Director's Blog
Continued Benefits of NF Clinic Relocations and a Discussion of Headaches in Individuals with NF1
A few months ago, we completed the relocation of our adult and pediatric NF Clinics to two distinct locations in the UAB Medical Center District; 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. We’re finding that our patients continue to reap significant benefits from this change in terms of both convenience and improved integration of care with other medical specialties involved in the multidisciplinary care we provide. For example, our patients can have imaging, bloodwork, and consultations with other specialists, when needed, in the same location without having to walk down the street to another building, as they did prior to the clinic relocations. Also, our staff has become accustomed to the streamlined integration of care and the advantages it provides. We continue to be pleased that the relocation has made our adult and pediatric clinics more efficient and patient-centered.
Headaches in NF1
Next, I’d like to briefly discuss the occurrence of headaches in individuals with NF1, which is fairly common in both adults and children. Because NF1 is a condition that increases the risk of tumor development, a common concern is that headaches are a sign of a brain tumor. In most cases, however, headaches are not due to the presence of a tumor. The most common brain tumors that occur in people with NF1 are optic gliomas, which are tumors of the optic pathway. These tumors do not usually get large enough to cause increased pressure in the brain, which is the typical cause of headaches associated with brain tumors. Other kinds of brain tumors can occur, and if they increase pressure in the brain they can cause headaches. Usually these are severe, wake a person from sleep, and are associated with other neurological symptoms as well as nausea and vomiting.
While it is possible for some individuals with NF1 to develop malignant brain tumors, most headaches in people with NF are benign and are related to non-tumor causes. A common possibility is the presence of neurofibromas located on the scalp or neck that can be tender to touch or movement. These can serve as trigger points for pain that occurs on pressure, such as when brushing the hair or lying down. The pain can sometimes be interpreted as a headache. Also, migraine headaches are more common in people with NF than in the general population and can occur in children and adults. These are throbbing headaches that last several hours and often cause light sensitivity. Children with migraines can often experience stomach aches with or without nausea and even vomiting, which can often be the primary symptom. Migraines in children can occur either infrequently or can happen often, sometimes interfering with daily living and resulting in missed school or work days, trouble with homework, and other problems. There are several approaches to management that can be helpful. Over-the-counter medications can be used and are often effective. If migraines are severe and frequent, prescription medications can be used when the headache presents, and other medications are also available that can help to prevent the development of migraines. While these medications can work remarkably well, not everyone needs to take a daily medication for the management of migraines.
Another condition that can be associated with headache is hydrocephalus, a condition of increased fluid pressure in the brain that is rare, but more common in people with NF than in the general population, and usually presents in childhood or young adulthood. The headaches tend to be severe and might be associated with other symptoms, such as vomiting and other neurological signs. In some other cases, headaches in association with NF1 can occur as a result of a problem called Chiari malformation. This is defined as an extension of the lower part of the cerebellum of the brain below the foramen magnum, which is the opening at the base of the skull that marks the beginning of the spinal cord. Chiari malformation appears to be more common in individuals with NF1 than in the general population, and can result in headaches, as well as other neurological signs, such as weakness or sensory changes in the upper part of the body. Also, tension headaches, which are associated with emotional stress, can occur in individuals with NF1. Additionally, some individuals with NF1 have elevated blood pressure that can cause headaches.
Brain imaging studies usually aren’t performed right away in association with headache if an individual’s neurological examination is normal there are no neurological deficits. However, imaging is indicated if headaches are persistent and frequent or if other neurological signs are present in addition to headache. It’s also important to note that immediate evaluation is required for pain that awakens a person from sleep or causes persistent nausea and vomiting.
Renewed Grant for the NF Clinical Trials Consortium and a Promising New Drug for the Treatment of NF1
As we begin a new year, I’m pleased to report that our application for a third cycle of funding for the NF Clinical Trials Consortium has been approved by the U.S. Department of Defense (DoD). The Consortium is a collaborative group of 21 medical centers across the country and one in Australia dedicated to conducting clinical trials of the most promising drug therapies for all forms of NF. As the coordinating center for the Consortium, UAB serves in several critical leadership and managerial roles during nearly every phase of the clinical trials. Although protocols for the trials may be developed at other medical centers, UAB is responsible for coordinating Institutional Review Board (IRB) approvals, collecting and analyzing the data, and facilitating the preparation of results for publication. This is a significant role that we’ve held since the inception of the Consortium in 2006 and one that reinforces our commitment to accelerating the pace of NF research by providing the opportunity for patients to participate in clinical trials throughout the country. The DoD reviews were laudatory of the Consortium’s contributions to the NF community as a major source of hope for NF patients seeking new approaches to treatment. It is encouraging that critical funding for this important research initiative will continue.
