Neurofibromatosis Type I in Adults

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Neurological institute. Neurofibromatosis type 1, a genetic condition that predominantly affects the skin and nervous system is associated with a range of medical and neurobehavioral complications, including the development of both non-malignant and malignant tumors. Neurofibromatosis type 1 is typically diagnosed in childhood, meaning that patients require long-term management and follow up care as they progressed into adulthood.

In today's episode, we're discussing care of adults with neurofibromatosis type 1. I'm your host, Glen Stevens, neurologist/neurooncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Mina Lobbous join me for today's conversation. Dr. Lobbous is a neurologist, neurooncologist in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center within Cleveland Clinic's Neurological Institute. Mina, welcome to Neuro Pathways.

Mina Lobbous, MD, MSPH:

Thank you. Thank you.

Glen Stevens, DO, PhD:

So Mina, tell us a little bit about your background, how you came to Cleveland Clinic, about your interest in neurofibromatosis, or fake mitosis in general.

Mina Lobbous, MD, MSPH:

So I trained at University of Alabama at Birmingham where I did my residency, my fellowship, my master's degree, and I had the privilege of working with Dr. Alyssa Reddy during my residency. She now leads a UCSF Neurofibromatosis Center. And then I trained with Dr. Bruce Korf as you know him. He's one of the international experts in the field of neurofibromatosis.

So I was fortunate to have the opportunity to train with great mentors, get to experience firsthand care for pediatric and adult patients with neurofibromatosis, drug development. And then moved to Cleveland Clinic in 2022, joined the Brain Tumor Center, it's a top-notch academic institute with great colleagues and international reputation, in the field of neuro-oncology. And here, we're standing on the shoulder of giants in the field of neurofibromatosis with Dr. Rothner in caring for children with NF1.

Glen Stevens, DO, PhD:

Well, we're very happy to have you at the Cleveland Clinic and certainly for those listening to the podcasts that are in the geographic area, if you have patients with neurofibromatosis, Dr. Lobbous will be happy to see those patients. And again, offers a multidisciplinary approach as you'll hear as we move forward.

So let's get started with the basics. Give us an overview of NF1 and its mechanism. I always remember that, you know the word, von Recklinghausen disease. So Dr. von Recklinghausen, as I recall, was a pathologist and what I really remember from medical school was that von Recklinghausen has 17 letters in it, and NF1 is on chromosome number 17. And that's how they said you could always remember the chromosome associated with it. Although we really don't hear his name associated with it much anymore. But he described it back in the late 1800s, although clearly many cases discussed before then. But tell us about NF and how we diagnose the criteria, those types of things.

Mina Lobbous, MD, MSPH:

So neurofibromatosis also known as NF, it's a genetic disorder that affect about one in every 3,000 people. There are three types of NF that's NF1, NF2 and schwannomatosis. And as you said, NF1 formerly known as von Recklinghausen disease. In fact, the NIH director, Dr. Francis Collins, who led the NIH through the COVID pandemic was on the team that discovered the NF1 mutation in the early '90s. And there is even now an award for recognizing his legacy in the field of Francis Collins Award for research done in the field of neurofibromatosis. But again, NF1 is the most common form of neurofibromatosis affecting 1 in 3000. The NF1 gene is located in chromosome 17, which is responsible for the production of the neurofibromin. It's a protein that prevents the cells from growing too quickly. So when it's mutated or not working right, then we get a malfunctioning gene that lead to the development of several symptoms throughout the skin, brain, eyes, nerves, and other organs.

The diagnostic criteria for neurofibromatosis type 1 has been revised, but most patients are in fact, diagnosed during childhood and that's using the clinical diagnostic criteria. The number of cafe au lait spots and neurofibromas, they have softening of the bones like tibial dysplasia. If they have spots in the iris of the eyes called the lisch nodules. So most of the patient can be diagnosed using these clinical criteria. Few of our patients in fact will need to have the genetic test to confirm that if the clinical criteria are not as clear. As you know, the disease can be very variable even within members of the same family. So as I mentioned, most commonly the diagnosis made clinically with few needed needing the genetic testing.

