Director's Blog
Sources of Variability in NF and What to Expect During an NF Chest Examination
By: Bruce Korf
Published Date: May 03
In previous blogs, I’ve discussed to the fact that NF is a highly variable condition that can manifest differently among affected individuals. For example, two people within the same family can have very different symptoms of the condition. It’s an enigma as to why such a high degree of variability exists within NF. However, we do have a general understanding of three probable sources of variability that could provide a framework for determining, through further research, the extent to which complications of NF are predictable.
Sources of Variability Among People with NF
The first possible source of variability is the specific genetic mutation associated with NF in an individual. More than 3,000 mutations have been identified in the NF1 gene, and there a few examples in which a specific mutation can be correlated to certain NF symptoms. The UAB Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene. While it is probable that certain mutations do predict specific NF symptoms, it’s also very likely that most mutations don’t predict the specific NF features or the course of the condition.
Another factor that likely plays a role in the variability of NF is an individual’s genetic background. Because individuals express genetic variants across the genome, it’s likely that there are other genes that can influence the manifestations of NF. Evidence for this phenomenon can be seen in mouse models. When the NF1 gene is introduced into genetically distinct strains of mice, the manifestations of NF can be very different. It seems likely that an individual’s distinct genetic background can help to determine the symptoms of NF that he or she experiences. It is difficult to design human studies to look for this phenomenon, however, due to the need to determine phenotypes (symptoms) and perform genetic sequencing on hundreds of patients, though efforts are underway to try to address this issue.
We are reasonably certain there is also a random nature to some of the physical manifestations of NF. Each individual is born with two copies of the NF1 gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or in most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. This “second-hit” mutation seems to be a random event that leads to a specific complication, such as a neurofibroma. It is possible that there may be factors in a person’s genetic background that increase the likelihood of a “second-hit”mutation.
NF Chest Examination
Turning back to our discussion in the previous blog about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during a chest examination. Because people with NF have an increased risk of congenital heart defects, the chest exam includes listening for a specific type of heart murmur associated with pulmonic stenosis. This condition causes a narrowing of the pulmonary valve, interfering with blood flow from the heart to the lungs. However, the condition is not as common in NF as in other RAS pathway disorders.
While the lungs are not commonly affected in NF, some adults may experience emphysema-like changes thought to be related to NF. It is also possible for neurofibromas to develop in the chest, which can interfere with inflation of the lungs and with breathing. Occasionally, we can feel a nodular neurofibroma at the base of the neck or near the collarbone. Some people develop plexiform neurofibromas deep inside the chest, although we usually don’t see plexiform neurofibromas in the lungs or heart muscle. The only treatment for plexiform neurofibromas is surgical removal, which is reserved for cases in which important structures are affected.
Sometimes a bony deformation of the chest wall, called pectus excavatum, can occur in people with NF. The condition causes a depression in the breast bone and usually doesn’t result in problems or require treatment unless it interferes with lung inflation and breathing. In these cases, surgical treatment can be offered. Another condition, called pectus carinatum, causes the chest wall to bulge out, probably due to disproportionate rib cage growth. In most cases, the condition doesn’t require treatment.
In some people with NF, spinal tumors can become large enough that they can push on the lungs, which may require surgical removal of the tumors if breathing is affected. Also, people with NF are at increased for developing abnormal tissue growth inside of blood vessels, including major arteries in the heart and lungs. This condition weakens the vessel wall and leads to narrowing and possible rupture, which is a serious emergency. Sudden onset of severe chest or abdominal pain is a symptom that this condition may be present, indicating the need for diagnostic testing, though many other things can lead to pain other than vascular rupture.
NF Awareness Month
Finally, I’d like to remind everyone that May is NF Awareness Month. The Children’s Tumor Foundation has developed a number of activities to inform the public about NF [http://www.ctf.org/NFawareness], and there will be events here in Birmingham as well. Keep an eye on our Facebook page [https://www.facebook.com/uabnfprogram/], as well as the Neurofibromatosis Alabama page [https://www.facebook.com/Neurofibromatosis-Alabama-Childrens-Tumor-Foundation-203255213153983/] for further details.
Sources of Variability Among People with NF
The first possible source of variability is the specific genetic mutation associated with NF in an individual. More than 3,000 mutations have been identified in the NF1 gene, and there a few examples in which a specific mutation can be correlated to certain NF symptoms. The UAB Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene. While it is probable that certain mutations do predict specific NF symptoms, it’s also very likely that most mutations don’t predict the specific NF features or the course of the condition.
Another factor that likely plays a role in the variability of NF is an individual’s genetic background. Because individuals express genetic variants across the genome, it’s likely that there are other genes that can influence the manifestations of NF. Evidence for this phenomenon can be seen in mouse models. When the NF1 gene is introduced into genetically distinct strains of mice, the manifestations of NF can be very different. It seems likely that an individual’s distinct genetic background can help to determine the symptoms of NF that he or she experiences. It is difficult to design human studies to look for this phenomenon, however, due to the need to determine phenotypes (symptoms) and perform genetic sequencing on hundreds of patients, though efforts are underway to try to address this issue.
We are reasonably certain there is also a random nature to some of the physical manifestations of NF. Each individual is born with two copies of the NF1 gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or in most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. This “second-hit” mutation seems to be a random event that leads to a specific complication, such as a neurofibroma. It is possible that there may be factors in a person’s genetic background that increase the likelihood of a “second-hit”mutation.
NF Chest Examination
Turning back to our discussion in the previous blog about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during a chest examination. Because people with NF have an increased risk of congenital heart defects, the chest exam includes listening for a specific type of heart murmur associated with pulmonic stenosis. This condition causes a narrowing of the pulmonary valve, interfering with blood flow from the heart to the lungs. However, the condition is not as common in NF as in other RAS pathway disorders.
While the lungs are not commonly affected in NF, some adults may experience emphysema-like changes thought to be related to NF. It is also possible for neurofibromas to develop in the chest, which can interfere with inflation of the lungs and with breathing. Occasionally, we can feel a nodular neurofibroma at the base of the neck or near the collarbone. Some people develop plexiform neurofibromas deep inside the chest, although we usually don’t see plexiform neurofibromas in the lungs or heart muscle. The only treatment for plexiform neurofibromas is surgical removal, which is reserved for cases in which important structures are affected.
Sometimes a bony deformation of the chest wall, called pectus excavatum, can occur in people with NF. The condition causes a depression in the breast bone and usually doesn’t result in problems or require treatment unless it interferes with lung inflation and breathing. In these cases, surgical treatment can be offered. Another condition, called pectus carinatum, causes the chest wall to bulge out, probably due to disproportionate rib cage growth. In most cases, the condition doesn’t require treatment.
In some people with NF, spinal tumors can become large enough that they can push on the lungs, which may require surgical removal of the tumors if breathing is affected. Also, people with NF are at increased for developing abnormal tissue growth inside of blood vessels, including major arteries in the heart and lungs. This condition weakens the vessel wall and leads to narrowing and possible rupture, which is a serious emergency. Sudden onset of severe chest or abdominal pain is a symptom that this condition may be present, indicating the need for diagnostic testing, though many other things can lead to pain other than vascular rupture.
