Chapters Transcript NF:1 Update on Diagnosis and Treatment Course: Advances in Child Neurology and Genetics All right, uh, thank you guys for, uh, inviting me. Uh, thanks, Lou, for putting this all together. Um, I'm gonna talk briefly about nerve fibromatosis type one. today, um, I will say that there's a lot of exciting, uh, things going on in the NF world, uh, not just in NF1, but also NF2, uh, and schwannomatosis, but today we'll focus on NF1. Uh, just in terms of disclosures, most importantly, I do, uh, get, uh, some financial compensation from Alexion, uh, which makes, uh, solumetinib, which is one of the drugs that we will talk about today. Um, just some take home points to start off with, um, and F1 diagnostic criteria have recently been updated, um, to improve diagnostic sensitivity and specificity, and so it's good to have a sense of the new diagnostic criteria, which we will talk about briefly. Um, genetic testing is now part of the diagnostic criteria. Previously it was all clinical criteria, um. Genetic testing is a nice adjunct, but is neither sufficient nor necessary uh to make the diagnosis. Um, accurate and early detection or diagnosis of NF1 is particularly important now that we have therapies that are relevant and and available for patients with neurofibromatosis. And there are now 2 FDA approved medications for uh for NF and we'll go into those in more detail. So this really has changed the the landscape of NF1 management and um it's, I mean, from my standpoint, having been taking care of NF patients for almost 25 years, this is a really exciting time to finally have therapies that are making a difference in in the lives of kids with NF1. So I just want to point you in the direction of a few specific uh publications to to look at. So, uh, the revised diagnos diagnostic criteria came out a couple of years ago, uh, for both for NF1 and NF2 schwannomatosis. I just want to point out that NF2 is no longer neurofibromatosis, it's now NF2 related schwannomatosis, where NF2 is the gene name and not neurofibromatosis. And this is really important because neurofibromatosis and NF2 are not the same thing. They are very distinct disorders, and there are neurofibromas and schwannomatosis or NF2, so, um, it was an important distinction to to make both for, um, researchers, clinicians, and, and patients and families as well. Um, and these are a couple of the pivotal papers that have come out recently regarding therapeutics. These are the two papers that led to FDA approval for solumetinib and myrtamenib in the treatment of plexiform neurofibromas in NF1, so we'll talk about those. So just by way of background, very briefly, as we all know, NF1 is an autosomal dominant genetic condition, uh, with almost 100% penetrance, um, incidence is probably in the 1 in 2001 in 3000 range, depending on the study. Uh, the gene is loc located on chromosome 17. And it has a high rate of de novo cases, so about half of patients will not have a family history of neurofibromatosis. Um, the gene encodes for neurofibroma, which has a whole myriad of, of, um, effects, and NF1 really is a multi-system disorder impacting the nervous system, of course, but also, uh, other systems as well, GI, um, bone, bone growth, cognition, etc. Um, I'm gonna skip through this, but, you know, the clinical manifestations really, um, can vary quite significantly. Patients can have all of these, uh, symptoms. They can have almost none of them except cafe lait spots. They can have, uh, just cafe lat spots and ADHD or they may have very aggressive, uh, cancer, so it's a highly variable, uh, phenotype. So, um, I won't go through the details of how the diagnostic criteria were revised other than to say it was a, a multi-year, uh, and multinational effort, um, that resulted in some mild changes, um, but, uh, a couple of, uh, important additions, so now cafe lace spots and freckling should be bilaterally localized in order to separate, um, uh, uh. Out the mosaic, uh, individuals whose prognosis and, and natural history may be quite different. Um There's a new ophthalmologic finding, choroidal abnormalities, which was added to the diagnostic criteria. These appear earlier than Lish nodules and are, we think, more specific and more sensitive for neurofibromatosis. So Lish nodules typically don't develop until kids are maybe adolescent age, and choroidal nodules are apparent into 2 and 3 year olds typically. So, um, that can allow for an earlier second, usually if cafela spots are the first diagnostic criteria. And caudal abnormalities may be um the second criterion in many instances. But you do have to have an ophthalmologist that knows to look for these. Um, there was some correction in some of the uh details around the, uh, bone abnormality seen in NF1. Um, and probably the most important change was the addition of, uh, having a pathogenic NF1 variant, and one of the main reasons this is important is not because it actually changes s sensitivity or specificity all that much, but it does allow for, uh, uh, genetic testing to be covered, um, by insurance. So by uh having it including it included in the diagnostic criteria, um, it has improved, uh, access for, for many of our patients. Um So, just in terms of genetic testing specifically, um, it does help with, uh, sensitivity and specificity. So, particularly in kids that present early just with cafe au lait spots, genetic testing can help differentiate from other related syndromes like spread one or Leis syndrome. There's wide variability in in the utilization of genetic testing for NF1. We, at our clinic, we're probably doing it in about 1/3 of kids. We don't do it in everyone. It really doesn't help much with the uh prognosis. Um, so if someone meets clinical criteria, um, we don't necessarily do, um, genetic testing. Um, sensitivity is improving. It's greater than 95% at this point, so, um, but there are still instances, uh, where someone clearly has NF1 and genetic testing is negative. Um, so, um, if a child meets clinical criteria and genetic testing is negative, we still follow them as if they have NF1 because they do. As I mentioned before, genetic testing is neither uh sufficient nor required uh to make a diagnosis, so you can't just have a mutate a pathogenic variant and no clinical symptoms and be diagnosed with NF1, and, um, and you can clearly make a diagnosis without um. Uh, having an identified mutation. So next gen sequencing has improved sensitivity for mosaicism, so you can now find mosaicism in as few as 10% of cells, um, and that has really changed our understanding of the phenotype of mosaicism. We're seeing it in many more kids than we had previously, or recognizing it more and realizing that it's not always just segmental, limited to one portion of the body that can be diffused, but just a a a reduced phenotype. And if one can be tested from blood or saliva, it's quite fast these days. Um, reflex testing for spread one or Leis syndrome is standard. Um, it's very useful for preimplantation genetic diagnosis, um, which is becoming more and more prevalent in this in this, uh, community. Um, I will say that where testing is done does matter quite a bit, um. Commercial labs may not be able to identify deatronic pathologic variants. Some labs are better than others in terms of uh uh sensitivity, and sensitivities can range from 70% to 95%, so it's important to know, um. Which labs uh do what? There's very poor genotype phenotype correlation in NF1, and NF1 is a very large gene mutations can occur anywhere along the gene and have pretty much the same range of phenotypes. There are a few exceptions, the deletion, microdeletion of the entire gene is associated with a more severe phenotype, with higher uh tumor burden and higher cancer risk, and then there are a couple of specific mutations that are correlate with a very mild phenotype. Um, we are in the process of variant curation for NF1, NF2, and schwannomatosis. Um, which may lead to additional genotype phenotype correlations, but more to come on that. Um, this is a child with an NF1 microdeletion with a very typical facial appearance. Um, these kids all sort of look like siblings. They have, uh, thickened lips, uh, down slanted puppybral fissures, um, and you can see a very high tumor burden both externally and internally. All right, for the remainder of the talk, I'm gonna focus on the targeted therapeutics that have been developed recently for NF1. Um, our understanding of the uh pathophysiology of NF1 has been, uh, growing leaps and bounds over the last decade, but we know that neurofibromin is a gap protein that maintains RAS in its inactive form, and RAS has a lot of downstream effects, a lot of downstream pathways. And there are probably non-RASS um mediated pathways in NF1 as well, but it's really the BRASS mediated ones that have been the most effective in uh ameliorating, uh, progression of tumors, in particular in animal models of NF1. So based on our understanding of of the pathogenesis, um, uh, drugs have been repurposed, so drugs for other conditions have been identified and, uh, tested in animal models and in