While the NF tumors are generating not cancerous, they may cause health problem by pressing on nearby body tissues. Sometimes a benign tumor may become malignant. But most people with NF1 will lead a healthy life with relatively mild or manageable symptoms. The risk of having a malignant tumor in neurofibromatosis type 1 is about 10 to 15%. Some of these peripheral nerve tumors, the neurofibroma can turn a malignant, so we call them the MPNST, or malignant peripheral nerve sheath tumors. We know that the women with NF1 has a higher risk of having breast cancer and we will touch on this in how we care for adults with NF1. But as I mentioned in general, most of the patient would have mild disease.

Glen Stevens, DO, PhD:

So take us through the diagnostic workup. I come see you, I'm concerned. I went to go see my family doctor, he said I got some brown spots on me, thinks I might have NF, sends me to see you. What's the diagnostic workup that you need to or is it all just clinical?

Mina Lobbous, MD, MSPH:

Majority clinical. So comprehensive exam including skin, eye exam, neurological exam, and also very detailed family history. About 50% of the patients with neurofibromatosis type 1 will be the first one in their family to have NF1. So we take detailed family history. If the patient meets the clinical diagnostic criteria, then we talk about the counseling, what to expect, what imaging studies we need, what experts and specialists we need to involve in their care. As you know, not every patient will need to see all the specialists. So we basically tailor a screening and then surveillance plan based on the clinical criteria we see.

Glen Stevens, DO, PhD:

I remember you mentioned Dr. Rothner and of course, I have known Dr. Rothner for many, many years. And I know that when they would see a child that they thought that might have neurofibromatosis, he would immediately take the parents that were there for the visit, put them in a gown and examine them because as you mentioned, it's an autosomal dominant disorder and 50% of the patients will be a new mutation. But that means that 50% of the patient's got it from the mom or the dad. So one of those will have it. So I guess that's one of the advantages of the pediatric patient is that they come with a parent and you assume you can't examine one of the parents to see that it's there.

The other thing I remember Dr. Kosmorsky always used to teach me that you really can't just look at the eye and tell that somebody has lisch nodules. I'd have residents work with me and they would say, "I think I saw a dark spot in the iris. I think they have a lisch nodule." But it could just be a freckle. And Dr. Kosmorsky always taught me they really need to have a slit lamp examination so that you can have a 3D look at it. It's really not a bedside test that can be done to meet it. But they can have a very clear criteria that you can pick up right away.

Mina Lobbous, MD, MSPH:

Correct. The brown spots, the cafe au lait spots, the neurofibromas like the skin tags or the softening of the bone, like the tibial dysplasia. These are the obvious clinical signs.

Glen Stevens, DO, PhD:

And most patients that present to their physician, are they symptomatic from their disease or they come in because someone just noticed abnormalities or a family history or are most having a problem.

Mina Lobbous, MD, MSPH:

So the adult patients that I see, some of them have symptoms but they haven't seen anyone about it until the adults are busy and sometimes they don't even have a primary care physician until they establish a care with a physician and then they refer them to an NF specialist. And some of them are transitioning the care from the pediatric colleagues in neurology, pediatric neuro-oncology, to the adult side. So not necessarily symptomatic. Sometimes it's more of a transition of care just to be plugged in with an NF specialist.

Glen Stevens, DO, PhD:

So if I have neurofibromatosis type 1 and I come and see you, what do you counsel me about the types of tumors that could show up or cancers that could show up in me or screening that I should have done?

Mina Lobbous, MD, MSPH:

So the disease is variable and it presents differently in different age group. For adolescent and adults, we counsel more about the neurofibroma. Cutaneous neurofibroma can continue to show up over the years. The larger nerve sheath tumor, we call them plexiform neurofibroma. These too can continue to grow and in 10 or 15%, they can turn malignant. So we counsel our patients about what is the alarming symptoms, what are the alarming signs, including rapid growth or if they become more painful or more solid. We also counsel about fertility. So as you know, now there is the preconception genetic diagnosis. So some families may pursue IVF to have the genetic diagnosis on the embryos if they don't want to have the chance of the 50/50 percent chance of passing the mutated neurofibromatosis gene to their children.

Glen Stevens, DO, PhD:

So certainly that would be a very reasonable area for medical genetics to be involved with these patients of childbearing age.

Mina Lobbous, MD, MSPH:

Correct, correct. Because you need to identify the mutation before you go further in the fertility evaluation. We have a wonderful team of medical genetics that we work very closely with.

Glen Stevens, DO, PhD:

And for the adolescents, other types of problems that you see in NF patients such as scoliosis, learning?