NF Awareness Month
Finally, I’d like to remind everyone that May is NF Awareness Month. The Children’s Tumor Foundation has developed a number of activities to inform the public about NF [http://www.ctf.org/NFawareness], and there will be events here in Birmingham as well. Keep an eye on our Facebook page [https://www.facebook.com/uabnfprogram/], as well as the Neurofibromatosis Alabama page [https://www.facebook.com/Neurofibromatosis-Alabama-Childrens-Tumor-Foundation-203255213153983/] for further details.
Re-Cap of Meetings in Washington, DC, for Renewed NF Research Funding and a Review of What to Expect During an NF Neck Exam
By: Bruce Korf
Published Date: Mar 29
Highlights of CDMRP Meetings
At the beginning of March, I spent a day in Washington, DC, meeting with congressional legislative aids to discuss the importance of continued NF research funding for the Congressionally Directed Medical Research Programs (CDMRP). The CDMRP was established in 1992 to support novel approaches in biomedical research to benefit the American public and the military. The program is funded by the Department of Defense (DoD) through the annual Defense Appropriations Act. However, funds for the program are not included in the DoD’s annual budget and must instead be renewed each year during the congressional budget approval cycle based on response to requests by consumer advocates and those affected by the condition. Our primary purpose in meeting with congressional aids was to explain the relevance and impact of NF research and the need for a continued investment that will lead to breakthrough treatments and improvements in patient care.
In addition to neurofibromatosis research, a wide range of biomedical research projects are funded by the CDMRP, including breast and ovarian cancer, autism, multiple sclerosis, and spinal cord injury, to name only a few. We emphasized during our meetings that NF research has implications for bone and wound healing, medical issues important to the military. Also, we discussed the fact that NF genetics research is yielding information that is applicable to several other areas of medicine. For example, it has been established that the NF1 gene is one of the most commonly altered genes in cancer. Some may wonder if these research projects could be funded through the National Institutes of Health (NIH), the nation’s largest government-funded medical research agency. While the NIH does fund important basic and translational research relevant to NF, it’s difficult for the NIH to direct funding to a specific condition, as the CDMRP has the flexibility to do. In fact, a hallmark of the CDMRP is filling critical research gaps by funding high-impact projects that would be not be feasible for other agencies. For example, the NF Clinical Trials Consortium – funded by a grant that integrates research at more than 17 sites coordinated by UAB – was developed 10 years ago in response to a funding need identified by the CDMRP for NF-related clinical trials. In this way, the CDMRP complements the work of the NIH by filling a critical niche. We found the congressional aids with whom we met to be supportive of continued NF funding for the CDMRP primarily because the program has a substantial return on investment. It also has the unique capability to leverage funds for high-impact research that might not otherwise receive needed support.
NF Neck Examination
Continuing our discussion about what to expect during an NF exam, I’d like to discuss issues that may be identified during a neck examination. The most common feature we look for on the neck is neurofibromas, benign nerve sheath tumors that appear on or under the skin. In children, neurofibromas can be sometimes difficult to distinguish from lymph nodes, which can usually be palpated in the neck; however, an experienced NF clinician can usually make this distinction.
Plexiform neurofibromas, which involve large branches of multiple nerves, can cause significant problems in the neck. In some people, they grow aggressively and can compress the airway and other structures in the neck. While it is possible for plexiform neurofibromas to encase the carotid artery and jugular vein, usually the blood flow is unimpaired.
Another problem associated with plexiform neurofibromas in the neck is possible compression of the spinal nerves as they exit the spinal cord, causing pain or weakness in one or both arms. For this reason, an NF exam should include monitoring of patients for pain and neurologic function in the arms. It’s also possible for plexiform neurofibromas to grow into the vertebral foramen, the gap between vertebral bones where nerve roots connect to the spinal cord. Surgical removal is the only treatment option for plexiform neurofibromas, which can be difficult in the neck due to the risk of damage to vessels and nerves that could cause serious bleeding and other problems. Because of these significant risks, we reserve surgery for critical cases in which important structures in the neck are affected.
Some people with NF develop narrowing of the major arteries, which commonly occurs in one or both kidneys. The reduced blood flow caused by the narrowing signals the kidneys to release hormones that result in high blood pressure, which is a significant health risk. During each NF exam, blood pressure is closely monitored to ensure this problem isn’t developing. Narrowing can also occur in one or both of the carotid arteries, the major arteries in the neck supplying blood flow to the brain. As this condition gradually develops, collateral blood vessels are formed to compensate for reduced blood flow to the brain. Although most people with carotid artery narrowing don’t experience significant symptoms, certain conditions, such as dehydration, significantly increase the risk of stroke in these individuals. We don’t routinely perform imaging tests to screen for this issue, although we’re alert to any symptoms a patient may be experiencing that could indicate this problem. When this problem is recognized we usually recommend starting a mild blood thinner, typically baby aspirin. In symptomatic cases, there are surgical approaches that can restore blood flow to the brain.
At the beginning of March, I spent a day in Washington, DC, meeting with congressional legislative aids to discuss the importance of continued NF research funding for the Congressionally Directed Medical Research Programs (CDMRP). The CDMRP was established in 1992 to support novel approaches in biomedical research to benefit the American public and the military. The program is funded by the Department of Defense (DoD) through the annual Defense Appropriations Act. However, funds for the program are not included in the DoD’s annual budget and must instead be renewed each year during the congressional budget approval cycle based on response to requests by consumer advocates and those affected by the condition. Our primary purpose in meeting with congressional aids was to explain the relevance and impact of NF research and the need for a continued investment that will lead to breakthrough treatments and improvements in patient care.
In addition to neurofibromatosis research, a wide range of biomedical research projects are funded by the CDMRP, including breast and ovarian cancer, autism, multiple sclerosis, and spinal cord injury, to name only a few. We emphasized during our meetings that NF research has implications for bone and wound healing, medical issues important to the military. Also, we discussed the fact that NF genetics research is yielding information that is applicable to several other areas of medicine. For example, it has been established that the NF1 gene is one of the most commonly altered genes in cancer. Some may wonder if these research projects could be funded through the National Institutes of Health (NIH), the nation’s largest government-funded medical research agency. While the NIH does fund important basic and translational research relevant to NF, it’s difficult for the NIH to direct funding to a specific condition, as the CDMRP has the flexibility to do. In fact, a hallmark of the CDMRP is filling critical research gaps by funding high-impact projects that would be not be feasible for other agencies. For example, the NF Clinical Trials Consortium – funded by a grant that integrates research at more than 17 sites coordinated by UAB – was developed 10 years ago in response to a funding need identified by the CDMRP for NF-related clinical trials. In this way, the CDMRP complements the work of the NIH by filling a critical niche. We found the congressional aids with whom we met to be supportive of continued NF funding for the CDMRP primarily because the program has a substantial return on investment. It also has the unique capability to leverage funds for high-impact research that might not otherwise receive needed support.
