Need for Effective Treatments

I’d like to focus this month’s blog post on a discussion of cutaneous neurofibromas, which are benign tumors that can grow on nerves throughout the body in some individuals with NF1. Typically beginning around the time of puberty, these tumors grow from small nerves either in or under the skin and appear as small bumps on the surface of the skin or as purplish spots when the tumors occur underneath the skin.  Although these tumors are sometimes also referred to as “dermal neurofibromas,” NF clinicians and scientists at a recent meeting of the Neurofibromatosis Therapeutic Acceleration Program (NATP) emphasized the need to move away from using this term in favor of the term “cutaneous neurofibromas.” The dermis is actually not the layer of the skin from which neurofibromas originate, while “cutaneous” is a general term referring to the skin and is therefore a more accurate term for these tumors.

In the past, we have found that obtaining funding for clinical trials of cutaneous neurofibromas has been somewhat difficult. Because these tumors are non-malignant and not life-threatening, the question often posed is:  Why is it necessary to treat cutaneous neurofibromas? Conversely, plexiform neurofibromas are much more serious and sometimes life-threatening due the risk of malignancy and the possibility of compression of the airway or the spine.  However, it is also true that cutaneous neurofibromas may be unfairly trivialized in their impact on the lives of individuals with NF. We receive numerous inquiries asking why cutaneous neurofibromas are not the subject of clinical trials.  Data indicate that quality of life for people with cutaneous neurofibromas can be significantly impaired. There are sometimes cosmetic concerns in a major sense, as these tumors may be quite disfiguring.  Also, the tumors may itch, can sometimes bleed, and even cause pain. 

Research Focused on Cutaneous Neurofibromas

A longitudinal study has been in progress at UAB for the past several years focused on understanding how cutaneous neurofibromas grow and change over time. As part of the study, 22 participants have had their neurofibromas counted and measured every three months. Our NF Program Genetics Counselor, Ashley Cannon, MS, PhD, CGC, assumed the principal investigative role in the study when she joined our program in 2015 and has now completed an analysis of eight years of quantitative data on many of the original study participants.  Dr. Cannon recently presented the study findings at the conference of the American College of Medical Genetics and Genomics (ACMG) in Phoenix and is preparing the results for upcoming publication. 

These findings will also serve as the basis of an upcoming clinical trial at UAB that will test the effectiveness of a systemic treatment for cutaneous neurofibromas administered in the form of a pill.  While development of a topical treatment was considered, it can be difficult to formulate a compound that permeates the skin layer. Also, for some people, cutaneous neurofibromas are too widespread on the body for a topical treatment to be effective.  Additional information about the trial and details about upcoming recruitment can be found at www.clinicaltrials.gov.

In other research for cutaneous neurofibromas, we are exploring other potential treatments for future clinical trials of cutaneous neurofibromas.  We’re also working to find ways to restore function to mutated genes or gene products, which could provide new ways of treating these tumors. Researchers at UAB are currently studying the more than 3,000 NF mutations contained in the library of the UAB Medical Genomics Laboratory to determine whether particular mutations increase the likelihood for cutaneous neurofibromas to occur. We know of two mutations that do not produce neurofibromas of any type. There are other mutations that don’t produce cutaneous neurofibromas but do produce neurofibromas deep inside the body (plexiform neurofibromas). We are currently developing animal models and other types of model systems to understand the characteristics of specific mutations with the goal of developing new treatments for cutaneous neurofibromas.
Raising Funds for the Children’s Tumor Foundation

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. 
Adult and Pediatric Clinic Relocations Continue to Reap Benefits

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.