Mina Lobbous, MD, MSPH:

We do see learning difficulties are more common in children. In fact, 50% of children with NF1 may experience learning difficulties and we have the support from the neuropsychology colleagues to help with that. Scoliosis in adolescents also is a vision nerve tumors, these may arise in childhood, they can progress, they can affect the vision. But they are less of a problem in adults. As I may have mentioned about the increased risk in women with NF1, breast cancer. So the guidelines that women with NF1, they start screening, like mammogram and breast MRI, at the age of 30 until they reach the age of 50. Cutaneous neurofibromas, one of the most common symptoms in NF1 can have an impact, psychological impact, feeling the disfigurement. So we involve our dermatology colleagues, we involve our neuropsychology colleagues and we talk to our patients also about clinical trials and therapeutics.

Glen Stevens, DO, PhD:

So in some ways it takes a village, a lot of organ system involvement.

Mina Lobbous, MD, MSPH:

True, it takes a village and we're very fortunate we have all the experts here at Cleveland Clinic, that are very knowledgeable when it comes to the adult care of NF1 because it's quite different than caring for children with NF1.

Glen Stevens, DO, PhD:

And just talk briefly about optic nerve gliomas.

Mina Lobbous, MD, MSPH:

So these are a type of tumor, called glioma, that they can grow anywhere on the optic nerve. Optic nerve is what would take, the signal from our eyes to our brain. Most common age at presentation is around the age of six and that can progress and start affecting the vision mainly in children, less of a problem in adult and treatment decisions for optic pathway glioma more based on the vision changes rather than the MRI changes. We have FDA approved chemotherapy that we use and now there are an ongoing clinical trial, a phase three clinical trial, that's testing the standard of care chemotherapy versus a targeted therapy called selumetinib.

Glen Stevens, DO, PhD:

And my understanding is that you can occasionally see some spontaneous regression in optic nerve gliomas.

Mina Lobbous, MD, MSPH:

Correct, in adults. But we still as we turn to adolescents and young adults, we see stability or even regression. But we still advise our patients with NF1 to continue have at least annual eye exam.

Glen Stevens, DO, PhD:

And I was always taught that if you didn't have an optic nerve glioma by the time you're sort of a later adolescent, your likelihood of developing one in adulthood is very low. Is that still true or not?

Mina Lobbous, MD, MSPH:

True. So it's extremely rare for an optic pathway glioma to show up in adults, same as it's extremely rare for plexiform neurofibroma to show up in adult. Same as for scoliosis and tibial dysplasia. These are more common to show up in children than they are in adults.

Glen Stevens, DO, PhD:

So transition of care, obviously most of these folks show up when they're kids. Transition of care to adult clinics is always difficult because the children have such a long association with whoever has managed their care. And I remember the pediatric people would be seeing 40, 50 year old people with NF and they just never wanted to leave, the person that was managing them. So talk a little bit about how we transition patients to the adult area.

Mina Lobbous, MD, MSPH:

You're exactly right. The transition of care from childhood to adult care is a real challenge. Not just in neurofibromatosis but in other chronic diseases as well as in oncology. We're fortunate to have a great team with great experience in different aspects and caring for adults with neurofibromatosis, including neuro-oncology, neurosurgery, dermatology, psychology, genetic counselor, and other specialists within our enterprise. I do take care of comprehensive care for adults with neurofibromatosis type 1. And we work very closely with our pediatric neurology and pediatric neuro-oncology colleagues. So once the patients reach the age of 18, our pediatric neurology and neuro-oncology colleagues start discussing about transitioning the care to adult specialists. We make sure that this process is very smooth to our patients, very seamless to our patients. We ensure our patients remain well-informed about updates in the field in term of diagnostics, therapeutics, clinical trials and other needs specific for NF1.

Glen Stevens, DO, PhD:

And I think that's really the way to do it, that it's just a natural that as you become an adult you will be transitioned. If you take people that are 35, they go, "Well, I'm just going to stay where I am." So we really just need to have a process to do it.

Mina Lobbous, MD, MSPH:

True. And believe it or not, as lot of the areas around the countries, you don't have specialists who are familiar with adult care in neurofibromatosis type 1. So the care ends up being fragmented in this situation and patients just stay longer with their pediatric neurologist or pediatric neuro-oncologist and that creates another layer of complexity, like this 30 or 35 year old patient, as you need a surgery, cardiac surgery or dermatologist or orthopedic. You still need to involve a surgeon in their care. So staying longer with the pediatric group after a certain age may create more complexity.