Results of Clinical Trial Show Effectiveness of New Drug
Next, I’d like to highlight the results of a small clinical trial of a new drug, called Selumetinib, published last month in the New England Journal of Medicine (www.nejm.org/doi/full/10.1056/NEJMoa1605943).
The study results are significant because they represent the first time a medication has demonstrated clear potential as a treatment in a clinical trial for plexiform neurofibromas in NF1. This was a small Phase I trial conducted at the National Cancer Institute of 24 patients. After receiving Selumetinib twice daily for a 30-month period, more than 70% of participants in the trial experienced a reduction in the size of the plexiform tumor. Additionally, symptoms of pain and pressure related to the tumors were reduced. It’s interesting to note that this trial was developed as a consequence of previous animal model testing conducted by scientists funded by the Children’s Tumor Foundation (CTF).
The medication acts as an inhibitor of the RAS/MAPK cellular signaling pathway that is hyperactive in people with NF1. The RAS/MAPK pathway achieves its signaling through a complex form of cell communication that is also implicated in other disease processes, including cancer. During the cell signaling process, each cell receives an intricate combination of signals that triggers many different signaling pathways in a cascading-like effect. Neurofibromatosis type 1 is caused by a genetic alteration in the gene that encodes for neurofibromin, a protein that regulates activity of the RAS/MAPK signaling pathway. When specific signaling pathways become altered as in NF1, cells respond with uncontrolled growth. Selumetinib is one of a family of drugs that has been developed to inhibit components of the RAS/MAPK signaling pathway implicated in the development of cancer and other diseases. Because we now understand that NF1 has underlying genetic alterations that occur in this signaling pathway, we can test this family of drugs for their effectiveness in treating NF. The results of this study are encouraging because they represent the first example of a notably positive trial of a medication to treat NF.
A larger clinical trial of the drug with a greater number of patients is underway. Selumetinib is currently considered an experimental drug and is not available clinically, although a similar drug, called Trametinib, is clinically available. While these are not harsh chemotherapy drugs, they do have potentially significant side effects and are not for every NF patient. Because of the demonstrated potential of the drug in the clinical trial, we are optimistic that this family of drugs will play a role in the future treatment of NF. Also, the NF Clinical Trials Consortium is conducting ongoing trials of other drugs that work by the same mechanism, and additional trials will be launched in the future. The positive results of the Selumetinib trial are both exciting and significant for the future of NF research.
Highlights of a Successful Year and a Look Ahead to New Goals for 2017
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.
Successful Relocation of Adult and Pediatric NF Clinics and a Discussion of Increased Breast Cancer Risk in Women with NF1
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.
A Successful 3rd Annual Alabama NF Walk and a Discussion of Developmental Issues and Cognitive Function in NF1
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 (www.ctf.org 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.
Highlights of NF Symposium, Plans for 3rd Annual NF Walk, Discussion of Mosaic NF1, and a Review of the NF Neurologic Exam
Last month saw another successful annual NF Symposium, held for the first time at the Children’s Harbor Building at Children’s of Alabama on Saturday, August 27th. Co-sponsored by UAB and Children’s Tumor Foundation (CTF), this half-day, free event, also known as NF Family Day, provided an invaluable opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics presented by clinical experts. A special program of activities was provided for the children in attendance, and our NF families also had an opportunity to learn about the range of services available at Children’s Harbor, a non-profit organization that supports seriously ill children and their families through education and counseling services. I opened the Symposium with an introduction to the features of NF as well as an overview of our research initiatives in the NF Program. UAB Professor of Pediatrics and Director of Neuro-Oncology Alyssa Reddy, MD, provided an update of NF-related clinical trials currently in progress, and UAB Assistant Professor of Pediatrics Critical Care Michele Kong, MD, gave an interesting and informative talk on developmental issues in children (not just those with NF). Also, our NF Program Genetic Counselor Ashley Cannon, MS, PhD, CGC, presented the natural history of dermal neurofibromas, followed by Birmingham patient advocate Renie Moss’ review of advocacy, fundraising, and upcoming events. In addition to providing an opportunity for NF patients and families to gain important information about NF, it’s also rewarding to know that this annual event facilitates connections among patients and families that allow them to share their unique challenges, experiences, and concerns.
