Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And today, we have a panel for you with two UAB Medicine physicians as we highlight neurofibromatosis and schwannomatosis. Joining me in this panel are Dr. Katie Metrock. She's a pediatric neuro-oncologist and an Associate Professor of Pediatrics; and Dr. Rebecca Brown, she's a neuro-oncologist, an Associate Professor of Adult Neuro-Oncology, and the Director of the Neurofibromatosis and Schwannomatosis Clinic at UAB Medicine.

Doctors, thank you so much for joining us today, Dr. Brown. I'd like to start with you, as you're new to UAB Medicine. Can you tell us just a little bit about yourself, your philosophy of care, both for other providers and patients when you're treating adult and pediatric patients?

Dr. Rebecca Brown: Absolutely. And I just wanted to say that I'm so glad to join. So, I'm an adult neuro-oncologist. My passion has always been treating patients with NF and schwannomatosis. And I have my PhD from UT Austin in Texas. And I got my PhD prior to earning my MD. So, I jokingly tell people I'm a PhD MD, but that gives me a bit of a leg up in understanding basic scientific papers and understanding how to bring that information to patients into clinical trials.

So along those lines, I am engaged in research. My specific area of interest is in what are called cutaneous neurofibromas, which are the skin bumps associated with NF. And I also have trained in removing those cutaneous neurofibromas as a service to my patient because there are very few providers who do so, at least not in the numbers that patients are hoping for.

And my philosophy of care is really to, number one, first and foremost, listen to the patient's concerns. And I also tell people that I'm the most sub-specialized specialist that could possibly be out there. But also, because I take care of the whole patient, I'm also a generalist.

Melanie Cole, MS: Thank you so much, Dr. Brown, for telling us a little bit about yourself. Now, as far as today's topic, can you please tell us the difference between NF1, NF2, and schwannomatosis, and how they all fit into this umbrella?

Dr. Rebecca Brown: Well, to start with, they're all very difficult to pronounce, but NF1 and schwannomatosis are also caused by mutations on different chromosomes in different genes. NF1 affects chromosome 17 and leads to the overgrowth of nerve sheath tumors in addition to a number of other different signs and symptoms. And I'll get into those in a little bit. NF2, the mutation occurs on chromosome 22. And as of the last couple of years, NF2 has now been folded under the umbrella of schwannomatosis. So, it's considered to be one of the many different types of schwannomatosis, the other of which are caused by different genes that are adjacent to NF2 or also by genes that we haven't really fully understood yet. So, there are several types of schwannomatosis for which we do not find a gene mutation.

Now, clinically, the big difference is that for NF1, patients get bumps in their skin, which is a prominent feature, cutaneous neurofibromas. They're at higher risk of gliomas, particularly optic pathway gliomas that can lead to loss of vision in childhood, and they're at higher risk of pheochromocytomas, breast cancer, bony abnormalities that can cause physical deformities and, with all of these disorders, pain.

With schwannomatosis, those patients tend to have more of their tumors hidden inside the body, they get nerve tumors. With NF2, which is the most severe form of schwannomatosis. There is bilateral involvement of the vestibular nerve, which causes hearing loss, and that's one of our biggest concerns. But patients are also susceptible to meningiomas and schwannomas of the cranial nerves that can also contribute to blindness in one or both eyes, and neurologic symptoms from compression of the brain, from the meningiomas. They can also get  ependymomas, which can cause spinal cord abnormalities that lead to peripheral weakness and numbness.

Melanie Cole, MS: You mentioned symptoms. Tell us a little bit about clinical presentation when this happens. Who sees it first?

Dr. Rebecca Brown: There's been a lot of information that has been propagated to general practitioners and other specialists to recognize the signs of NF1. And I'm actually going to hand this one over to Dr. Metrock, who sees children with NF1, she can talk about those signs because typically, they're diagnosed in infancy.

Dr. Katie Metrock: For NF1, children present in all kinds of ways, to be honest with you. Most of them are diagnosed by their pediatricians or at least the pediatrician has suspicion for NF1. And then, those patients are referred to our center, usually starting with the genetics team.

So, a common way that a patient might be diagnosed is that they come and they have some dark spots around on their body. And those are called Café-au-lait macules. And those are very typical of patients with NF. They can also have some freckling in their axilla or their groin. Sometimes there's a family history of NF. And so, that obviously would make somebody much more suspicious of that diagnosis. But it can also be a sporadic mutation. And so, patients may not have a family history at all, and it may be a brand new issue that this family will be facing.