NF Neck Examination
Continuing our discussion about what to expect during an NF exam, I’d like to discuss issues that may be identified during a neck examination. The most common feature we look for on the neck is neurofibromas, benign nerve sheath tumors that appear on or under the skin. In children, neurofibromas can be sometimes difficult to distinguish from lymph nodes, which can usually be palpated in the neck; however, an experienced NF clinician can usually make this distinction.
Plexiform neurofibromas, which involve large branches of multiple nerves, can cause significant problems in the neck. In some people, they grow aggressively and can compress the airway and other structures in the neck. While it is possible for plexiform neurofibromas to encase the carotid artery and jugular vein, usually the blood flow is unimpaired.
Another problem associated with plexiform neurofibromas in the neck is possible compression of the spinal nerves as they exit the spinal cord, causing pain or weakness in one or both arms. For this reason, an NF exam should include monitoring of patients for pain and neurologic function in the arms. It’s also possible for plexiform neurofibromas to grow into the vertebral foramen, the gap between vertebral bones where nerve roots connect to the spinal cord. Surgical removal is the only treatment option for plexiform neurofibromas, which can be difficult in the neck due to the risk of damage to vessels and nerves that could cause serious bleeding and other problems. Because of these significant risks, we reserve surgery for critical cases in which important structures in the neck are affected.
Some people with NF develop narrowing of the major arteries, which commonly occurs in one or both kidneys. The reduced blood flow caused by the narrowing signals the kidneys to release hormones that result in high blood pressure, which is a significant health risk. During each NF exam, blood pressure is closely monitored to ensure this problem isn’t developing. Narrowing can also occur in one or both of the carotid arteries, the major arteries in the neck supplying blood flow to the brain. As this condition gradually develops, collateral blood vessels are formed to compensate for reduced blood flow to the brain. Although most people with carotid artery narrowing don’t experience significant symptoms, certain conditions, such as dehydration, significantly increase the risk of stroke in these individuals. We don’t routinely perform imaging tests to screen for this issue, although we’re alert to any symptoms a patient may be experiencing that could indicate this problem. When this problem is recognized we usually recommend starting a mild blood thinner, typically baby aspirin. In symptomatic cases, there are surgical approaches that can restore blood flow to the brain.
New Discoveries in the UAB Medical Genomics Laboratory, Animal Model Progress, and NF-Related Features of the Head
By: Bruce Korf
Published Date: Mar 07
In previous blogs, I’ve referred to the leading-edge work conducted in the UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D. Viewed in the medical and scientific communities as the gold standard for NF genetic testing, the laboratory has identified mutations in more than 8,000 unrelated NF1 patients and has identified more than 3,000 NF1 mutations. A recent UAB School of Medicine web site article highlights the groundbreaking work of Dr. Messiaen and her colleagues in determining correlations between specific NF1 mutations and symptoms of the disorder (http://www.uab.edu/medicine/news/latest/item/956-uab-researchers-work-to-unravel-the-complex-genetic-disease-neurofibromatosis-type-1). Using the database of more than 3,000 different NF1 mutations and a catalogue of phenotypes (symptoms) in NF1 patients, Dr. Messiaen led a team of 74 researchers and clinicians from 58 centers (from 24 U.S. states and 8 non-U.S. countries) in identifying only the third genotype/phenotype correlation ever found for NF1. The details of this and other recent investigations conducted by Dr. Messiaen’s team were published last year in the journals Human Mutation (http://www.ncbi.nlm.nih.gov/pubmed/26178382) and The American Journal of Human Genetics (http://www.ncbi.nlm.nih.gov/pubmed/26189818).
This finding is significant in giving patients and clinicians a better understanding of the expected course of the disease, including the symptoms that are likely to be most prominent, with a specific type of NF1 mutation. As we’ve discussed previously, there is broad clinical variability in the expression of NF among individual patients, and the course of the disease is often difficult to predict. This uncertainty can be anxiety-provoking and unsettling for families of children facing a diagnosis of NF1. Dr. Messiaen’s continued efforts in developing, utilizing and expanding the laboratory’s extensive mutation database to identify additional genotype/phenotype correlations will help to explain the causes of variability of expressions of NF and provide a greater degree of clarity and predictability for patients and clinicians about the expected course of the disease.
Our NF research program is continuing to accelerate the development of new animal models of NF mutations. Recently, we have been in discussions with various groups about developing models of individual mutations. Our goal remains to create models that allow us to test or develop new drugs that will restore function to the mutated gene or gene product. We will soon have completed our first mouse model preclinical trial of one new approach to therapy, and expect to launch others in the upcoming months.
I’d like to continue our discussion, featured in the previous few blogs, briefly reviewing specific NF features and symptoms clinicians may identify during a patient examination. When conducting an exam of the head, the most obvious NF-related feature is often the presence of neurofibromas, soft benign tumors that develop on or under the skin. These are not usually seen in young children but typically appear during adolescence and continue to develop throughout life. Because skin neurofibromas are harmless, the primary concern may be cosmetic in individuals who have a significant distribution of neurofibromas on the face and neck. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another tumor that can occur on the face is a plexiform neurofibroma, a type of tumor that involves multiple branches of small or large nerves. Some children with NF1 develop a plexiform neurofibroma behind an eye, which may show up as a swelling of the upper eyelid in the early years of life. These can grow rapidly in childhood and cause significant disfigurement and interference with vision. Approximately 2% to 3% of people with NF1 develop orbital plexiform neurofibromas. Treatment involves surgical removal when possible, although surgery is complex and challenging due to the location of these tumors and the involvement of cranial nerves. Because recurrence after surgical removal is common, close follow-up with an experienced NF clinician as well as an ophthalmologist and plastic surgeon is important.
In some cases, distinctive facial features may be present in people with NF. An example of a feature that may be noted by a clinician is palpebral fissures – the longitudinal opening between the eyelids – which slant downward from the midline to the lateral area. While many people with NF share this feature, it doesn’t appear in everyone with NF. There also may be slight drooping of the upper eyelids. Other NF features on the head include scalp neurofibromas, which can become painful and sometimes bleed, usually in adults. Also, some people with NF retain a soft spot on the head, usually behind the left ear, that doesn’t completely close during the normal process of skull bone fusion that begins in early childhood. While this feature is uncommon, it may be noted by an experienced clinician during an examination. It is a benign feature that usually does not require treatment.
This finding is significant in giving patients and clinicians a better understanding of the expected course of the disease, including the symptoms that are likely to be most prominent, with a specific type of NF1 mutation. As we’ve discussed previously, there is broad clinical variability in the expression of NF among individual patients, and the course of the disease is often difficult to predict. This uncertainty can be anxiety-provoking and unsettling for families of children facing a diagnosis of NF1. Dr. Messiaen’s continued efforts in developing, utilizing and expanding the laboratory’s extensive mutation database to identify additional genotype/phenotype correlations will help to explain the causes of variability of expressions of NF and provide a greater degree of clarity and predictability for patients and clinicians about the expected course of the disease.
Our NF research program is continuing to accelerate the development of new animal models of NF mutations. Recently, we have been in discussions with various groups about developing models of individual mutations. Our goal remains to create models that allow us to test or develop new drugs that will restore function to the mutated gene or gene product. We will soon have completed our first mouse model preclinical trial of one new approach to therapy, and expect to launch others in the upcoming months.
