This month’s blog post launches a series highlighting the three main categories that comprise our UAB NF Program – clinical care, research, and education. I’ll provide an overview of our program in these areas, while upcoming posts will give more in-depth information about specific aspects of the program and feature insights from our clinicians and scientists.

Before beginning this month’s blog topic, I want to mention a couple of developments related to our UAB NF Program.  First, one of the adult neuro-oncologists who worked with patients in our NF Clinic, Mina Lobbous, MD, recently left UAB for a position at another medical center.  I know that many of our patients benefitted greatly from Dr. Lobbous’s expertise, and we wish him well in his new role.  However, adult NF patients in our clinic still have the same access to specialists in the UAB neuro-oncology group, which assists NF patients with the management and treatment of NF-related neuro-oncological issues, including brain and spinal tumors and complex plexiform neurofibromas. In another development, we are planning a virtual UAB NF Symposium Family Day, scheduled to occur on Saturday, April 30. As we have for the past two years, we are holding this important event virtually this year to limit the spread of COVID-19. This free, half-day event, co-sponsored by the UAB Department of Genetics and the Children’s Tumor Foundation (CTF), gives patients and families the opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. The agenda will be posted shortly on our UAB NF Program website (link) and Facebook page (link).

Previously, I have discussed the fact that NF is a highly variable condition that can express differently among affected individuals. For example, two people within the same family can have very different symptoms of the condition. In this post, I’ll briefly review the genetics and inheritance patterns of all forms of NF and discuss the primary reasons for variability in expression among people with NF.

The focus of this month’s blog post is a discussion of malignant peripheral nerve sheath tumors (MPNSTs), which represent one of the few potentially life-threatening complications of neurofibromatosis type 1. Because these tumors, which occur in about 10% of people with NF1, are not responsive to any known mode of treatment when they have spread through the body, early diagnosis and surgical treatment are currently important for a better outcome. Clinical trials are underway to identify more effective approaches to early detection and treatment.

In early May, the UAB NF Clinic resumed in-person visits as the COVID-19 vaccine became widely available and cases decreased significantly in most parts of the U.S. However, due to the later resurgence of COVID-19 cases related to the Delta variant, UAB clinics were again encouraged to utilize telemedicine as much as possible to reduce viral transmission and protect patients. Before the pandemic, our NF Clinic had plans to integrate telemedicine into patient care. The explosion of the pandemic in early 2020 served to accelerate our adoption of telemedicine as a practical tool that allowed us to continue serving patients. As telemedicine continues to play an integral role in patient care in the UAB NF Clinic, I’d like to discuss the limitations and benefits of the technology as well as the potential role of telemedicine in the future of patient care.

In May, revised diagnostic criteria for NF1 were published in Genetics in Medicine, the journal of the American College of Medical Genetics and Genomics (Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation | Genetics in Medicine (nature.com). The revised criteria are the product of a systematic, multi-year collaborative project of more than 90 NF experts from the international scientific community to arrive at a broad consensus.

We are pleased that in-person visits have resumed in our UAB Adult NF Clinic each Thursday in the Whitaker Building and in our Pediatric NF Clinic on the second and fourth Tuesday of each month at Children’s of Alabama.  To ensure the continued safety of patients and staff, requirements for masking and social distancing remain in place, and each person entering the clinic will also be screened for fever. We also plan to continue utilizing telemedicine visits because of the convenience and improved access this method provides our patients, particularly when reviewing test results or following up after an in-person visit. Because pre-pandemic licensing restrictions have been restored, our telemedicine visits are now limited to patients in Alabama and Florida.

As our UAB NF Clinics resume in-person visits for the first time since the start of the pandemic, this is a good time to address a question that patients frequently ask: How often should an individual with NF be seen in an NF specialty clinic? The answer is that the frequency of clinic visits depends on whether an individual with any of the three forms of NF is experiencing active problems that require frequent follow up. For example, regular clinic visits are part of the treatment plan for individuals taking the medication selumetinib. However, for people with NF who are stable and doing reasonably well, the general recommendation is to be seen by an NF specialist about once a year. While the guidance for an annual clinic visit is somewhat arbitrary, it is straightforward and easy to remember for most people and helps to maintain an active relationship with a care provider, as well as identify potentially treatable complications as early as possible.