Glen Stevens, DO, PhD:

So you mentioned Selumetinib, very excited. I think it was the first FDA approved drug.

Mina Lobbous, MD, MSPH:

Correct.

Glen Stevens, DO, PhD:

For treatment of NF patients. So talk to us a little bit about this drug.

Mina Lobbous, MD, MSPH:

So it's a first FDA approved drug. It's approved in April of 2020, the year of COVID. It underwent comprehensive clinical testing of the drug in patients at NIH. And it showed 70% of patients with neurofibromatosis with inoperable plexiform neurofibromas experienced tumor size reduction, that went anywhere from 20 to 60% in size. In addition to both visible and actual tumor reduction, patients also reported a higher quality physical function, reduced pain, improved mobility and enhanced emotional and psychological status. So it is FDA approved for patients younger than 18 and it's in the process with the FDA to approve it for adult patients.

There are other forms with the same category of drugs, it's called the MEK inhibitor. So that's a targeted therapy. This drug is not a big gun chemotherapy. This is more of a targeted therapy that works on trying to fix the problems that the malfunctioning neurofibromin has created. There are other forms of MEK inhibitor that's currently in clinical trial including binimetinib, trametinib, mirdametinib, in phase two trial. And as I mentioned earlier, selumetinib is in phase three trial for optic pathway gliomas.

Glen Stevens, DO, PhD:

So very exciting to hear that there are some drug options out there. So let's say someone has a plexiform neurofibroma on their arm. Why can't the surgeon just go in and cut it out? What's unique about it?

Mina Lobbous, MD, MSPH:

That's a great question. So the issue is that these tumors are not like a solid ball that the surgeon can shell out. They're typically encasing, involving the nerve. So you're running into a risk of damaging the whole nerve. So what ends up happening with some of these surgeries is just taking the bulk without trying not to damage the nerve. And we are fortunate we have a neurosurgeon, she's very, very knowledgeable, with great expertise in operating on peripheral nerve sheath tumors. And that's part of our multidisciplinary care. So if I have a patient that has a growing nerve sheath tumor, either they're having pain from it or problem with strength or sensation, we usually discuss this within our team. Is surgery an option? And for some of the patients, it can be surgery, it can be feasible, but for others it may carry more risk.

Glen Stevens, DO, PhD:

And you had mentioned schwannomatosis, but surgical differences if someone was doing surgery on schwannoma versus a neurofibroma?

Mina Lobbous, MD, MSPH:

Correct. The histopathology, the tumor structure is different between neurofibromatosis and schwannomatosis. Schwannomatosis has a capsule, so it's an encapsulated lesion. So the surgical approach to it is different than the neurofibromatosis. Neurofibromatosis tend to have other cell types within it and it tends to more engulf or encase nerve. So the surgery for neurofibroma can be more challenging, more complex than one for schwannoma.

Glen Stevens, DO, PhD:

You mentioned a little bit some of the unique medical issues with the breast cancer. Any other unique medical issues that we need to follow with these patients?

Mina Lobbous, MD, MSPH:

I believe it's predicting how the disease will impact one's life over the years. The disease can be quite variable in how it presents, even within the same family. So how do we know who needs more frequent screening? What is the business screening tool and what is the time to intervene? So we know the increased risk of cancer on this patient, as I mentioned 15%. So we counsel our patients about the symptoms to look for. We get imaging, including PET scan, to early identify any signs of malignant transformation. But I believe there are more efforts through the research in how we understand the genotype, phenotype. If we know a specific mutation can predict a more aggressive disease, then we tailor the screening and the surveillance different for those patients.

Glen Stevens, DO, PhD:

So that's really the crux of it, isn't it, trying to determine what an individual's penetrance and manifestation is going to be? So are we at that point, can we do that?

Mina Lobbous, MD, MSPH:

We know that certain mutations can cause patients to have more spinal cord tumors than the other, like spinal neurofibromatosis. But still, the data sharing among academic institutions undergoes the whole regulatory process that take time. But one of the ongoing research efforts through the REiNS, response evaluation in neurofibromatosis and schwannomatosis is international collaboration, trying to better understand and predict these sort of the questions, the phenotype, the genotype correlation. And right now, we operate based on reactive model, meaning we don't intervene medically or surgically unless a problem starts to happen. And if you think about it, it can be somewhat frustrating. But I believe one day we will switch to more a proactive model when we can intervene at a earlier time point to prevent complication, prevent even tumors from happening or even reverse the course of the disease. Right now, the more we know and learn, the more we can empower our patients. As I mentioned, the screening for breast cancer in women with NF1. So more to come in this arena.