I’d like to continue our discussion, featured in the previous few blogs, briefly reviewing specific NF features and symptoms clinicians may identify during a patient examination. When conducting an exam of the head, the most obvious NF-related feature is often the presence of neurofibromas, soft benign tumors that develop on or under the skin. These are not usually seen in young children but typically appear during adolescence and continue to develop throughout life. Because skin neurofibromas are harmless, the primary concern may be cosmetic in individuals who have a significant distribution of neurofibromas on the face and neck. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another tumor that can occur on the face is a plexiform neurofibroma, a type of tumor that involves multiple branches of small or large nerves. Some children with NF1 develop a plexiform neurofibroma behind an eye, which may show up as a swelling of the upper eyelid in the early years of life. These can grow rapidly in childhood and cause significant disfigurement and interference with vision. Approximately 2% to 3% of people with NF1 develop orbital plexiform neurofibromas. Treatment involves surgical removal when possible, although surgery is complex and challenging due to the location of these tumors and the involvement of cranial nerves. Because recurrence after surgical removal is common, close follow-up with an experienced NF clinician as well as an ophthalmologist and plastic surgeon is important.
In some cases, distinctive facial features may be present in people with NF. An example of a feature that may be noted by a clinician is palpebral fissures – the longitudinal opening between the eyelids – which slant downward from the midline to the lateral area. While many people with NF share this feature, it doesn’t appear in everyone with NF. There also may be slight drooping of the upper eyelids. Other NF features on the head include scalp neurofibromas, which can become painful and sometimes bleed, usually in adults. Also, some people with NF retain a soft spot on the head, usually behind the left ear, that doesn’t completely close during the normal process of skull bone fusion that begins in early childhood. While this feature is uncommon, it may be noted by an experienced clinician during an examination. It is a benign feature that usually does not require treatment.
New Year’s Resolutions for the NF Program and Common Skin Issues Detected During an NF Clinic Visit
By: Bruce Korf
Published Date: Jan 19
With the beginning of a new year, I’d like to follow the time-honored tradition of outlining a few key New Year’s resolutions for the UAB NF Program in 2016 that will continue to build on our commitment to excellence in patient care, research, and education. First, we continue our important mission of finding and developing new, life-changing therapies for people with NF by expanding and enhancing our program’s innovative research efforts during the upcoming year. As part of this effort, we are actively recruiting an additional faculty member to join our drug discovery initiatives. Also, we continue to make significant progress in animal model development that will allow us to test the effectiveness of potential NF medications more quickly and efficiently. To accomplish this objective, a graduate student in our program has developed new animal models with NF features that develop more rapidly than previous animal models that have neurofibromas, which are often slow-growing. We believe these new models hold promise in allowing for more expeditious drug testing efforts that will enable us to test more medications more quickly.
Also, as part of our ongoing drug discovery efforts in 2016, we continue to test the effectiveness of potential new drug therapies for NF1 using specialized types of cells derived from individuals with the NF1 gene mutation, called induced pluripotent stem (iPS) cells. Using cells from a biopsy taken from either skin or a neurofibroma of a patient with NF1, we can create iPS cells by manipulations that cause them to behave like undifferentiated cells. These patient-specific cell lines can be used to test the effectiveness of potential new drug therapies for NF1. An additional research goal for this year is to launch a clinical trial for skin neurofibromas in 2016. We are currently following patients and collecting data on the growth and progression of their neurofibromas, which is a necessary step before the clinical trial can begin.
In a recent blog post, I mentioned that we have plans to remake a video that was produced while I was Boston more than 10 years ago featuring a counseling session with a family regarding the new diagnosis of NF1 in a child (called “Understanding NF1,” available at (www.understandingnf1.org). Based on that post, we received a response from a family interested in participating and the project is now moving forward. Our Community Advisory Board, which held their initial meeting last October, will meet this spring with the overall objective of providing valuable input and direction regarding patient information, education, support, and coordination of care in our NF Clinic. Based on feedback from the Board, we are currently developing several projects for new approaches to patient education. Also, the Community Advisory Board will play a key role in helping to organize this year’s NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included.
In continuing our discussion from last month’s blog regarding important issues NF clinicians are focused on during a patient evaluation, I’d like to briefly review what we look for on the skin during an NF clinic visit. While NF1 includes many features, the appearance of multiple flat, brown spots called café-au-lait spots is the most common sign. These spots, which have flat margins and distinct borders, commonly appear in the first few months of life and may continue to increase in number through age two, though they often fade in adulthood. The coloring of café-au-lait spots is typically at least a shade darker than the general pigmentation of the skin. Anyone can have one or two café-au-lait spots without having NF1; however, most people with NF have at least six and most have many more. It’s important to understand that the presence of this feature only suggests the possibility of NF1. Legius Syndrome is another condition that causes café-au-lait spots, although this is a benign condition that does not cause the development of tumors and is much more rare than NF1
Freckling in the skin fold regions is another common NF1 feature that we look for during an exam. This distinctive freckling appears between three and five years of age and most commonly occurs in the groin region, under the arms, at the base of the neck, and under the breasts in women. Unlike typical freckling that occurs on sun-exposed areas of the skin, NF-related freckling manifests as many freckles in the region, as if paint were spattered from a brush. In addition to freckling, we also look for neurofibromas, soft benign tumors that develop under the skin. Although we occasionally see these in young children, the more visible neurofibromas appear later in childhood or adolescence and continue to develop throughout life, especially during pregnancy in women. While the size of neurofibromas can vary, the average size is that of a pencil eraser, though some can be larger or smaller. Skin neurofibromas are generally harmless, although they can be a significant cosmetic concern for individuals who have many neurofibromas distributed over large areas of the body such as the face, neck, and arms. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another skin condition that can be detected during an NF exam is a type of lesion called nevus anemicus, which can be associated with NF1. These lesions appear as a flat white patch on the skin, often on the chest or back. They are irregular in shape and sharply marginated. Usually present at birth or early childhood, the lesions seem to be caused by the incomplete formation of blood vessels in the skin and are harmless. Lastly, we sometimes see children with skin nodules called xanthogranulomas that occur more frequently in people with NF1. These appear as small, yellowish-orange bumps on the skin, especially at the hairline, in infants or very young children. Because xanthogranulomas regress spontaneously, they don’t require any special treatment. An experienced NF clinician can provide information and guidance about the clinical significance of the various skin conditions detected during an examination.
Also, as part of our ongoing drug discovery efforts in 2016, we continue to test the effectiveness of potential new drug therapies for NF1 using specialized types of cells derived from individuals with the NF1 gene mutation, called induced pluripotent stem (iPS) cells. Using cells from a biopsy taken from either skin or a neurofibroma of a patient with NF1, we can create iPS cells by manipulations that cause them to behave like undifferentiated cells. These patient-specific cell lines can be used to test the effectiveness of potential new drug therapies for NF1. An additional research goal for this year is to launch a clinical trial for skin neurofibromas in 2016. We are currently following patients and collecting data on the growth and progression of their neurofibromas, which is a necessary step before the clinical trial can begin.