In my experience, this guideline is generally well-followed for children with NF but less so for adults. There are several reasons for this, including the fact that parents often prioritize their children’s healthcare over their own. Also, NF can evolve rapidly in childhood, and it’s important for children to be monitored for the development of complications such as optic glioma, scoliosis, bone dysplasia, and plexiform neurofibromas. Another impetus for parents to have children seen annually is that most children are well-covered by either private insurance or Medicaid, whereas some adults may not have adequate insurance coverage for annual visits.

Adults with NF who are experiencing few active symptoms may question why it’s necessary to have an annual NF clinic visit. The rationale for yearly clinic visits for adults is that they provide an opportunity to catch the signs of serious complications such as malignant peripheral nerve sheath tumors (MPNSTs) or hypertension that might otherwise go unnoticed until they are advanced. Another 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, such as selumetinib, that did not exist a few years ago. Also, 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 eventually arise.

Because 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, we may consider other options to make this easier for established patients, such as alternating annual in-person visits with telemedicine visits. This option might help ease the time and financial burden for many patients by giving them more flexibility and convenience. If something concerning arises during a telemedicine visit, we can schedule an in-person visit to follow up.

A Final Note

Just as this month’s blog was being completed, new diagnostic criteria for NF1 and Legius syndrome were published.  This is an important advance in clinical care for NF patients.  I will cover this in detail next month.

Before beginning this month’s blog topic about NF issues related to COVID-19, I’d like to mention that our annual UAB NF Symposium Family Day was held on Saturday, March 13, as a virtual event this year. Co-sponsored by the UAB Department of Genetics and Children’s Tumor Foundation (CTF), this half-day, free event typically occurs in the fall each year. While concerns about COVID-19 did not allow the Symposium to be held in person at the usual time of year, we felt it was important to host the event in a virtual format this year to give patients and families the same opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. The event also provides an important way for families to establish a connection with others sharing the same journey, which can be especially meaningful for those who are newly diagnosed.

This year’s Symposium opened with an overview that I provided of NF clinical care and research, now and into the future. Other featured speakers included UAB adult neuro-oncologist Mina Lobbous, MD, who gave a presentation on adult care as well as a clinical trials update, as well as UAB pediatric neuro-oncologist Katie Metrock, MD, who provided a talk on pediatric care and clinical trials research. The event also included a question-and-answer session featuring Dr. Lobbous, Dr. Metrock, and me. I’m pleased to report that we had more than 180 participants at this year’s Symposium, which exceeds typical attendance at the in-person event. A clear benefit of the virtual format is that it allows for greater participation by eliminating the need for participants to travel. Although most attendees in past years have been from our immediate geographical region, this year we had many participants from around the nation and overseas.  It was rewarding that our reach expanded significantly this year due to the virtual format and that we were able to provide NF patients and families with important information from clinical experts.  Based on this experience, we will be exploring the possibility of continuing to have a virtual meeting option for future symposia.

UAB NF Clinic Developments

In news related to the UAB NF Clinic, we are planning to resume in-person appointments in the UAB NF Clinic in May as clinic staff become vaccinated against COVID-19. Even when in-person visits begin, we will continue conducting telemedicine visits indefinitely because of the benefits this format provides to our patients in terms of convenience and improved access in certain instances. During the pandemic, medical licensing restrictions on providing care to patients in other states through telemedicine were loosened, allowing us to serve patients outside of Alabama. Many of these restrictions have been restored, so our ability to offer telemedicine visits to patients outside Alabama is limited, but we expect to continue to offer the option of telemedicine within the state into the future.  It is possible that, in the future, there will be greater access to telemedicine even outside the state.

Considerations for Individuals with NF Related to COVID-19

At the start of the pandemic, we discussed the question of whether people with NF are at greater risk of complications from COVID-19. As explained at that time, there is no evidence of immune dysfunction in people with NF that puts them at greater risk of complications from the novel coronavirus. However, individuals with NF who have specific medical problems with lung involvement might be at greater risk of complications of COVID-19 illness, including people with large plexiform neurofibromas in the chest cavity, chronic lung disease, or severe scoliosis, all of which can impair lung function.