clinical trials. So capazantinib, for instance, is a receptor tyrosine kinase inhibitor. Um, solumetinib, binietnib, mertametinib are all MC inhibitors, um, and these are some of the medications that have had the biggest, um, signal in terms of both pre-clinical and and clinical trials. We're also drugs which are indicated here, Varnesyl transferase inhibitors, which actually um act right at the gap protein level and recapitulate neurofibroomin. Um, and then there are also additional studies underway, uh, looking at ways to up regulate the, um, the good copy of NF1. So NF1, some of the symptoms may be, uh, secondary to the haplo insufficiency of NF1, some require a second hit, but for instance, the cognitive deficits of NF1 are thought to be, um, present in haplu insufficiency, and so up regulating the remaining copy may be sufficient to, um, to treat those aspects of NF. So these are the uh clinical trials that have um that are currently completed in NF1, um, it's not an exhaustive list, but these are the, the, the biggies. I'm not gonna go through all of these, but I will um go briefly through uh the sprint trial from 2020 for soluettinib and the renewed trial for memenib, um, uh, which have led to, uh. Uh, FDA approval recently for that drug and the comment study for solumeanin. So all of these trials that I'm gonna talk about today have focused on plexiform neurofibromas, and just by way of reminder, plexiform neurofibromas come in several different types, nodular plexiforms, which grow um adjacent to the spinal cord and arise from the roots, often in the foramina, and can be all up and down the spine and can cause significant spinal cord compression, myelopathy. Um, this is a patient of mine who's actually on solumetanib currently for treatment of multiple, um, spinal neurofibromas. Flexiform neurofibromas can also be more diffuse. They can, they typically show up very, uh, subtly in kids, maybe an area of hyperpigmentation or an area of um uh faint raised reddish uh hypertrichotic skin, and over time that skin can change and the tumor can grow to the point where it's very functionally and cosmetically impactful. Um, these tumors, depending on location, can be impactful in terms of, um, Oops. Uh, airway impingement or, uh, other functional, uh, uh, impingement that can be life threatening. Cosmesis can be a huge issue, um, especially facial plexiform neurofibromas, which we see in about 2% of people with NF, um, which can be, uh, as, as you can imagine, have a very big social impact. Um, you can get large flexible neurofibromas that involve, um, dire limbs or brachial or lumbosacral plexus, all of which have, um, significant functional impairment. Kids with NF and flexible neurofibromas, uh, the, the rate of growth tends to be highest in the youngest age group, so just in terms of rate by age, you can see that the fastest growing tumors cluster in the young years, and then as people age, they tend to slow down. Um, there is variability to this, however, and, and tumors can continue to grow at any point in the lifespan. So, um, based on what we understand of the pathophysiology, uh, animal models of, uh, NF1 have been developed, and, um, a variety of different drugs have been tested in both fly and mouse models. Uh, the first drug that, uh, uh, has become approved for NF1, uh, is cellumettinib, uh, which, uh, demonstrates on this waterfall plot, at different doses, a reduction in the size of flexor neurofibromas in pediatric population. Um, which correlates with both radiographic and functional and cosmetic improvement, um, in the majority of kids. It doesn't work for everybody, um, about 60% of kids will have some 60 to 70% of kids will have some benefit. Um, this initial trial, uh, was followed up by a larger, um, trial through the NIH called the Sprint trial, which is a phase two trial of kids with inoperable plexiform neurofibromas, um, and the Kappelmeyer curve again shows, um, marked improvement in terms of natural history of these tumors, um, with far less progression. Um, and you could see these patients had a long history of growth, and treatment was initiated, and you see growth stopped and, and some reduction in the size. Some patients just have plateauing, but it again with a condition like this where there's uh ongoing growth, even plateauing is, is of benefit. We now have data that's 8 years old for these patients, and there continues to be significant benefit, although some patients do progress through treatment. Um, I won't go through this in great detail, but adults, uh, have recently