containing an NF1 gene alteration. These cells will not become neurofibromas, however, if only one NF1 gene copy is altered. The problem for individuals with NF1, however, is that this “backup copy” of the NF1 gene is already altered, which is why a neurofibroma will develop. Genes function in the cell to direct the production of proteins. The key question is whether we can find a way to restore function to an NF1 gene that has been damaged by mutation, or perhaps restore function to the abnormal neurofibromin that in some cases is produced.
Therapies Focused on Blocking the Ras/MAPK Signaling Pathway
The majority of therapeutics developed so far for NF1 has focused on blocking the Ras/MAPK signaling pathway that is hyperactive in cells in which both copies of the NF1 gene have been impaired. Neurofibromin regulates the activity of the Ras/MAPK cellular signaling pathway that helps to control cell growth and division. This pathway is also implicated in other diseases, such as cancer. Several drugs have been developed that have shown promise in inhibiting components of the Ras/MAPK signaling pathway implicated in NF1 and other diseases. For example, selumetinib is one of a family drugs that has been developed as an inhibitor of one of the components of the pathway and has been shown to have efficacy in reducing the size of plexiform neurofibromas. The development of therapies that inhibit the over-activated Ras/MAPK pathway and other Ras-connected pathways opens new opportunities for treatment for NF1, cancer, and other disorders that share a similar mechanism.
Development of Genome-Guided Therapies Based on Genetic Mutations
While the development of therapies that target Ras signaling is an important approach to developing potential treatments for NF, the possibility of restoring function to mutated genes using genome-guided therapies has gained increasing attention from the NF scientific community and represents an area of focus for the UAB NF Research Program. An advantage of this approach is that restoring function to the mutated gene might result in fewer side effects than with drug treatments that block Ras signaling. On the other hand, Ras signaling seems integral to the mechanism of disease in all patients with NF1, whereas genome-guided treatments are based on the specific type of genetic mutation causing an individual’s NF1, and therefore one treatment will not work for all patients. There are thousands of different mutations in different patients with NF1. These mutations are distributed across the gene with no specific mutation predominating. There are, however, subsets of mutations that can be identified through genetic testing, which enable the development of specific approaches to restore function to specific types of mutated genes. In this way, rather than require development of thousands of drugs, one for each mutation, it may be possible to develop a handful, each of which targets a specific type of mutation.
Mutation Subsets
The thousands of mutations can be classified into a number of types. A deletion mutation results in the total loss, or deletion, of the entire gene and usually produces a severe form of NF. Approximately 3% - 5% of NF mutations are of this type. There are currently no effective methods for replacing large genes, such as the NF1 gene, although this capability may be developed at some future point.
Another type of mutation, called a truncating mutation, causes a blockage or interruption in the formation of a protein. Neurofibromin is comprised of a chain of 3,818 amino acids strung together in a unique sequence. One type of truncating mutation, called a premature stop mutation (or nonsense mutation), inserts a signal that tells the protein production machinery in the cell to cease production of neurofibromin before the complete protein is made. Drug therapies currently in development have shown potential effectiveness in overcoming the effects of premature stop mutations. The UAB NF Research Program is currently testing drug compounds that read through the premature stop signals caused by these mutations, with the goal of allowing cells to produce a full-length, functional protein.
A frameshift mutation is caused by insertions or deletions of a number of nucleotides in a DNA sequence that is not divisible by three. When DNA is used by the cell to produce protein, the genetic information is read out in groups of three DNA elements, called “bases.” Hence a specific building block of a protein (an amino acid) is inserted into the protein because of the presence of a specific three-letter base sequence in the gene. If there is a loss or gain of one or two bases in the DNA sequence for that gene, the reading of the three-letter “words” is confused. This results in the sequence of amino acids being significantly altered, and at some point there will be a premature stop in the sequence. These types of mutations may be hard to correct, but we are exploring an approach that would jump over the segment of a gene that contains a frameshift when the gene is being processed for reading the sequence and producing the protein.
Splice-site mutations also result in a meaningless sequence that causes the production of a nonfunctional protein. A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. The genetic code in the DNA of a gene is first copied into a molecule called RNA, which is then read out to instruct the production of a protein. Initially, both the exons and introns are copied into the RNA, but then the introns are cut out and the exons spliced together to make the final “messenger RNA.” The process of splicing is precisely controlled by the base sequence of the gene, and some mutations occur at the sites that control this process, and therefore disrupt splicing. It may be possible to restore the normal splicing pattern using medications that interact with the splicing system. This may restore function to a gene disrupted by a splicing mutation; it is also the same method that might be used to jump over a segment with a frameshift mentioned above – this is called “exon skipping.”
Lastly, missense mutations result in the production of a full protein, although one amino acid in the sequence is incorrect. With some sequences, this error won’t cause a problem; however, if the error is related to the production of a critical part of a protein it may disrupt function. We’re currently working to develop compounds that that interact with protein to restore its function, at least partially. This has been a useful approach to therapeutics in the treatment of conditions such as cystic fibrosis. The exon skipping approach also might be useful here.
Gene Editing or Replacement
A final possibility is to try to get into the cell and actually correct the gene mutation, or perhaps even to replace the mutated gene entirely. There has been a lot of interest in these kinds of possibilities, especially recently with the advent of the CRISPR/Cas9 system. This system was developed based on a natural mechanism discovered in bacteria that protects bacterial cells from infection by viruses. It has been modified to permit editing of DNA sequences, including potentially correction of gene mutations. Our lab, and many around the world, are using CRISPR/Cas9 as an approach to creation of model systems that require producing a specific mutation of interest. Applying this to the treatment of a genetic disorder is much more complicated, especially one like NF1 that affects a very large number of cells in the body. This is, however, a new area of research, and one where we may see significant progress in the years to come.
Conclusion
We are beginning to see benefits from small molecule treatments that target Ras signaling, but in the long run we are likely to need many parallel approaches to effectively treat NF1. Our group, and many others, are pursuing such approaches, including the development of genome-guided therapeutics. It is likely that the eventual treatments of NF1 will require combinations of different approaches that will synergize with one another to control the symptoms of the disorder.