In a recent blog post, I mentioned that we have plans to remake a video that was produced while I was Boston more than 10 years ago featuring a counseling session with a family regarding the new diagnosis of NF1 in a child (called “Understanding NF1,” available at (www.understandingnf1.org). Based on that post, we received a response from a family interested in participating and the project is now moving forward. Our Community Advisory Board, which held their initial meeting last October, will meet this spring with the overall objective of providing valuable input and direction regarding patient information, education, support, and coordination of care in our NF Clinic. Based on feedback from the Board, we are currently developing several projects for new approaches to patient education. Also, the Community Advisory Board will play a key role in helping to organize this year’s NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included.
In continuing our discussion from last month’s blog regarding important issues NF clinicians are focused on during a patient evaluation, I’d like to briefly review what we look for on the skin during an NF clinic visit. While NF1 includes many features, the appearance of multiple flat, brown spots called café-au-lait spots is the most common sign. These spots, which have flat margins and distinct borders, commonly appear in the first few months of life and may continue to increase in number through age two, though they often fade in adulthood. The coloring of café-au-lait spots is typically at least a shade darker than the general pigmentation of the skin. Anyone can have one or two café-au-lait spots without having NF1; however, most people with NF have at least six and most have many more. It’s important to understand that the presence of this feature only suggests the possibility of NF1. Legius Syndrome is another condition that causes café-au-lait spots, although this is a benign condition that does not cause the development of tumors and is much more rare than NF1
Freckling in the skin fold regions is another common NF1 feature that we look for during an exam. This distinctive freckling appears between three and five years of age and most commonly occurs in the groin region, under the arms, at the base of the neck, and under the breasts in women. Unlike typical freckling that occurs on sun-exposed areas of the skin, NF-related freckling manifests as many freckles in the region, as if paint were spattered from a brush. In addition to freckling, we also look for neurofibromas, soft benign tumors that develop under the skin. Although we occasionally see these in young children, the more visible neurofibromas appear later in childhood or adolescence and continue to develop throughout life, especially during pregnancy in women. While the size of neurofibromas can vary, the average size is that of a pencil eraser, though some can be larger or smaller. Skin neurofibromas are generally harmless, although they can be a significant cosmetic concern for individuals who have many neurofibromas distributed over large areas of the body such as the face, neck, and arms. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another skin condition that can be detected during an NF exam is a type of lesion called nevus anemicus, which can be associated with NF1. These lesions appear as a flat white patch on the skin, often on the chest or back. They are irregular in shape and sharply marginated. Usually present at birth or early childhood, the lesions seem to be caused by the incomplete formation of blood vessels in the skin and are harmless. Lastly, we sometimes see children with skin nodules called xanthogranulomas that occur more frequently in people with NF1. These appear as small, yellowish-orange bumps on the skin, especially at the hairline, in infants or very young children. Because xanthogranulomas regress spontaneously, they don’t require any special treatment. An experienced NF clinician can provide information and guidance about the clinical significance of the various skin conditions detected during an examination.
Animal Model Research Update, Plans for Adult and Pediatric NF Clinics, and the Focus of Exams in an NF Clinic
By: Bruce Korf
Published Date: Dec 11
As the year draws to a close, I’d like to provide a brief update on the NF Program’s research progress in the important area of animal model development. Animal models allow scientists to study the process of specific diseases and often serve as an important foundation of drug research before clinical trials can begin in humans. Our research program is continuing work on a mouse model we developed with a specific type of gene mutation, called a premature stop mutation, that is responsible for ~20% of NF1 cases. A mouse clinical trial is currently in progress with the objective of determining whether certain medications are effective in overcoming the stop mutation by either shrinking existing tumors in the mice or delaying or preventing tumor growth. In addition to the premature stop mutation model, we have also expanded the number of mutations for which we’re developing animal models, with an overall goal of establishing a library of animal models that can be used to test the efficacy of potential medications. We’re using the new gene editing approach called the CRISPR/Cas9 system, which allows investigators to “edit” the genome and quickly introduce mutations into these model systems. Although the results of our research initiatives can’t be released until they have been peer-reviewed and published (and a set of papers are now in preparation), it’s important to know that significant progress is being made in the development of animal models that are allowing us to test new drug therapies that hold promise in restoring function to genes with specific types of mutations.
In other developments, we are anticipating that by early 2016, the NF Clinic will be separated into adult and pediatric clinics located at two distinct sites: the adult clinic will be located in the Kirklin Clinic at UAB, while the pediatric clinic will be at the downtown Children’s Hospital of Alabama location. Both of these facilities provide more convenient patient parking than our current NF Clinic location in the Hugh Kaul Human Genetics building. Most importantly, the new locations will allow for a more seamless integration with the range of other medical specialties involved in the multidisciplinary approach to care that we provide to our NF patients.
Lastly, I’d like to briefly discuss some of the important issues that we, as NF clinicians, are focused on during a patient evaluation by highlighting three main points: the value of NF patients being followed by NF specialists; the purpose of annual follow-up exams; and a brief explanation of what NF clinicians are looking for during an NF exam. First, we understand that most patients have a primary care physician and we try to work together with these providers. Primary care physicians play an integral role in the healthcare continuum by providing recommended screenings, risk assessments, and vaccinations, for example. Our goal as NF clinicians is to serve as consultants by providing support and assistance. NF is a progressive disorder, and an NF clinician has experience in detecting changes in NF patients before significant problems develop and in recognizing NF-related problems when they do occur. We occasionally see patients with NF-related problems whose diagnosis was delayed, which can make the problem more difficult to manage.
Once a patient is established in an NF Clinic, exams at one-year intervals are a convenient and useful benchmark for clinicians to stay in touch with patients and detect any NF-related problems that may be developing. Also, the state of knowledge in the NF field changes significantly from year to year, especially with the progress in clinical trials and other research, and we want our patients to benefit from new treatment advances or opportunities to participate in research. The emphasis of annual exams varies depending on many factors, including the age of the patient, the type of NF involved, and the complications the patient is currently experiencing. As NF clinicians, we follow people with all forms of NF at all ages, from birth to advanced age; the problems a clinician looks for in an NF patient vary with all these factors. For example, we keep a close watch on the formation of optic nerve tumors in children with NF1 because they are more common in pediatric patients, while we’re not as concerned about this issue in adults. In general, an annual exam focuses on keeping track of known problems, identifying new signs or symptoms, and anticipating likely future issues. In an NF clinic, exams are performed by experts who can detect problems early and customize care to the needs of individual patients and their life stage.
In other developments, we are anticipating that by early 2016, the NF Clinic will be separated into adult and pediatric clinics located at two distinct sites: the adult clinic will be located in the Kirklin Clinic at UAB, while the pediatric clinic will be at the downtown Children’s Hospital of Alabama location. Both of these facilities provide more convenient patient parking than our current NF Clinic location in the Hugh Kaul Human Genetics building. Most importantly, the new locations will allow for a more seamless integration with the range of other medical specialties involved in the multidisciplinary approach to care that we provide to our NF patients.