I also want to mention that plans are underway for another important NF event, the 3rd Annual Alabama NF Walk, which is scheduled for Sunday, October 16th, at 1 p.m. in Veteran’s Park in Hoover. The purpose of the event is to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults. Last year’s event raised more than $73,000 and registered more than 400 participants, which was a significant accomplishment for an event that was launched in our local area only two years ago. We’re pleased that the NF Walk has continued to generate increased interest each year and has become a significant means of raising critical funds to support NF research focused on the development of breakthrough treatments. To learn more about the Alabama NF Walk or to register, visit www.nfwalk.org.
Brief Review of Mosaic NF1
In previous blogs, I’ve referred to the fact that some people have features of NF that are confined to a certain region or segment of the body. A possible explanation for the occurrence of isolated NF features in some individuals is mosaicism, caused by a genetic mutation of the NF1 gene that arises after conception and during early embryonic development. As a result, some cells in the body have the mutation while other cells do not. The area of the body affected may be a cluster of cells in one region, such as an arm or leg, resulting in café-au-lait spots or a cluster of neurofibromas in one region of the body. Because genetic testing for NF1 using blood doesn’t always detect the mutation in people with mosaicism, the best method of diagnosing this form of NF is to perform genetic testing using a biopsy of affected tissues, either neurofibromas or café-au-lait spots.
A question that often arises related to mosaicism is whether there may be features of NF present in the body that are not visible on the surface. In the majority of people with mosaicism, the outward manifestation is the only NF feature that is present, but we do remain vigilant for other manifestations that may occur internally. Unless specific symptoms are present, there is usually no need for imaging to detect tumors.
Another important question related to mosaic NF1 is whether it can be passed to a child at conception. An individual with mosaic N1 cannot have a child with the mosaic form of NF1. However, it is possible for someone with mosaicism to have a child with generalized NF1, in which every cell in the body has the NF1 mutation. If we know an individual has a mosaic form of NF, we can offer prenatal counseling and genetic testing to assist in pre-conception planning.
Neurologic Exam
Continuing our discussion from last month’s blog about what to expect during an NF exam, I’d like to briefly review the components of the neurologic exam. First, mental status is evaluated by determining if the patient is awake and alert and able to understand and speak. For a child, this part of the exam involves an evaluation of developmental status, including a determination of whether the child can talk and follow basic commands in accordance with his or her age level. In addition, we evaluate the function of the 12 cranial nerves, which originate from the brain and brain stem and affect the head and neck. Each nerve has a specific sensory or motor function. For example, the 3rd, 4th, and 6th cranial nerves are responsible for eye movements and could be affected either by neurofibromas or problems in the brainstem related to NF. We also perform a visual assessment to evaluate functioning of the 2nd cranial nerve, the optic nerve, which carries visual information from the retina to the brain. People with NF may develop tumors on the optic nerve, called optic gliomas, that can cause loss of vision and can also affect hormone secretion in the pituitary gland that may lead to early onset of puberty. It’s important for children with NF to have a comprehensive eye exam yearly to check for symptoms of optic glioma.
Also as part of the neurologic exam, we evaluate the strength of the facial and jaw muscles, the tongue, and the neck and shoulders; muscle weakness in these areas may indicate a problem in the brain stem or a tumor on the nerve itself. Next, we evaluate the peripheral nervous system, which involves an assessment of overall muscle strength as well as reflexes and coordination. We look closely for asymmetry of motor strength, which could indicate the presence of a neurofibroma on the nerve as it exists the spine. Abnormal reflexes provide a possible indication that a tumor may be compressing the nerve or the spinal cord. The last component of the exam is the sensory evaluation. Some individuals with NF have symptoms of neuropathy, or peripheral nerve damage, which may include numbness, tingling, or burning sensations usually in the feet and hands.
