- Written by Bruce Korf
I am completing this blog post just hours after finishing the New York City half marathon with a team from the Children’s Tumor Foundation. It was a cold start, but otherwise a beautiful day – a lot nicer than the rain/snow mix the day before. We were raising funds for the Children’s Tumor Foundation and it’s not too late to add to the dollars contributed. My fundraising page is at: https://join.ctf.org/fundraise?fcid=674407. Any help in reaching my goal would be greatly appreciated!
UAB Rare Disease Genomics Symposium Advances Role of Genomics in Everyday Medicine
The fourth annual Rare Disease Genomics Symposium, held March 3rd at UAB, was a successful and well-attended 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. As a rare disorder, NF1 is a condition that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders. Titled Genetics and Genomics in Day to Day Medical Practice, this one-day seminar covered a range of topics on the application of genomics in medicine. The Symposium featured a panel discussion led by parents of children with rare diseases that provided insight into the challenges and emotional needs of families of children with a genetic condition. One of the parents on the panel was the newly appointed director of the UAB Hugh Kaul Personalized Medicine Institute, Matthew Might, Ph.D., who provided a personal perspective of the potential of genomic medicine, as his son was diagnosed with a rare genetic disorder in 2012. The Symposium serves as an important forum for presenting topics to faculty and clinicians at UAB and in the community that demonstrates the increasingly important role of genomic medicine in the diagnosis and management of rare disorders.
Visual Screening in Children with NF1
I’d next like to discuss the issue of visual screening in children with NF1. As I’ve mentioned previously, the primary concern regarding visual problems is the development of an optic glioma, a tumor of the optic pathway, which occurs in approximately 15% of children with NF1. Most of the time, these tumors occur early in life, usually between the ages of 18 to 24 months. More than half of patients with optic gliomas have no symptoms. The most common presentation in patients who show symptoms is loss of visual acuity, and/or loss of peripheral vision, although other symptoms may include proptosis, or bulging of the eye; swelling, retraction, or drooping of the eyelid; and the onset of early puberty, which results in abnormally short stature in adulthood.
Although optic gliomas are fairly common in NF1, the majority do not require treatment. Fewer than half of optic gliomas in children with NF1 do progress and require treatment with chemotherapy. An important question for clinicians is how to identify those patients with optic gliomas who need treatment.
The current consensus recommendation for identifying NF1 patients with optic gliomas is to perform a comprehensive ophthalmologic assessment one time per year beginning at the age of diagnosis until late childhood, as the greatest risk for development of these tumors is through approximately the first six years of life. Ophthalmologic exams – which include tests for visual acuity, peripheral vision, and optic nerve health – are often difficult to perform in young children. For this reason, some ophthalmologists are testing advanced tools for administering exams in these patients. Sometimes, parents ask whether a school eye exam will suffice, and the answer is that it will not. Appropriate screening for optic glioma and other vision problems in children with NF1 requires a comprehensive eye exam administered by an experienced ophthalmologist.
If concerns arise based on the ophthalmologic exam, a brain MRI scan would be performed. If an optic pathway tumor is found, this may lead to more closely following the child’s visual function and monitoring growth of the tumor using MRI. If there is radiographic evidence of tumor growth but no symptoms are present, often it is possible to continue close clinical and radiographic follow-up without initiation of treatment. Some of these tumors grow for a period of time and then stop, and in rare cases may even regress. Because of this, if a tumor does not cause symptoms, treatment may not be necessary. Some clinicians prefer to obtain a baseline MRI scan of the brain in all children with NF1. I do not tend to do this, since identifying an optic glioma in a child with NF1 using MRI is not in itself an indication to begin treatment if there are no symptoms of tumor growth. We may be missing some optic gliomas by not using MRI as a screening tool, but if we’re not going to treat unless we see symptoms, the value of using an MRI to identify one in an asymptomatic child is unclear. This is consistent with current consensus recommendations for screening for optic glioma.
In the area of research for optic gliomas, there is an ongoing natural history study that is collecting data on NF patients with optic gliomas to help identify risk factors to predict those who will need treatment and those who will not (http://www.ctf.org/news/the-ctf-and-gilbert-family-nf-institute-opg-consortium-is-underway). Also, because the UAB Medical Genomics Laboratory performs the highest volume of NF genetic testing of any laboratory in the world, we have some limited data on patients with optic gliomas that may be used to identify gene mutations that might be associated with these tumors. Lastly, our program is exploring the development of more advanced ophthalmologic assessment tools for use in children with NF1.
- Written by Bruce Korf
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.
- Written by Bruce Korf
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.