As a new year begins, plans are underway for the 8th Annual Rare Disease Genomics Symposium to be held on February 26th and 27th.  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.