Upcoming NF Symposium at Children’s Harbor, Applications of New Gene Editing Technology, and a Review of the NF Extremities Exam
Plans are finalized for the upcoming Neurofibromatosis Symposium to be held in the Bradley Lecture Center of the Children’s Harbor Building at Children’s of Alabama on Saturday, August 27th. This will be the first time the Symposium will be held in Children’s Harbor, a non-profit organization that supports seriously ill children and their families through educational and counseling services; we’re pleased that our NF Clinic has formed a collaboration with Children’s Harbor to enable our families to take advantage of the services they provide. Also known as NF Family Day, the NF Symposium is a half-day, free event, co-sponsored by UAB and the Children’s Tumor Foundation, that supports a key mission of our program in providing NF patients and their families with valuable information on a range of NF-related topics presented by clinical experts.
Janice Crow with Children’s Harbor will discuss the services offered by the organization and will be available to meet with parents one-on-one during the Symposium to discuss educational needs. Also, a tour of the facility will be available later in the day for those interested. Additional presentations during the Symposium will include an overview of NF1, NF2, and schwannomatosis as well as activities in the UAB NF Clinic; an update on clinical trials; developmental difficulties for children with NF; the natural history of dermal neurofibromas and upcoming clinical trials; and a review of advocacy, fundraising, and upcoming events. For the convenience of our families, breakfast, lunch, and childcare will be provided. Children participating in childcare in the Children’s Harbor facility will have access to a variety of activities including art projects, video games, and board games. While there is no cost to attend, reservations should be made by August 24th by emailing ashleycannon@uabmc.edu or calling 205-996-2916. The NF Symposium is an invaluable opportunity for NF patients and families, especially those facing a new diagnosis, to learn key information and answers to questions about neurofibromatosis. It also provides a unique forum for patients and families to connect with one another and gain understanding and strength through their shared experiences, challenges, and concerns. We look forward to serving our NF patients and families again this year through hosting this meaningful and informative event.
Neurofibromatosis Symposium: Family Day 2016
Saturday, August 27th, 2016
Schedule:
08:00-08:30 a.m. Register/Breakfast
08:30-8:45 a.m. Welcome – Dr. Bruce Korf
8:45-9:00 a.m. Children’s Harbor/Educational Assistance – Janice Crow
9:00-10:00 a.m. NF 101/Updates – Dr. Bruce Korf
10:00-10:30 a.m. Clinical Trials Update – Dr. Alyssa Reddy
10:30-10:45 a.m. Break
10:45-11:15 a.m. Developmental Difficulties – Dr. Michelle Kong
11:15 -11:45 a.m. Dermal Neurofibromas – Dr. Ashley Cannon
11:45-12:00 p.m. Advocacy, Fundraising, Upcoming Events – Renie Moss
12:00-12:30 p.m. Children’s Harbor Tour
12:30-1:30 p.m. Lunch
1:30 p.m. Closing Remarks
Applications of the CRISPR/Cas9 Gene Editing Technology
A question that frequently arises related to NF research is regarding the application of the gene editing technology CRISPR/Cas9 system. This technology allows investigators to “edit” the genome by targeting a particular gene sequence and changing it to something different. The technology has received a good deal of publicity lately, including a recent feature on the cover of TIME magazine.
The system has immediate application for creating models of disease. For example, if an investigator wants to create a mutation in mice or stem cell lines, the CRISPR/Cas9 enables targeting of the NF gene and introduction of a mutation. Our NF research program is currently using the technology for this purpose. The question is whether the technology could be used to restore the mutated gene back to normalcy. The challenge here is in targeting all the cells in the body. With a condition such as NF, in which the mutation causes the lack of production of a substance (neurofibromin) that affects growth of specific cells throughout the body, you would have to be sure to target every cell that could possibly form a neurofibroma. If you miss a cell that has the potential to form a neurofibroma, that particular cell could still grow into a tumor. For now, the technology does not enable correction of a mutation in every cell. There is much left to be learned about how the CRISPR/Cas9 system might be applied in the treatment of neurofibromatosis, however, so the possibility of it therapeutic use is in consideration.