So, pediatricians often are suspicious, refer to Children's of Alabama. They see our genetics team where you can make a diagnosis sometimes clinically. Often genetic testing is sent now on the blood to learn exactly which mutation the patient might carry. Sometimes patients are found in other ways. Sometimes the skin findings aren't as apparent, for example, or may have been missed, and a patient may have vision problems and an ophthalmologist may find vision deficits. That eventually leads to a path where an MRI is done and an optic pathway glioma is seen. And some other very typical lesions in the brain can be seen on that MRI that makes somebody suspicious of NF. So, they can come to our clinic in many different ways. But usually, it starts with a good thorough exam at the pediatrician's office.

Melanie Cole, MS: Well, thank you so much. So Dr. Brown, please speak a little bit about diagnosis. What's involved in the clinical workup? Tell us how it's diagnosed.

Dr. Rebecca Brown: There are many different subtypes of schwannomatosis. The most common being NF2-related schwannomatosis. And for those individuals, if they're the first one in their families to present with the disease, it's frequently identified due to hearing loss in adolescents and young adults. That is out of proportion to their sound exposure and to their age. And then, an MRI scan is performed, and the tumors associated with NF2 are identified being bilateral vestibular schwannomas, meningiomas, and  ependymomas. And then, genetic testing is performed. It also is a genetic disease. And so, sometimes we see whole families who are affected by NF2-related schwannomatosis. And then, parents will sometimes upfront will have their children undergo genetic testing so that they can receive the monitoring that they need as they're growing to identify nascent tumors and to treat them.

Non-NF2-related schwannomatosis most frequently presents with a pain-like syndrome, and these patients can have a fibromyalgia-like pain that we understand scientifically is due to small tumors in the peripheral nerves that may be microscopic in nature, and the pain can be widespread. It can be in every limb, or it could be associated with a particular nerve with a recognizable tumor inside that nerve that can be seen on an MRI scan.

Melanie Cole, MS: Dr. Metrock, I've heard there are now two FDA-approved treatments for NF1. I'd like you to speak about pediatrics for a minute, what it treats, what's the difference. Tell us a little bit about what we know now.

Dr. Katie Metrock: Yes. So, this was very exciting breakthrough for the NF community. The first drug was selumetinib, and it was FDA-approved to treat pediatric patients less than 18 years old with plexiform neurofibromas. So, we talked earlier about different signs and symptoms that patients with NF can have. We talked about the skin findings, the café-au-lait macules, the axillary and inguinal freckling, the optic pathway gliomas. They can have Lisch nodules in their eyes, but another very common finding for these patients are plexiform neurofibromas. So, anywhere that there's a nerve in the body can have a tumor related to that nerve.

So, like we talked about, the optic pathway can be affected as they get older. They can develop cutaneous neurofibromas. But at any point, they can have these plexiform neurofibromas in early childhood. And it's basically a group of nerves that have tumor cells intertwined. And there was really no good treatment for these tumors before selumetinib was FDA-approved in 2020. There were many clinical trials that tried different medicines, but conventional chemotherapy was ineffective. Surgery can sometimes help with these tumors, but it can also be very complex. Because this bundle of nerve fibers, it's often, one, hard to get out the whole tumor. Two, there can be a lot of bleeding with surgery. Three, they can grow back. And four, they can have a lot of functional deficits based on where that location is. So, surgery is difficult. It can still have its role in treating these tumors, but it really was not enough.

And so, the drug selumetinib was the first one. It's a MEK inhibitor. So, MEK targets in the Ras/Raf pathway that's active in these tumors. It can be taken orally. So, it's taken twice a day by mouth and was a significant breakthrough. So, the SPRINT trial was run through multiple centers headed by the NIH and there was a great response rate. Not everybody responded, but there was a 20-25% reduction in volume in over 60% of the patients. So, that was a big deal. And we were starting to be able to treat these patients. Again, it was only FDA-approved in patients less than 18 years of age, and it only comes in a tablet form, which for pediatric patients is not always an easy way to get down the drug. So, that has come with its own set of challenges. They are working on what's called a sprinkle formulation for selumetinib. But that was an issue with getting it for all the patients that could benefit.

More recently, a similar drug, another MEK inhibitor called mirdametinib was FDA-approved in early 2025, and it has both a liquid and a pill formulation. So, it can be given in the younger patients that can't swallow tabs. And it was FDA-approved in both pediatrics and adults. The side effects are something that we do need to touch on because, while this drug may help some patients, it does have its side effects. Both of the drugs have similar side effects.

And so, I always go over those risks and benefits with patients. I say, "Look, we have this medicine. It's FDA-approved for patients that have these plexiform neurofibromas in places that are causing significant impairment or have the potential to cause significant impairment. And so if your tumor fits that distinction, we need to talk about how likely it is to work and also the side effect profile. So, I kind of divide the side effects into. those that affect patients on a day-to-day basis. And some that are more rare, but significant. So, the day-to-day for pediatric patients, they may experience a rash. In my younger kids, that looks more like kind of an eczema-type rash, red, irritated skin. In my older kids, teenagers, it tends to be more of an acneiform rash. Often, we will start doxycycline with that to help prevent the acne rash in our older kids. Or once it starts, we can begin the doxy at that time and sometimes see a lot of benefit from that. But the rash can be very frustrating for some children.