Lastly, I’d like to briefly discuss some of the important issues that we, as NF clinicians, are focused on during a patient evaluation by highlighting three main points: the value of NF patients being followed by NF specialists; the purpose of annual follow-up exams; and a brief explanation of what NF clinicians are looking for during an NF exam. First, we understand that most patients have a primary care physician and we try to work together with these providers. Primary care physicians play an integral role in the healthcare continuum by providing recommended screenings, risk assessments, and vaccinations, for example. Our goal as NF clinicians is to serve as consultants by providing support and assistance. NF is a progressive disorder, and an NF clinician has experience in detecting changes in NF patients before significant problems develop and in recognizing NF-related problems when they do occur. We occasionally see patients with NF-related problems whose diagnosis was delayed, which can make the problem more difficult to manage.
Once a patient is established in an NF Clinic, exams at one-year intervals are a convenient and useful benchmark for clinicians to stay in touch with patients and detect any NF-related problems that may be developing. Also, the state of knowledge in the NF field changes significantly from year to year, especially with the progress in clinical trials and other research, and we want our patients to benefit from new treatment advances or opportunities to participate in research. The emphasis of annual exams varies depending on many factors, including the age of the patient, the type of NF involved, and the complications the patient is currently experiencing. As NF clinicians, we follow people with all forms of NF at all ages, from birth to advanced age; the problems a clinician looks for in an NF patient vary with all these factors. For example, we keep a close watch on the formation of optic nerve tumors in children with NF1 because they are more common in pediatric patients, while we’re not as concerned about this issue in adults. In general, an annual exam focuses on keeping track of known problems, identifying new signs or symptoms, and anticipating likely future issues. In an NF clinic, exams are performed by experts who can detect problems early and customize care to the needs of individual patients and their life stage.
Successful 2nd Annual Alabama NF Walk and Update on Newly Formed NF Community Advisory Board
By: Bruce Korf
Published Date: Nov 16
I’m pleased to report that the 2nd annual Alabama NF Walk, held on October 18th in Veterans Park in Hoover, was a huge success both in terms of fundraising and attendance. The purpose of the event is to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults. This year’s NF Walk raised more than $73,000 and registered more than 400 participants, a significant accomplishment for this important event that was launched in our area only one year ago by Birmingham resident Renie Moss, a dedicated patient advocate and mother of two children with NF. Through the tireless efforts of the Moss family, as well as other Birmingham families who have been affected by NF, the Alabama NF Walk has become a significant fundraising event in our area that supports critical NF research focused on the development of breakthrough treatments.
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the newly formed NF Community Advisory Board held its first meeting at the Kaul Human Genetics Building last month. Comprised of NF patients and family members, the primary purpose of the Board is to provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets the needs of our community. Due to the collective expertise and experience of our NF Clinic specialists and staff, I’m confident that our patients are receiving the highest level of NF care available. However, we also want to ensure that our patients have the best possible experience in our Clinic with respect to patient information, education, support, and coordination of care. The Board, which will meet three or four times a year, will maintain an emphasis on community outreach and education regarding NF and the clinical and research programs available at UAB. In addition, the Board will serve an integral role in helping to organize the NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included. Other goals for the group include identifying any needs that are currently not being addressed by our NF program and offering advice to our program leadership to help make the NF Clinic as strong and responsive as possible. Also, the Board will explore the development of smart phone and tablet apps to assist patients in documenting and storing information about their own care that can also be shared with clinicians to expedite communication and enhance patient care. These and other initiatives will serve to improve our patients’ experience in the Clinic and ensure that our NF program continues to maintain our commitment to meeting patients’ needs in every area.
One final point: More than 10 years ago, while I was still in Boston, we produced a video of a counseling session with a family regarding the new diagnosis of NF1 in a child. It can be viewed online at www.understandingnf1.org. We have gotten a lot of good feedback about the video over the years, as many families have found it helpful to understand the many issues that arise with a new diagnosis of NF1. A lot has happened in NF research – genetic testing and clinical trials, for example – since the video was done, and therefore I’d like to redo it and include this new information. The couple who were featured in the video actually do have a child with NF1, though this was not really their first time hearing about it. It works best to have a couple with a young child who has been diagnosed in the relatively recent past. If anyone reading this would like to consider working with us on this, please let me know (bkorf@uabmc.edu).
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the newly formed NF Community Advisory Board held its first meeting at the Kaul Human Genetics Building last month. Comprised of NF patients and family members, the primary purpose of the Board is to provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets the needs of our community. Due to the collective expertise and experience of our NF Clinic specialists and staff, I’m confident that our patients are receiving the highest level of NF care available. However, we also want to ensure that our patients have the best possible experience in our Clinic with respect to patient information, education, support, and coordination of care. The Board, which will meet three or four times a year, will maintain an emphasis on community outreach and education regarding NF and the clinical and research programs available at UAB. In addition, the Board will serve an integral role in helping to organize the NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included. Other goals for the group include identifying any needs that are currently not being addressed by our NF program and offering advice to our program leadership to help make the NF Clinic as strong and responsive as possible. Also, the Board will explore the development of smart phone and tablet apps to assist patients in documenting and storing information about their own care that can also be shared with clinicians to expedite communication and enhance patient care. These and other initiatives will serve to improve our patients’ experience in the Clinic and ensure that our NF program continues to maintain our commitment to meeting patients’ needs in every area.
One final point: More than 10 years ago, while I was still in Boston, we produced a video of a counseling session with a family regarding the new diagnosis of NF1 in a child. It can be viewed online at www.understandingnf1.org. We have gotten a lot of good feedback about the video over the years, as many families have found it helpful to understand the many issues that arise with a new diagnosis of NF1. A lot has happened in NF research – genetic testing and clinical trials, for example – since the video was done, and therefore I’d like to redo it and include this new information. The couple who were featured in the video actually do have a child with NF1, though this was not really their first time hearing about it. It works best to have a couple with a young child who has been diagnosed in the relatively recent past. If anyone reading this would like to consider working with us on this, please let me know (bkorf@uabmc.edu).
Upcoming 2nd Annual Alabama NF Walk and Understanding the Role of NF Genetic Testing
By: Bruce Korf
Published Date: Oct 12
Plans are in place for the 2nd annual Alabama NF Walk in Birmingham to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both adults and children. This year’s event will be held on Sunday, October 18th, at 1 p.m. in Veterans Park located in Hoover. For more information or to register, visit the following page on the CTF web site: www.nfwalk.org/alabama. Last year’s inaugural NF Walk was a landmark event for our city and a huge success, raising more than $50,000 for CTF. Birmingham resident Renie Moss, a dedicated patient advocate and mother of two children with NF, spearheaded our local NF Walk last year in conjunction with CTF. Working with other Birmingham families who have been affected by NF, the Moss family continues to play an integral role in organizing and publicizing this important event that supports critical NF research focused on the development of breakthrough treatments.