NF Extremities Examination
Turning back to our previous discussion about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during an examination of the extremities. First, plexiform neurofibromas can affect the brachial plexus, a network of nerves that originate near the neck and shoulder and send signals from the spine to the arm and hand. Plexiforms can also affect the lumbar plexus, a network of nerves in the lower spine that send signals to the pelvis and legs. Some plexiform neurofibromas can cause infiltration of nerves in these areas that can compress the nerves and cause pain. In some cases, the presence of plexiform neurofibromas in these areas can cause a visible overgrowth of the extremity. In other cases, the problem presents with lower back pain. An MRI will confirm lumbar involvement. Due to the location in the body, these tumors are not surgically accessible; however, it is sometimes possible to perform surgery to help relieve pain. The other primary treatment option is pain management.
Another extremity-related problem that can occur is bone dysplasia, which is an abnormality of a long bone, usually involving the tibia in the leg but sometimes also affecting the fibula or even bones in the arm. This problem sometimes presents as a bowing of the leg in infancy, although it can be hard to diagnose that early because most infants have some normal leg bowing. By the time a child can stand, one can usually determine if this problem exists. An X-ray is performed to confirm dysplasia, and the child is referred to an orthopedist for treatment with a leg brace to prevent fracture. If the bone does fracture, it can be hard to treat. Also, surgery is difficult because the bone is not well formed. For this reason, prevention of fracture is important when this problem exists.
Plexiform neurofibromas can also affect any part of the foot or hand. While it’s not possible to surgically remove all of the tumor, surgery can be performed to remove a portion of the tumor (debulking surgery). Lastly, certain types of tumors discovered fairly recently, called glomus tumors, can occur under the nail beds of the fingers and toes in adults with NF. Although they are not easily visible, they are usually exquisitely painful with pressure applied at the tips of fingers and toes. Fortunately, they can be removed surgically to eliminate the associated pain. It’s important for NF clinicians and patients to be alert to this potential problem.
NF Clinic Genetics Counselor Receives Esteemed Scholars Award, Re-Cap of NF Forum, and What to Expect During an NF Genital Exam
In another special recognition of a dedicated individual in our local NF community, Renie Moss, tireless patient advocate, was recently presented with the Volunteer of the Year Award by the Children’s Tumor Foundation (CTF) during the CTF Volunteer Leadership Council Meeting in Austin, TX. Renie was recognized for her inspirational leadership and dedication to patient advocacy and increasing NF awareness nationwide as well as her unique spirit of caring and compassion for NF families. The NF community is very fortunate to have someone with Renie’s many talents dedicated to the cause of patient advocacy and education.
Re-Cap of NF Forum
Last month, 10 people from our NF program attended the annual NF Forum held in Austin, TX, which marks the largest group from our team to attend this meeting. The NF Forum is the largest worldwide meeting dedicated to NF, bringing together patients and families as well as more than 300 NF clinicians and scientists from around the world to discuss advances in patient care, treatment, and research. The meeting provides an invaluable collaborative environment in which to exchange ideas and research findings with international clinicians and scientists working in the field of NF. Several members of our team gave poster presentations summarizing research conducted as part of our NF research program. The meeting left all of us energized with new ideas and goals for our program. One of the most interesting aspects of this year’s meeting was learning about new animal models that have been developed using pigs instead of mice. The pig model replicates the features of NF1 more closely than the mouse model, providing significant research advantages. We’re currently establishing a collaboration with one of the groups that developed the pig model and are hoping to incorporate these models into our research in the near future.
NF Genital Exam
In continuing our discussion of what to expect during an NF exam, I’d like to briefly review issues that could be detected during a genital exam. The most relevant potential problem we’re looking for is evidence of early or delayed puberty. As clinicians, we’re looking for changes such as the appearance of pubic hair and an early growth spurt as indicators of precocious (early) puberty. Sometimes, precocious puberty occurs for no known reason, but usually it is associated with optic nerve tumors (optic glioma) that involve the nearby hypothalamus that controls hormonal production in the brain. If signs of precocious puberty are found, we use MRI to check for the presence of an optic glioma and obtain hormonal studies. We also arrange for referral to a pediatric endocrinologist. Early puberty is difficult for children both emotionally and psychologically, and it causes them to be significantly taller than their peers at a very young age, but, because of premature closure of the growth plate, ultimate height attainment is shorter than normal. Precocious puberty can be successfully treated hormonally; if there is an optic glioma, sometimes that, too, requires treatment, though if there is no impairment of vision or evidence of progression, the optic pathway tumor may not require treatment. Aside from precocious puberty, signs of puberty can also occur later than normal. If delayed puberty is suspected based on a lack of physical indicators such as pubic hair and an adolescent growth spurt, we would also perform hormonal testing and refer to an endocrinologist.