Many NF patients are also understandably concerned about whether there is any safety risk of the vaccine for people with NF; fortunately, we have no evidence of specific safety concerns related to the COVID-19 vaccine in people with NF.  Those who are on treatments that would depress the immune system, such as chemotherapy for a malignant tumor, should discuss the safety and efficacy of vaccination with their health provider.  Lastly, some people are concerned about whether the Pfizer and Moderna vaccines, both of which are mRNA-based vaccines, can interact with the NF1 gene or its mRNA transcript. Messenger RNA (mRNA) is the RNA copy of a specific gene that is the code used to make a protein.  In the case of NF1 the protein is neurofibromin, for NF2 it is called merlin; for the vaccine, it is a protein that is unique to the virus.  It is important to understand that these mRNAs have nothing to do with one another and do not interact with one another.  Hence, there is no danger that the COVID-19 vaccine mRNA will have any adverse effect on the function of the NF1 or NF2 mRNA or the NF1 or NF2 genes.  The vaccines also do not modify the DNA in any way, and therefore do not pose any specific safety risks to persons with any form of NF.

As a new year begins, plans are underway for the 8^th Annual Rare Disease Genomics Symposium to be held on February 26^th and 27^th.  The two-day event will be virtual this year to limit the spread of COVID-19, and that, in turn, will make it more accessible to participants, even those who reside far from Birmingham. As in previous years, the Symposium is designed to share information about the role of genomics in the diagnosis and treatment of rare disease with members of the community and healthcare practitioners who are non-genetic specialists. While the event is not specific to neurofibromatosis, NF1 is a rare disorder that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders. To view the full Symposium agenda or to register, please visit: 8th Annual Rare Disease Genomics Symposium - School of Medicine - Genetics | UAB

The focus of this month’s blog post is to discuss the difference in treatment options for plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). While medications called MEK inhibitors can help treat plexiform neurofibromas in approximately 2/3 of individuals with NF1, treatment options for MPNSTs are more limited. Many patients understandably want to know whether MEK inhibitor drugs will successfully treat MPNSTs. These tumors occur in about 10% of people with NF1 and represent one of the few potentially life-threatening complications of the condition. The tumors occur mostly in teens and young adults with NF1 and usually arise from pre-existing plexiform or nodular neurofibromas. Atypical neurofibromas, which have distinct clinical and pathological features, may be a precursor to the development of an MPNST. These atypical tumors appear as homogenous nodules that, if superficial, have a firm consistency when palpated. MEK inhibitor drugs are not currently part of the standard treatments for MPNSTs, although clinical trials are underway to investigate the effectiveness of using MEK inhibitor drugs in combination with other medications to treat these tumors. The approach of using several biological compounds together as part of a treatment regimen is common in cancer treatment.

The difference in treatment options for plexiform neurofibromas and MPNSTs is based on fundamental differences in the genetic drivers of these tumors. Plexiform neurofibromas have the NF1 germline mutation, which is a genetic change that occurs in the egg or sperm cell that is passed directly from a parent to a child or arises due to a new mutation. This NF1 mutation is present in every cell of the body. For a neurofibroma to develop, a random genetic mutation must occur to the second copy of the NF1 gene in the tissue that will become the neurofibroma. (Remember that everyone has two copies of every gene, other than those on the X or Y chromosome.) This is referred to as the “second hit” mutation.  Except for these genetic changes to the NF1 gene, plexiform neurofibromas are usually genetically normal. MEK inhibitors block a component of the Ras/MAPK signaling pathway, called MEK, that is hyperactive in cells in which both copies of the NF1 gene have been impaired. Selumetinib is a MEK inhibitor drug recently approved by the FDA for treatment of plexiform neurofibromas in children and is the first medication specifically approved for use with NF1.

In contrast to plexiform neurofibromas, MPNSTs have numerous genetic changes, or mutations, that are characteristic of cancer. Cancer cells are fueled by an accumulation of genetic changes that drive altered cells to divide rapidly and spread throughout the body. The genetic changes in MPNSTs make these tumors difficult to control. While chemotherapy is still useful in treatment, these tumors continue to acquire rapid genetic changes that often cause them to develop resistance to chemotherapy and other traditional cancer treatments after a period of time.

Due to the features of MPNSTs that present challenges for treatment, the question is: What are the treatment options for MPNSTs?  Current treatments usually include surgery and may also include radiation or chemotherapy.  Looking to the future, there are at least three possible areas for treatment for future development.