Also, patients can get water retention. So, they are kind of gaining weight, which can be difficult to manage. They can have paronychia, so infections of their fingernail and toenail beds that we have to treat with bleach soaks, and, you know, sometimes even need to send them to a podiatrist for nail trimmings and that sort of thing. We have to watch their laboratory values, their creatinine phosphokinase. The CPK value can go up very significantly in these patients. Usually, it's not symptomatic. Usually, it's something we're following and the patients are okay. But we do have very specific guidelines on how to hold or re-dose the drug based on those findings. Some get nausea, some get diarrhea that can be managed with loperamide, but those are not side effects that we can ignore. And then, the more significant side effects are things like pressure in the eye that has to be followed by an ophthalmologist. We do echocardiograms every three months to look at the ejection fraction, which can go down.

So, there's a long list of side effects. We tell patients they're not going to get all of them, but they're going to get some of them. And so, we have to really manage that side effect profile with the potential benefits for each patient.

Melanie Cole, MS: Dr. Brown, would you speak about adults please?

Dr. Rebecca Brown: So previously, selumetinib was the only FDA-approved drug, but it was only approved for the pediatric population. Now, we have mirdametinib, which is approved for both adults and children. And I agree with Dr. Metrock completely that both drugs are very similar and have very similar side effect profiles.

In the adult population, we're using these medications, not only to treat the plexiform neurofibroma in and of itself, but sometimes to shrink the plexiform neurofibroma before a surgery. So, sometimes the tumor is too large to be resected at the start. But with these medications, you can shrink the tumor and then subsequently achieve a much better resection. And also, we're hopeful, and we don't know the answer to this yet, but there may also be a link between taking these MEK inhibitor medications and delaying or preventing a malignant conversion of these tumors. So when they do develop into a malignancy, which happens in 8-13% of individuals with plexiform neurofibromas, that is almost always a fatal diagnosis. Rarely can it be treated. And if it can be treated, it's only when the tumor is in a limb and the limb can be removed. So, it's a very severe condition. So, we're hopeful that treating the plexiform neurofibromas may prevent or delay the onset of the malignancy.

One other thing that I wanted to add would just be that if you look at the drug adverse event list, it is daunting. And many practitioners out in the community may feel like they don't have the bandwidth or the knowledge to institute these medications. But I would advise them that the company, the drug companies, provide so much information and support for physicians that the patient doesn't necessarily have to be sent to an NF center if there's not an NF center nearby them. Ideally, these patients would be seen by NF experts. But these medications can be started in the community, and there are very clear lists of labs and imaging and studies that should be ordered at very distinct moments of time, and also guidance from the company on how to remediate the side effect profiles. And we really would love to see more NF patients receive these medications that are needed, especially in situations where they live very far away from an NF center of excellence.

Dr. Katie Metrock: I can chime in there. I think, we seek children from all over the state and surrounding states with NF. And often it's hard for them to come back for all of their follow-ups. So, I often work in conjunction with their pediatrician or their local provider. We can help get them started and then really guide, the outside provider, if that's helpful to both the patient and that provider to make sure that these children or, you know, in Rebecca's case, the adults are getting what they need. So, they may not see me for every visit. They may be seeing their pediatrician for some of those visits when a provider feels comfortable with that. That's worked very well for a lot of patients that live several hours away.

Dr. Rebecca Brown: I would second that. And I would also say that, Dr. Metrock, you probably can ascertain that there are some parents who are very motivated to help their child remain on the medication, and they are also an excellent resource.

Dr. Katie Metrock: Every family is different and every family brings their own background knowledge for the disease and for the drugs, and their own set of struggles with how to manage in the healthcare world. And so, it really does take a team of people to manage the care for these patients very holistically. We have Child Life specialists. We have the nurses, the nurse practitioners, the school liaisons that can really help. We have neuropsychologists that can help with a lot of their needs. And so, we love to have these patients plugged into our system so that we can help get them all those resources, and then really meet the family where they are within those needs. We're very lucky here to have a center that really tries to focus on taking care of these patients as a whole.

Melanie Cole, MS: Thank you for telling us about the multidisciplinary team and what's involved in taking care of these complex situations, because they definitely are. And UAB has the only comprehensive NF and schwannomatosis clinic in Alabama. I'd love to give you each a chance for a final thought here. So Dr. Metrock, how is the practice different than, say, local primary care doctors or neurologists? You just told us about that multidisciplinary approach. Tell us just a little bit about the clinic itself and what really sets it apart.