In some people with NF, plexiform neurofibromas can affect the genital region, sometimes causing an overgrowth of the genitalia in males and females. Surgical treatment can be performed in these cases to help manage the problem. In women, plexiform neurofibromas can also sometimes impinge on the uterus and cause issues during pregnancy that might require surgical treatment, though sometimes these are too large to be amenable to surgical resection.
Upcoming NF Symposium, Enhanced Patient Exam Procedure, and a Review of the NF Abdominal Exam
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the NF Community Advisory Board was developed last year with the objective of providing input and direction regarding patient information, education, support, and coordination of care. Comprised of NF patients and family members, the Board meets four times a year. During the Board’s second meeting of the year held last month, plans were discussed for the upcoming NF Symposium scheduled for August 27th. Also known as NF Family Day, this half-day, free event co-sponsored by UAB and the Children’s Tumor Foundation (CTF), provides valuable information to NF patients and families through a series of presentations given by clinical experts on a range of NF-related topics. The Board was very helpful in offering suggestions for this year’s Symposium, which will be held for the first time in the Children’s Harbor Family Center at Children’s of Alabama. Children’s Harbor is a non-profit organization that supports seriously ill children and their families through educational and counseling services. Although the previous NF Symposia have been held at the Kaul Building in the UAB Medical District, the Children’s Harbor Building offers better facilities and parking for this type of event. Also, our NF Clinic has formed a collaboration with Children’s Harbor so that our NF patients and families can take advantage of the educational and counseling services they provide.
Enhanced Patient Exam Procedure in the NF Clinic
We’re pleased to announce the addition of Tammy Skelton, MSN, CRNP, NP-C, a certified nurse practitioner, to our team of specialists in the UAB NF Clinic. Tammy is enhancing patient care by performing preliminary patient examinations after our certified genetic counselor, Ashley Cannon, MS, PhD, CGC, collects or reviews a patient’s history. After I review the history and notes from Tammy’s preliminary examination, I perform a more focused exam and talk to the patient/family. We then confer as a team regarding next steps. The feedback from our Community Advisory Board on this new procedure has been very positive. Our goal is to reduce the backlog of patients waiting to be seen in the clinic by streamlining the examination process. By having Tammy perform preliminary exams, we’re able to see more patients in clinic and spend more focused time with them. We’re hoping our NF patients and families will be pleased and that the new procedure will make us more accessible.
On another note, a team from our NF Program will be attending the Neurofibromatosis Conference in mid-June in Austin, Texas. We’re presenting several abstracts and participating in a series of workshops and presentations. Stay tuned for a re-cap of this important meeting in next month’s blog.
Review of the NF Abdominal Exam
To continue our discussion of what occurs during the typical NF examination, this month we will consider the abdominal portion of the exam. Because the abdomen is covered by a large expanse of skin, neurofibromas are usually very visible in this area; sometimes they are obvious, and other times they can be seen using a pen light to illuminate the skin from the side. We’re also looking for masses, although it’s not very common to feel a mass through the skin. While the liver and spleen can be palpated, these organs aren’t usually involved in NF.
The two main abdominal-related concerns in people with NF are episodes of nausea and sometimes vomiting, which tend to occur mostly in children, as well as the lower GI problem of constipation. Children with NF have a tendency to develop migraine headaches, and I find that stomachaches, nausea, and occasional vomiting are common presentations of migraines in children. Sometimes treating children for migraines can be effective in resolving gastrointestinal symptoms. Constipation also seems to be more common in people with NF, probably because the condition affects the nerves in the intestine.