Next, I’d like to discuss the role of genetic testing in diagnosing NF and explain when it can be useful. The UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., offers clinical genetic testing for all forms of neurofibromatosis and Legius syndrome, as well as a group of related disorders collectively referred to as the “rasopathies.” In 2003, Dr. Messiaen launched the first routine, reliable, and affordable clinical genetic test for NF1 that has the capability to detect more than 95% of the mutations in persons who fulfill diagnostic criteria. Prior to the development of this test, it was difficult to perform testing for NF1 because of the vast number and diversity of the mutations involved, of which there are thousands. Because of her pioneering efforts, the UAB Medical Genomics Laboratory run by Dr. Messiaen is viewed in the medical and scientific communities as the gold standard for NF genetic testing. The laboratory offers the most scientifically reliable, leading-edge genetic testing currently available for the diagnosis and characterization of mutations in NF1, NF2, and schwannomatosis and performs the highest volume of neurofibromatosis genetic testing in the world. The laboratory has performed more than 7,000 NF1 tests and has identified more than 3,000 different NF1 mutations. Dr. Messiaen and her colleagues were also able to discover a new gene, designated LZTR1, responsible for some cases of schwannomatosis.
Several factors are involved in determining when genetic testing can be useful to patients with neurofibromatosis. In most cases, a diagnosis of NF1 is made clinically, based on the presence of two or more of the seven NIH criteria for the disorder. In some cases, however, a clinical diagnosis of NF1 may be inconclusive or needs to be confirmed, and here genetic testing can be very helpful. For example, if a child has café-au-lait spots and no other clinical features, genetic testing can be used to confirm an NF diagnosis and also to rule out Legius syndrome (which can cause the appearance of café-au-lait spots but not the tumors that are characteristic of NF1).
In addition, there are some cases in which particular mutations predict certain features of NF; for example, a whole gene deletion predicts a more severe course of the disorder and there are a few other mutations that predict a mild course. People who have an unusual presentation, including either isolated or severe features, can also benefit from genetic testing to determine if an NF1 mutation is involved. Finally, identification of an NF1 mutation can make it possible to offer prenatal testing to determine if the mutation has been passed on to a fetus who is at risk based on the mother or father being affected.
One additional interesting point on genetic testing for NF has recently emerged. There is evidence that individuals with NF1 are at increased risk of breast cancer – not to the extent of those with mutations in genes such as BRCA1 or BRCA2, but still at a greater risk than the general population. For this reason, many companies offering genetic testing to persons diagnosed with breast cancer are including a test for NF1 on their genetic testing panel, and a few examples of people with unexpected NF1 mutations have been found. Some of these are likely to be people who actually have neurofibromatosis but had never realized they were affected. Others may have few signs or symptoms, making the finding a real surprise. It remains to be seen how this is explained, and it represents a new area of research in neurofibromatosis genetic testing.
Next, I’d like to discuss the role of genetic testing in diagnosing NF and explain when it can be useful. The UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., offers clinical genetic testing for all forms of neurofibromatosis and Legius syndrome, as well as a group of related disorders collectively referred to as the “rasopathies.” In 2003, Dr. Messiaen launched the first routine, reliable, and affordable clinical genetic test for NF1 that has the capability to detect more than 95% of the mutations in persons who fulfill diagnostic criteria. Prior to the development of this test, it was difficult to perform testing for NF1 because of the vast number and diversity of the mutations involved, of which there are thousands. Because of her pioneering efforts, the UAB Medical Genomics Laboratory run by Dr. Messiaen is viewed in the medical and scientific communities as the gold standard for NF genetic testing. The laboratory offers the most scientifically reliable, leading-edge genetic testing currently available for the diagnosis and characterization of mutations in NF1, NF2, and schwannomatosis and performs the highest volume of neurofibromatosis genetic testing in the world. The laboratory has performed more than 7,000 NF1 tests and has identified more than 3,000 different NF1 mutations. Dr. Messiaen and her colleagues were also able to discover a new gene, designated LZTR1, responsible for some cases of schwannomatosis.
Several factors are involved in determining when genetic testing can be useful to patients with neurofibromatosis. In most cases, a diagnosis of NF1 is made clinically, based on the presence of two or more of the seven NIH criteria for the disorder. In some cases, however, a clinical diagnosis of NF1 may be inconclusive or needs to be confirmed, and here genetic testing can be very helpful. For example, if a child has café-au-lait spots and no other clinical features, genetic testing can be used to confirm an NF diagnosis and also to rule out Legius syndrome (which can cause the appearance of café-au-lait spots but not the tumors that are characteristic of NF1).
In addition, there are some cases in which particular mutations predict certain features of NF; for example, a whole gene deletion predicts a more severe course of the disorder and there are a few other mutations that predict a mild course. People who have an unusual presentation, including either isolated or severe features, can also benefit from genetic testing to determine if an NF1 mutation is involved. Finally, identification of an NF1 mutation can make it possible to offer prenatal testing to determine if the mutation has been passed on to a fetus who is at risk based on the mother or father being affected.
One additional interesting point on genetic testing for NF has recently emerged. There is evidence that individuals with NF1 are at increased risk of breast cancer – not to the extent of those with mutations in genes such as BRCA1 or BRCA2, but still at a greater risk than the general population. For this reason, many companies offering genetic testing to persons diagnosed with breast cancer are including a test for NF1 on their genetic testing panel, and a few examples of people with unexpected NF1 mutations have been found. Some of these are likely to be people who actually have neurofibromatosis but had never realized they were affected. Others may have few signs or symptoms, making the finding a real surprise. It remains to be seen how this is explained, and it represents a new area of research in neurofibromatosis genetic testing.
A Successful and Memorable NF Family Day and Plans for Future Dermal Neurofibroma Trials
By: Bruce Korf
Published Date: Sep 23
The month of August neared an end with yet another successful and memorable Neurofibromatosis Symposium held at the UAB Hugh Kaul Genetics Building on August 29th. Also known as NF Family Day, this half-day, free event co-sponsored by UAB and the Children’s Tumor Foundation (CTF) provided NF patients and their families with valuable information through a series of presentations given by clinical experts on a range of NF-related topics. We were especially pleased to have 100 people registered for the Symposium, which marks the largest attendance for the event to date. A unique highlight of NF Family Day this year was a special program designed for the children in attendance, provided by our genetic counseling students, that included special materials donated by the Homewood Library as well as an exciting and memorable visit by members of the Birmingham Fire Department replete with an authentic fire truck the children could tour during our lunch break.
To begin the Symposium, I gave an overview of neurofibromatosis including information about each of the three types of NF, a general summary of current research findings, and the role of genetic testing. Some families in attendance may have heard this information previously while for others, especially those facing a new diagnosis, it may have been new. Alyssa Reddy, MD, director of the Children’s Hospital of Alabama Neuro-Oncology Program, explained UAB’s dual role as both the national coordinating center for the NF Clinical Trials Consortium and one of the national patient recruitment sites for clinical trials. She also provided an overview of her efforts in recruiting patients for NF-related clinical trials and explained enrollment criteria and the informed consent process. In addition, Dr. Reddy discussed some of the latest treatment options for specific NF tumor types, such as optic gliomas and plexiform neurofibromas. Continuing with information about the NF Program’s robust research initiatives, graduate student Ashley Turner, MS, summarized her work in the NF laboratory developing mouse models with human NF mutations in order to test compounds that might prove effective in treating tumors; this research serves an important foundational step in the drug discovery process by helping to identify potential drugs that could be tested in future human clinical trials.