Dr. Katie Metrock: I'm very excited about our clinic. I think we have so many wonderful things we can offer these patients and families. So, like I was speaking to, I do feel very much like it takes a team of people to help these kids in their journey, because it starts in infancy and they go into adulthood. And so, we can work with them each step of the way through that journey.

So, we have the Pediatric Neurofibromatosis Tumor Clinic here. So, I see all the patients that are pediatric that have tumors. And with that, we are plugged in through the Children's of Alabama Pediatric Blood and Cancer Center. So, that just offers a lot of resources. We have, again, the pediatric neuropsychologist. Because as children get older, they will need neuropsych testing. And neurofibromatosis can have a spectrum of neuropsychological issues Sometimes, you know, some of our patients have severe learning problems and some are very gifted children as well. And so, it can really be anywhere on that spectrum. And we need, to really do that specialized testing to understand how each child's brain is processing information. We have social workers, which can be just so incredibly valuable to the care of these patients. They can help provide resources for transportation. They can help pull together that multi disciplinary approach if they have issues outside of what our clinic is doing. They can meet the family where they are. We have Child life specialists that can work with each child and they get to know the kids so well, and being able to teach that child and work with them through whatever it is they're going through in those moments of life. That's their specialty and it's really awesome to see them at work. We have a pediatric neuro-ophthalmologist who has a special interest in NF and sees our patients and really has a great interest in taking each of these Kids under his wing and following them. And I think that longitudinal care with Ophthalmology is hugely important. Because if we haven't gotten into these details, but with an optic pathway glioma, for example, we don't always treat those tumors when we find them. If the vision is stable and not being affected by that tumor, then we don't have to treat that child and we can spare them the difficulties of treatment. So, it takes a very skilled neuro-ophthalmologist to discern that sometimes on what their visual acuity is doing over time.

So, I think there's just a long list of ways that I hope our team provides the most excellent care for these kids. And we loved having them all plugged into our system, and we work with them on where they live and where they are, if they want to do some of their care more locally, and come to us once or twice a year if that works for them, or sometimes they're seeing us monthly for different reasons. And so, it can look very different for each patient. But I think that's a part of that whole approach, that multidisciplinary approach that is tailored for each patient.

Melanie Cole, MS: Thank you so much. And Dr. Brown, last word to you, you're a neurologist, but you also remove skin tumors. What made you decide to train in that technique? How are your resection clinics set up? And what would you like the key takeaways to be for other providers today on the clinic at UAB?

Dr. Rebecca Brown: So, I decided to train in the resection of cutaneous neurofibromas because NF patients can develop tens, hundreds, thousands, ten thousands of these tumors over their lifetime, and they're benign tumors. They have no malignant potential. But at the same time, these tumors are highly bothersome to patients. They can actually be symptomatic, painful, or itchy. They can catch on clothes and bleed. But sometimes it's just a matter of the patient saying that they don't like the way they look, and they want to be just like everyone else who can wear a swimsuit on the beach and not be self-conscious about these bumps, not have people look at them sideways.

So, that's the reason I trained in it. And at the same time, I discovered that there is a lack of providers who have the bandwidth to take off as many tumors as the patients want and deserve to have removed. And this goes back to how different specialties structure their resection clinics and which specialties can resect cutaneous neurofibromas. Typically, it's plastic surgery and dermatology, sometimes general surgery. But some of those other specialties require the patient to undergo anesthesia. And then, we'll do an excellent job at removing one, two, or three tumors, but at a cost. Because the insurance costs and reimbursements for booking an operating room are quite different than those for having tumors removed in a non-sterile clinic.

So, that is in a nutshell why I trained in this. And the way that it's structured is that each patient is given a 90-minute time slot. If they come in from a very long distance away, I'll sometimes offer them a two-hour time slot and I will address whichever tumors concern them during that period of time. And it may be three very large tumors. It may be 35 smaller tumors. And by very large, I mean above five centimeters in size and subcutaneous. And for the smaller tumors, I mean approximately one centimeter or less. And the smaller they are, the easier they are to resect, and the more I can do at a time.

I would just like other providers to know that we are a service to the community, and that includes the medical community as well as the patient community. When people are referred to our clinics, we ask them, "How can we make your life easier? What can we do for you?" And if the patients should remain with the referring provider, we're good with that too. So, I would echo what Dr. Metrock said that, you know, our number one philosophy is that we want to help in whatever way we can for this amazing patient population that's so resilient and honestly delightful. And however we can do that, we will work together with community physicians and other specialists to administer the best care we possibly can.

Melanie Cole, MS: Thank you doctors so much. That was so interesting and informative. Thank you again for joining us and sharing your expertise. And for more information, please visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole.