Pediatric neurologist Alyssa T. Reddy, MD, director of the UCSF Neurofibromatosis Program, breaks down the complex, multisystem signs of NF1, among the most common inherited neurologic disorders. To facilitate early diagnosis, she offers valuable tips on distinguishing NF1 skin – as well as other – abnormalities; explains when genetic testing is indicated; and reveals the promise of a recently approved drug, selumetinib, for shrinking certain neurofibromas.
I'm Dr Alyssa Ready director of the UCSF neurofibromatosis program. My role in caring for patients with NF is that of a neurologist and neuro oncologist, Children with NF often require multiple sub specialists over the course of their life. From infancy to adulthood, you as a primary care physician play a key role in their overall care. Also critical is the ongoing preclinical lab work to understand and better treat this disorder. In this video, I plan to review the diagnosis of NF some of the common complications and let you know about a recent significant breakthroughs in treatment. NFL one is one of the most commonly inherited neurologic disorders, descriptive recognition of it in the medical literature dates back to the 17 hundreds And affects one in 3000 individuals. It is autism, a dominantly inherited with about 50% of the cases coming from a parent and the other 50% being news. Sporadic mutations, it doesn't skip generations, but presentation is extremely variable and some parents don't even know they have it until a child is diagnosed At least 2.5 million people worldwide are living with NFL Type one. In the 1980s NIH established clinical criteria that are used to make the diagnosis based on history and clinical findings. Patients must have at least two of the following findings to make the diagnosis. These include six or more cafe ole molecules, actual larry or England or struggling a plex, a farm or subcutaneous neurofibromatosis, lish, nah jewels an optic pathway glioma or a skeletal dysplasia. If a patient has a first degree relative with NF, one that also counts as one criteria, it's important to know that the clinical findings are not all present early in life but rather develop over time. This can make it challenging to make the diagnosis in a young child. Some of the diagnostic criteria that are seen in very young Children are Cafe les molecules and bowing of the fibula patients can also have motor delay and hippo Tonia. Although this is non specific. As Children age, they develop skin fold freckle ng and can develop optic pathway clear. Almost again non specific is speech delay and learning disabilities. School age Children can develop scoliosis, lish nah jewels and other tumors. And then as Children age into adolescence, they develop more obvious flex a form neurofibromatosis which at times can transform to a malignancy. Adults often have cutaneous neurofibromatosis. These often aren't seen until after adolescence. They are at risk to develop other tumors as well. Here are some examples of the common skin findings. This picture shows typical cafe ole molecules and this picture next to it shows axillary freckle ng. Here are some pearls about the skin findings in an F one. Cafe ole molecules are typically present since infancy but they increase in number and size over the child's lifetime. Now it's pretty typical for patients to have 2-3 cafe ole molecules and that's normal in the population, remember in order to meet the clinical criteria for NF one, someone needs to have six or more and they have to meet a certain size specification. Cafe ole molecules are not always the same color, but rather darker than the patient's natural skin pigment Traveling doesn't appear until patients are five years of age or older. So the absence will not rule out an F one. It's also important to remember and assure families that these findings, although diagnostic are not harmful for the patient and do not transform into a malignancy. Dermal or subcutaneous nerves, I promise typically occur later in life. These are some examples of cutaneous neurofibromatosis. As we've said, these emergent teen years and can increase in number with age. Almost all adults with NF have at least one dermal neurofibromatosis and there's no way to predict in a child what their burden will be in adulthood. These are benign missions but can cause significant morbidity. This picture, this woman depicts a pretty extreme example of a burden of cutaneous neurofibromatosis. This can be quite disfiguring and again, impact someone's quality of life and they often cause itching. It is possible for these to be surgically resected if there is isolated mission or treated with laser therapy and there are ongoing studies looking at a class of drugs called neck inhibitors, which I'll go into more detail later in the talk, flex a farm neurofibromatosis are masses that arise from one or more nerve root. They may come to attention during childhood and at least half of adults with NFS will have one plex form neurofibromatosis or more. However, most neurofibromatosis don't require intervention. They may have overlying skin manifestation. These are important to recognize because they may cause pain in patients with NF and they also can cause morbidity by compressing on adjacent structures and vital organs. These have a benign histology, but at times can transform to a malignant tumor. These pictures demonstrate some examples of plexi form neurofibromatosis. In this picture, you can see this patient has a bulky mass protruding over his shoulder. There are overlying skin findings consistent with cafe ole spots. When we look at his MRI we can see the lesion here in bright white and not only is it involving the muscles and nerves of the shoulder area, but the tumor also goes into his thorax. We know that plexi for neurofibromatosis can also affect patient's limbs. These are two examples this, of the patient's leg and a different patients arm where the plexi form neurofibromatosis is disfiguring the limb reducing its function and these can also cause pain and itching. Another common location. Perplexing for neurofibromatosis is around a patient's eye. These are called orbital plexus forms. These are also disfiguring and can affect vision by compressing the optic nerve and the actual globe of the eye. Some patients have flecks of form neurofibromatosis internally in their abdomen and pelvis and again, these can often cause pain in compression of vital organs. The eye finding use in the clinical diagnosis of NF. One include lash modules. These are well circumscribed hammer thomas of the iris, They typically don't develop until a patient is about five or 6 years of age. But once they do develop them they occur in about 90% of patients with NF, they can be seen by visual inspection, especially in patients with blue or hazel colored eyes, such as this one. These dark brown pigmented areas are lish nah jewels. Sometimes it takes ophthalmological examination to see these again are benign, but they are very helpful in making the diagnosis. Patients can also develop optic pathway. Gliomas as we've mentioned previously, Genetic testing for NF. One is readily available and can be done on both blood and saliva. The gene was sequenced in the 1990s and thousands of alterations have been identified. Most of the genetic changes are PSV s. Don't predict what complications of patient will have. But there are a few PSV's that do. I do offer genetic testing to patients as they can confirm the diagnosis before. The clinical diagnosis can be made differentiated from other disorders with similar features and at times help predict complications. If I was giving this talk a decade or two ago, NF would be included in other fake mitosis or neuro cutaneous disorders. These are multi system disorders involving the ectodermal structures like central nervous system skin and i as the genetics of developmental disorders became better understood. We no longer group. These disorders. Fiona typically, but by genetic changes, an aberrant pathway signaling. The wrasse map kinase pathway is one of the best studies signal transaction pathways and is critical in the regulation of cell cycle and cellular growth differentiation and senescence. All of these things are critical to normal development. Germline alterations in the rocks pathway lead to several known disorders, including an F. One, which you can see here as well as other disorders, tumors form in patients with NF. One in the following way depicted in this cartoon, Every cell in a patient's body contains one abnormal copy of the N. F. Gene. In order for a neurofibromatosis form a Schwann cell requires a second abnormal copy of the gene. This results in proliferation of abnormal Schwann cells and the neurofibromatosis. Rose. Sometimes the narrow fabromano will take on other changes that lead to malignant tumor called a malignant peripheral nerve sheath tumor Abnormal Wrasse Pathway signaling occurs in many tumors, including those that occur in patients with NFL one dR frank McCormick here at UCSF has done some of the seminal research in the lab, looking at different drugs that block grass pathways to different steps. This work led to many clinical trials for NF associated tumors, including plexi for neurofibromatosis. This cartoon illustrates some of the points in the wrasse pathway where the drugs have been developed to block it in 2000 and 16, a group at the NC reported their results using the MAC inhibitor Cellmate nib it's with plexi forms that have grown or cause significant morbidity. This plot here shows the decrease in volume of each enrolled patients. Plexi for neurofibromatosis at different doses levels, 71% of patients met the criteria for a partial response. And after review the FDA reproved the drug for treatment of pediatric patients with NF. One. These pictures are from the NIH groups trial demonstrating the clinical response from the patient. The MRI at the top shows the neurofibromatosis. At baseline. You can see that this tumor, which is the bright white on the picture, is infiltrating through the patient's musculature and nerves into their leg. The subsequent MRI pictures shows a decrease in the size of the tumor over time while taking the drug. These pictures below demonstrate how the tur impacted the patient clinically. You can see here the patient stance is significantly affected by the tumor and we can imagine that this likely impacts the leg function as a patient has taken the drug. However, the stance and appearance improves This graph demonstrates the increase in size of the patient's plex a form nor fibra mope prior to their entry into the trial and then the decrease in size over time. Their ongoing studies with this and other mechanism bitters MEC inhibitors also appear effective in treating low grade gliomas in patients with NF. This is an example of patient with NF and low, greatly almost the patient had been treated with several therapies and the tumors group. She was then treated with a mech in him bitter and you can see here the bright white when she started the making him bitters and the decrease over time the Children's oncology group is now studying this in the up front setting. We are very excited about our programs at UCSF for patients with NF. One. We are caring for more than 700 patients, about half of which are less than 18. These patients are cared for by multiple sub specialists throughout the health system. We are happy to partner with you and caring for your patients with NF. We have a coordinated multidisciplinary clinic that allows patients to see several specialists in one setting. We are expanding this program to our Oakland campus and also growing the adult program which allows us to smoothly transition patients from the pediatric to adult setting. We have a strong collaboration with UCSF and other investigators to bring new therapies to patients. Of course none of this would be possible without support from funding agencies, patient and advocacy groups and most importantly, patients and families may is designated as NF awareness month and one of our patient families was instrumental in having san Francisco City Hall lit up in recognition of this. Thank you so much for your attention. I hope this video was helpful for you and your practice. We're happy to help you with your patients for more information about our neurofibromatosis program. Please see the Benioff Children's hospital website. Thank you so much.