• Genome sequencing provides information about the genetic landscape of malignant tumors, helping to identify genes that are drivers of these tumors. Using this information, therapies may be developed that effectively target these genes.
• Immunotherapy, which trains the individual’s immune system to attack tumors, is an important new area of potential treatment, though not yet tested extensively on MPNSTs.
• Because MPNSTs are difficult to treat, early detection may be the best way to treat these tumors. It is important to report instances of chronic pain or rapidly growing tumors. Studies are underway to find better indicators of tumors that have a potential to become malignant to facilitate early detection and treatment.

When the NF1 gene was discovered in 1990, it was quickly learned that the gene product functions as a regulator of a protein called Ras.  Ras is a key component of a cell signaling pathway that controls cell growth and development.  This pathway involves multiple proteins that are involved in transmission of signals received at the cell surface to regulation of genes in the cell nucleus.  In more recent years it has been learned that variants in genes that encode these other proteins also lead to medical disorders, which now are collectively called “Rasopathies.”  These have distinctive, but in some cases overlapping, clinical features.  I will briefly review some of these features here.   

Syndromes Associated with Disruptions in the RAS/MAPK Pathway

Legius syndrome – This condition, which produces café-au-lait spots, skin fold freckles, and learning disabilities, is due to a mutation of the SPRED1 gene.   Leguis syndrome can be impossible to distinguish from NF1 in young children who have only café-au-lait spots and skin fold freckles; other features of NF1, especially neurofibromas, are not seen in Legius syndrome, but even in NF1 these may take years to develop.  Diagnosis of Legius syndrome is done by genetic testing of the SPRED1 gene, which is usually tested alongside the NF1 gene in evaluation of a child with multiple café-au-lait spots.  NF1 is much more common than Legius syndrome, so most children with multiple café-au-lait spots will turn out to have NF1, but for those few who do have Legius syndrome, there is less need to carry out surveillance for tumors.

Noonan syndrome –  Noonan syndrome is characterized by short stature, cardiac defects, characteristic facial appearance, and learning and developmental problems.   It has long been noted that some people with NF1 have facial features similar to those with Noonan Syndrome, and now it is clear that the reason for this is that the conditions share a disruption of Ras signaling.  Also, some people with Noonan syndrome have café-au-lait spots, and even neurofibromas, that may overlap with NF1.  Noonan syndrome is caused by a mutation in any one of many genes that encode various proteins involved in Ras signaling, including some forms of Ras itself.  This alteration of the normal RAS/MAPK signaling disrupts the regulation of cell growth and division, resulting in the characteristic features of Noonan syndrome.

Cardiofaciocutaneous (CFC) syndrome – This condition does not share many characteristics with NF1.  It can be caused by mutations in any one of several genes involved in the Ras pathway, and affects many parts of the body, including the heart, skin, and facial features. People with CFC also have developmental and intellectual disability, ranging from moderate to severe.

Costello syndrome – This disorder affects many parts of the body, including the heart and skin, and is also characterized by developmental and intellectual disabilities and distinctive facial appearance.  Costello syndrome is associated with mutations in the gene that encodes one of the many Ras proteins, called HRAS.  

Mechanism-based Therapies as Potential Treatments for RASopathy Disorders

An important question that has emerged in recent years is whether mechanism-based therapies developed for NF1, such as MEK-inhibitor treatments, may be effective in treating other RASopathy disorders. Mechanism-based therapies that inhibit the over-activated RAS pathway and other RAS-connected pathways may open new avenues of therapeutic intervention for the many complications of the RAS-related disorders. When considering the potential effectiveness of inhibitor-based therapies, there are a few factors that present challenges in using these therapies to treat RASopathies other than NF1. It is unclear whether the cognitive or developmental manifestations can be improved with treatment, for example.   Another consideration is that it’s relatively straightforward to evaluate treatment success in people with NF because tumor growth is measurable.  Identifying such measurable outcomes for other Rasopathies may be more difficult.  A notable exception is the occurrence of cardiomyopathy in several of the Rasopathies.  Cardiomyopathy is a failure of the function of heart muscle and can be debilitating and even life-threatening in some with Rasopathies.  This important manifestation is a subject for study of medications that inhibit Ras signaling.

Lastly, our NF Clinic is continuing to see patients for routine visits using telemedicine as part of an effort to slow the spread of COVID-19 and protect our patients. Telemedicine has been helpful in addressing specific patient concerns, arranging diagnostic testing, and discussing the results of imaging and other tests. Though we’re looking forward to seeing patients for in-person clinic visits again in the near future, we also believe many of our patients will continue to benefit from the enhanced access and convenience that telemedicine can provide, and we’ll be  glad to provide this option going forward.  

One of the most impactful events that our program sponsors each year is the UAB NF Symposium Family Day, a free half-day event that gives NF families and patients an opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. Co-sponsored by the UAB NF Program and the Children’s Tumor Foundation (CTF), the Symposium also offers a venue for NF families to connect with others who are sharing the same journey, which can be especially helpful for those who are newly diagnosed. Unfortunately, this year’s NF Symposium Family Day was cancelled due to concerns about COIVD-19, although we’re currently considering the possibility of rescheduling the Symposium as a virtual event for a date in 2021. Through our program’s frequent use of Zoom and other online meeting platforms during the pandemic, we realize that a virtual event can be easier for many people to attend than an in-person event. However, a disadvantage of a virtual event is that it eliminates the possibility of face-to-face interaction and networking that has become a meaningful part of this event in past years.  I’ll provide updates here as our plans develop regarding the possibility of a rescheduled, virtual event next year.

Brain MRI Findings in NF1

In this post, I’d like to discuss a few characteristic brain MRI findings that can occur in people with NF1, including T2 hyperintensities. These are also sometimes referred to as “unidentified bright objects” (UBOs) or “NF spots.” These are benign lesions that appear brighter on specific MRI sequences, predominantly in the basal ganglia, thalamus, brainstem, and cerebellum. These lesions do not enhance with contrast on MRI and are considered an incidental finding that do not require additional follow-up. However, if the lesions enhance with contrast on MRI or exert pressure in the brain, this could indicate the presence of a low-grade glioma, which requires more active follow-up. 

Most children with NF1 have these changes, but these eventually regress and may disappear without causing neurologic problems. Some literature suggests that people with a larger number of these changes, or their presence in specific brain regions, have an increased risk of learning disabilities.  I haven’t found that MRI changes are that useful in clinical practice to predict learning problems, however. The presence of these signal changes has not been used as part of the diagnostic criteria for NF because similar changes sometimes can also occur in individuals who do not have NF. Therefore, brain MRI is not a critical component of the diagnostic evaluation of NF1, unless there are signs or symptoms suggestive of a problem in the brain.

In some children with NF1, the corpus callosum – a large c-shaped bundle of nerve fibers that connects the two hemispheres of the brain – is thicker than normal. This condition may be associated with learning problems, but not with other neurological problems. Another incidental MRI finding sometimes seen in people with NF1 is the presence of Chiari malformation, a structural defect in which part of the cerebellum and brainstem extends below the foramen magnum and into the upper spinal canal. In most people, this condition is mild and doesn’t cause any problems. However, in some individuals it can cause headaches or neurologic problems and requires surgical correction.

A final NF complication that may be diagnosed by brain MRI is the occurrence of occlusion of a major artery to the brain.  This occurs in a small proportion of affected individuals, and in most cases is asymptomatic.  The reason there may be no symptoms seems to be that alternative pathways of blood flow develop, as the occlusion seems to occur slowly, probably over a period of years.  In some instances, however, this collateral circulation may not be able to keep up with demand and can lead to symptoms due to transient reduction of blood flow, or even a stroke.  Detection of this altered blood circulation can be done with MRI, particularly a method called MR angiography, which visualizes blood vessels.  It’s not something we do routinely in all individuals with NF1, but may be done if there are signs or symptoms suggestive of a problem with blood flow.  Sometimes you may hear the term “moyamoya,” which is the name given when multiple small collateral blood vessels are visualized.  Moyamoya can occur to anyone in the population, usually for unknown reasons, but is more common in those with NF1.  If an occluded artery to the brain is identified, it is common to prescribe baby aspirin as a mild blood thinner in the hope of reducing the risk of stroke.  In some cases, a surgical procedure can be performed to attach a blood vessel in the brain to another blood vessel to bypass the blockage.  This disorder of cerebral blood flow is one example of a risk of occlusion of arteries that can occur in some individuals with NF1, affecting for example the renal arteries (arteries to the kidneys) or others.  I’ll go into more detail about this in a future post.