been, um, shown to have improvement as well, uh, with improvement both in tumor size as well as pain, um, and quality of life. Um, and then, uh, Murtamenib was, uh, just, this was just published, uh, in this past year. Uh, this is a phase two adult and pediatric trial, um, with similar results in reduction in tumor size, um, which you can see both clinically and radiographically, um, and again with uh improvement in pain and quality of life for both adults and kids. Um, looking across all the MC inhibitors, cellumetnib, myrnamenib, which are approved, remetinib and bibiniettanib, which are not, we see response rates between 50% and 74%. These drugs do have side effects, probably the most important of which is a, a, a rash, so pretty significant acne in some of these patients. If you're aggressive with treating the, the rash, you can get it under control and not dose reduce Panychia are also fairly common. So these kids do require visits more frequently, um, including scans, echocardiogram, blood work, um, but, uh, quite generally speaking, quite manageable manageable. I'm just gonna end with a case. Um, this is a little boy that, uh, I started seeing during the pandemic, um, but basically he presented at one month with a mass in his face, um, and, uh, he would, NF1 was not initially recognized. A biopsy was performed which found this mass to be a plexiform neurofibroma. He was referred to genetics, who diagnosed him with NF1 and referred to us, and this is him at 7 months. See this mass, uh, pericular cheek. On imaging These masses, these facial plexiforms are quite complex, involve multiple vessels and nerves, very poor surgical candidates. Um, he was having airway obstruction with sleep, so we started him on a mech inhibitor. This was his scan at 9 months. 12 months, so ongoing growth, treatment was initiated at 12 months. And here's a scan at 15 months and 18 months, so you can see a marked reduction in the size of the tumor, almost to the point where you can't find it anymore. This is a good response, not everyone has this good a response, but can have quite a dramatic um impact. Here he is over time. Um, so, at this point, I mean, looking at him, you would not see the tumor, you would notice that his hair is blonde, which is another side effect of MC inhibitors, um, and has led to some kids refusing to come off because they like the, it is the most expensive way one could imagine to get a hair, hair dye job. It's $30,000 a month, um, so. Probably easier to go to your salon. I won't go into this. This is all, you know, just sort of a pathway that we use for uh how we decide who to treat. Basically, we're treating patients with pain, with cosmetic impact, with functional impact, um, or risk to organs, uh, or the spinal cord, um, and, you know, we still use surgery in some patients, we still use medication, and sometimes we use a combination of both. Um Not everyone I said has a, a, a dramatic decrease in the size of tumors, but even a small decrease in the size of tumors can have a big impact. So this is a patient that presented with myelopathy, and you can see multiple, uh, levels of cord compression with intrinsic cord change, and after a few months of treatment, you know, there's only a few millimeters of reduction in the size of the tumor, but that's enough for his gait to improve and symptoms to improve dramatically. Um, we're also using it for optic pathway gliomas, um, so you can see here, pre-treatment, post-treatment with the MEC inhibitor. Um, optic chiasm here compared to here. So, just to conclude, um, You know, uh, these two new medications, mertametinib and Solumetanib, really have changed the landscape of, of, uh, treatment for NF1. Um, it is not the be all and end all, but can be helpful for very many patients. Um, there are upcoming clinical trials. We're just about to open one for, uh, something called Helix 1502, which is a very well tolerated antibiotic that was discovered through an AI screen, uh, to be, um, helpful for preventing neurofibroma growth. Um, there's a prevention trial that we're about to open, um, looking at whole body MRI in kids with no known plexiform neurofibromas, and if we find a plexiform neurofibroma, they're gonna get randomized to placebo or a treatment to see if we can prevent symptoms from developing. Topical mech inhibitors are in development for cutaneous neurofibromas, and we're expanding indications into low grade gliomas, high grade gliomas, cutaneous neurofibromas, and cognitive deficits. Published November 7, 2025 Created by
CME Knowledge Hub