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. 

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.

The start of 2018 also marked my 15-year anniversary at UAB, having begun my tenure as Chairman of the Department of Genetics and Director of the UAB NF Program on January 2nd, 2003. At that time, the Department of Genetics consisted of only two full-time faculty members, subsequently merging with another department and increasing to 15 faculty. Today, the UAB Department of Genetics has grown to include 35 distinguished faculty members who continue to make significant contributions in clinical care, education, and research. Our program has also grown in scope over the past 15 years, with expanded patient care and initiatives in research and education. As part of a reorganization into adult and pediatric clinics, NF patients are now served at two distinct locations, including Children’s of Alabama and The Kirklin Clinic.  The NF Clinical Trials Consortium, for which UAB serves as the National Coordinating Center, is now in its third five-year funding cycle and is actively engaged in developing multiple new clinical trials for all forms of NF. In addition, our program has successfully secured NIH grants in genomic medicine focused on integrating genomics into diagnostic and therapeutic decision-making.  The department has three clinical laboratories, one of which – the Medical Genomics Laboratory – performs the most scientifically reliable and highest volume of NF genetic testing in the world. We also have an ongoing commitment to patient education through our annual support of key events such as the NF Symposium, NF Walk, and Rare Disease Genomics Symposium.

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.