Glen Stevens, DO, PhD:

And will insurance cover genetic testing if I felt I wanted to have it done on myself or it's a flip of the coin?

Mina Lobbous, MD, MSPH:

Well, if you have no indications, they're not going to cover it. But if the patient has a medical indication, it well. And that's a part of the discussion with our excellent genetic counselor. Upfront, we clarify all these financial issues upfront before we even send the genetic test. And there are other avenues to explore financial assistance to cover this test if the insurance ends up not covering it.

Glen Stevens, DO, PhD:

Does every patient need to see medical genetics?

Mina Lobbous, MD, MSPH:

Not necessarily. As I mentioned, the diagnosis is most commonly done clinically. But for those that it's unclear clinical criteria or for family planning, these are the ones that will need to see medical genetics.

Glen Stevens, DO, PhD:

They used to talk about a slight increased risk of renal cell cancer, pheochromocytoma in patients with NF, Moyamoya, vasculopathy, those types of things. Any new data out on that stuff?

Mina Lobbous, MD, MSPH:

It's a part of our comprehensive evaluation. So assess the risk for vascular complications. So we check the patient's blood pressure, we send certain blood tests that can detect pheochromocytoma, certain vessel imaging that can detect that as well. Not every patient, we need all these system modalities. It's more tailored, depends on the clinical presentation.

Glen Stevens, DO, PhD:

And any upcoming novel unique treatments, research-wise, what's going on?

Mina Lobbous, MD, MSPH:

So the field is rapidly evolving. We have now an FDA approved drug. There are more drugs coming down the pike, including combinatorial therapies. Can we attack these tumors using different treatment modalities? There are trials using topical MEK inhibitors, like the class of the drug, similar to the Selumetinib. Topical MEK inhibitors to address the cutaneous neurofibromatosis. There are new targeted therapies including the multiple tyrosine kinase drugs that through phase one and phase two clinical trial and also the gene editing initiative, which are currently in the very early phases. But that will be a game changer if it succeeds. As you know, the Children's Tumor Foundation as well as the Gilbert Family Foundation are huge supporters for these efforts.

Glen Stevens, DO, PhD:

Mina, in terms of research, what else is going on? Imaging wise, is anything on the horizon?

Mina Lobbous, MD, MSPH:

Yes. So imaging biomarkers are a very important tool of understanding the disease as well as predicting which patient will respond to which drug. So we come up with a personalized treatment plan that's very precise and personalized to the patient. Imaging biomarkers that look at predictability to respond to targeted therapy or immunotherapy. And also, the collaborative work of coming up with more predictable endpoints in our clinical trial. What do we look for in the clinical trial? Are we just looking to make the scans look better because that's not reflective on the quality of life. We include improvement in function, in pain, in emotional wellbeing. All of these are very valid endpoints in our clinical trial design for patients with neurofibromatosis type 1.

Glen Stevens, DO, PhD:

Excellent. Any last tips or takeaways for our audience?

Mina Lobbous, MD, MSPH:

Well, thanks again for having me. There is hope and we are at different point now compared to 10 years ago, and I'm hopeful we will come up with a more effective therapies. As you said, it takes a village to care for patients with NF and we are fortunate to have a great one here at Cleveland Clinic.

Glen Stevens, DO, PhD:

Yeah, I would just implore anybody listening to the podcast that has or sees NF patients, that it's worthwhile to have them come in and have a, at least an initial comprehensive evaluation with you.

Mina Lobbous, MD, MSPH:

I totally agree. And we have a very amazing care team. We make the visit very fruitful for our patients. They were able to see multiple experts, talk about different domains of care throughout the whole process.

Glen Stevens, DO, PhD:

Well, Mina, was great having you join us today. I was so excited that you brought your expertise to the Cleveland Clinic and have you as a colleague and get to interact with you on a daily basis. So appreciate your time and insights and just remind everyone that Mina's always happy to see your NF patients.

Mina Lobbous, MD, MSPH:

Well, the pleasure is mine and thanks for having me.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.