It’s rare that a tumor is the cause of a GI problem. Although plexiform neurofibromas can occur in the abdomen, they are usually too deep to palpate and are mostly asymptomatic. Tumors can also occur in the wall of the intestine, but these are usually also asymptomatic, though sometimes they can cause obstruction or bleeding. Gastrointestinal stromal cell tumors are more common in people with NF1 than in the general population. They present with abdominal pain and bleeding in the GI tract. It’s important that an individual with abdominal pain and blood in the stool be evaluated for this potential problem. Lastly, some people with NF may develop a specific type of tumor on the adrenal gland called pheochromocytoma. The most common presentation is high blood pressure, which is caused by increased secretion of the hormones epinephrine and norepinephrine. Some people may also experience episodes of skin flushing and a racing heart. If symptoms are present, a blood test is performed to determine the presence of elevated hormone levels. If this is confirmed, a 24-hour urine collection is performed to further detect the presence of increased hormones followed by a scan to identify the tumors. If they are found during a scan, careful surgical removal is required as the treatment.
Sources of Variability in NF and What to Expect During an NF Chest Examination
Sources of Variability Among People with NF
The first possible source of variability is the specific genetic mutation associated with NF in an individual. More than 3,000 mutations have been identified in the NF1 gene, and there a few examples in which a specific mutation can be correlated to certain NF symptoms. The UAB Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene. While it is probable that certain mutations do predict specific NF symptoms, it’s also very likely that most mutations don’t predict the specific NF features or the course of the condition.
Another factor that likely plays a role in the variability of NF is an individual’s genetic background. Because individuals express genetic variants across the genome, it’s likely that there are other genes that can influence the manifestations of NF. Evidence for this phenomenon can be seen in mouse models. When the NF1 gene is introduced into genetically distinct strains of mice, the manifestations of NF can be very different. It seems likely that an individual’s distinct genetic background can help to determine the symptoms of NF that he or she experiences. It is difficult to design human studies to look for this phenomenon, however, due to the need to determine phenotypes (symptoms) and perform genetic sequencing on hundreds of patients, though efforts are underway to try to address this issue.
We are reasonably certain there is also a random nature to some of the physical manifestations of NF. Each individual is born with two copies of the NF1 gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or in most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. This “second-hit” mutation seems to be a random event that leads to a specific complication, such as a neurofibroma. It is possible that there may be factors in a person’s genetic background that increase the likelihood of a “second-hit”mutation.
NF Chest Examination
Turning back to our discussion in the previous blog about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during a chest examination. Because people with NF have an increased risk of congenital heart defects, the chest exam includes listening for a specific type of heart murmur associated with pulmonic stenosis. This condition causes a narrowing of the pulmonary valve, interfering with blood flow from the heart to the lungs. However, the condition is not as common in NF as in other RAS pathway disorders.
While the lungs are not commonly affected in NF, some adults may experience emphysema-like changes thought to be related to NF. It is also possible for neurofibromas to develop in the chest, which can interfere with inflation of the lungs and with breathing. Occasionally, we can feel a nodular neurofibroma at the base of the neck or near the collarbone. Some people develop plexiform neurofibromas deep inside the chest, although we usually don’t see plexiform neurofibromas in the lungs or heart muscle. The only treatment for plexiform neurofibromas is surgical removal, which is reserved for cases in which important structures are affected.
Sometimes a bony deformation of the chest wall, called pectus excavatum, can occur in people with NF. The condition causes a depression in the breast bone and usually doesn’t result in problems or require treatment unless it interferes with lung inflation and breathing. In these cases, surgical treatment can be offered. Another condition, called pectus carinatum, causes the chest wall to bulge out, probably due to disproportionate rib cage growth. In most cases, the condition doesn’t require treatment.
In some people with NF, spinal tumors can become large enough that they can push on the lungs, which may require surgical removal of the tumors if breathing is affected. Also, people with NF are at increased for developing abnormal tissue growth inside of blood vessels, including major arteries in the heart and lungs. This condition weakens the vessel wall and leads to narrowing and possible rupture, which is a serious emergency. Sudden onset of severe chest or abdominal pain is a symptom that this condition may be present, indicating the need for diagnostic testing, though many other things can lead to pain other than vascular rupture.
NF Awareness Month
Finally, I’d like to remind everyone that May is NF Awareness Month. The Children’s Tumor Foundation has developed a number of activities to inform the public about NF [http://www.ctf.org/NFawareness], and there will be events here in Birmingham as well. Keep an eye on our Facebook page [https://www.facebook.com/uabnfprogram/], as well as the Neurofibromatosis Alabama page [https://www.facebook.com/Neurofibromatosis-Alabama-Childrens-Tumor-Foundation-203255213153983/] for further details.