Our new NF Program genetics counselor Ashley Cannon, PhD, MS, CGC, presented information about NF-related learning disabilities and explained the process of navigating the often complex terrain of establishing IEP and 504 plans for school-aged children. Dr. Cannon stressed to parents that while NF-related learning disabilities and difficulties most often become evident in school-aged children, learning challenges do not go away as children move into adolescence and adulthood; instead, people with NF can struggle with learning difficulties throughout their lives, particularly if they do not receive appropriate educational services during early childhood.
Also, Dr. Cannon provided information about the NF registry (https://nfregistry.patientcrossroads.org) established by CTF in 2012 and provided attendees the opportunity to join while at the Symposium; the purpose of the NF Registry is to help notify NF patients who may be eligible for clinical trials or other research studies and to determine the frequency of specific NF characteristics. Next, UAB Associate Professor of Anesthesiology and pain expert James Weisberg, PhD, discussed pain management for NF patients, emphasizing the need to utilize a holistic approach in treating pain that incorporates medication with cognitive-behavioral therapies.
To close the program, well-known patient advocate and Birmingham parent of two children with NF, Renie Moss, presented information on patient advocacy while Kristen Stanley from CTF spoke about the work of the organization and upcoming events. The annual NF Symposium, in addition to providing patients and families with an important forum about NF-related topics, also serves to help NF families establish supportive connections with others facing similar challenges and concerns. We find it rewarding to have the opportunity to facilitate these two meaningful purposes through this event.
As I mentioned in a previous post, I often receive questions from patients asking why clinical trials focus on plexiform neurofibromas, while there are no clinical trials in progress for dermal neurofibromas. Part of the reason is that the complications of plexiforms are often more medically serious than for dermal neurofibromas and can sometimes be life-threatening. However, some good news to share is that our program recently submitted a grant proposal for a dermal neurofibroma clinical trial; although it will be a while until we know if we will receive funding, our program is committed to actively pursuing clinical trials of dermal neurofibromas.
To begin the Symposium, I gave an overview of neurofibromatosis including information about each of the three types of NF, a general summary of current research findings, and the role of genetic testing. Some families in attendance may have heard this information previously while for others, especially those facing a new diagnosis, it may have been new. Alyssa Reddy, MD, director of the Children’s Hospital of Alabama Neuro-Oncology Program, explained UAB’s dual role as both the national coordinating center for the NF Clinical Trials Consortium and one of the national patient recruitment sites for clinical trials. She also provided an overview of her efforts in recruiting patients for NF-related clinical trials and explained enrollment criteria and the informed consent process. In addition, Dr. Reddy discussed some of the latest treatment options for specific NF tumor types, such as optic gliomas and plexiform neurofibromas. Continuing with information about the NF Program’s robust research initiatives, graduate student Ashley Turner, MS, summarized her work in the NF laboratory developing mouse models with human NF mutations in order to test compounds that might prove effective in treating tumors; this research serves an important foundational step in the drug discovery process by helping to identify potential drugs that could be tested in future human clinical trials.
Our new NF Program genetics counselor Ashley Cannon, PhD, MS, CGC, presented information about NF-related learning disabilities and explained the process of navigating the often complex terrain of establishing IEP and 504 plans for school-aged children. Dr. Cannon stressed to parents that while NF-related learning disabilities and difficulties most often become evident in school-aged children, learning challenges do not go away as children move into adolescence and adulthood; instead, people with NF can struggle with learning difficulties throughout their lives, particularly if they do not receive appropriate educational services during early childhood.
Also, Dr. Cannon provided information about the NF registry (https://nfregistry.patientcrossroads.org) established by CTF in 2012 and provided attendees the opportunity to join while at the Symposium; the purpose of the NF Registry is to help notify NF patients who may be eligible for clinical trials or other research studies and to determine the frequency of specific NF characteristics. Next, UAB Associate Professor of Anesthesiology and pain expert James Weisberg, PhD, discussed pain management for NF patients, emphasizing the need to utilize a holistic approach in treating pain that incorporates medication with cognitive-behavioral therapies.
To close the program, well-known patient advocate and Birmingham parent of two children with NF, Renie Moss, presented information on patient advocacy while Kristen Stanley from CTF spoke about the work of the organization and upcoming events. The annual NF Symposium, in addition to providing patients and families with an important forum about NF-related topics, also serves to help NF families establish supportive connections with others facing similar challenges and concerns. We find it rewarding to have the opportunity to facilitate these two meaningful purposes through this event.
As I mentioned in a previous post, I often receive questions from patients asking why clinical trials focus on plexiform neurofibromas, while there are no clinical trials in progress for dermal neurofibromas. Part of the reason is that the complications of plexiforms are often more medically serious than for dermal neurofibromas and can sometimes be life-threatening. However, some good news to share is that our program recently submitted a grant proposal for a dermal neurofibroma clinical trial; although it will be a while until we know if we will receive funding, our program is committed to actively pursuing clinical trials of dermal neurofibromas.
A New Specialist Joins the NF Clinic Team, Upcoming NF Symposium at UAB, and Understanding RAS Disorders and their Relationship to NF
By: Bruce Korf
Published Date: Aug 03
As I mentioned in the previous blog, we are pleased to announce the addition of Dr. Ashley Cannon, a genetic counselor and clinical researcher, to our team of specialists in the UAB NF Clinic. With a unique and diverse background that includes a Ph.D. in neuroscience and a degree in genetic counseling (completed at UAB), Dr. Cannon brings a range of capabilities that will further enhance both patient care and clinical research. She will play an integral role in seeing patients in the clinic, helping to identify the needs of individual patients, organizing genetic testing, and providing genetic counseling. In addition, Dr. Cannon will serve a key role in coordinating clinical trials and research studies conducted in the NF research program. I have also asked her to begin the process of establishing our community advisory board, which will be comprised of NF patients and family members who will provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets their needs.
Currently, Dr. Cannon is assisting with final preparations for the upcoming Neurofibromatosis Symposium to be held at the Finley Conference Center in the Kaul Human Genetics Building on Saturday, August 29th. Co-sponsored by UAB and the Children’s Tumor Foundation (CTF), this half-day, free event is designed to provide NF patients and their families with information about a range of NF-related topics including: an overview of neurofibromatosis; updates on clinical trials and other research advances; genetic counseling and the NF registry; pain management; a patient and family roundtable discussion; advocacy, fundraising, and upcoming events in the NF community; and a question-and-answer session. Breakfast, lunch, and childcare will be provided for the convenience of our families. While there is no cost to attend, reservations should be made by August 24th by emailing acannon@uab.edu. This is an invaluable opportunity for NF patients and families – especially those facing a new diagnosis – to gain information, support, and answers to questions about neurofibromatosis. Each year, we look forward to serving NF patients and their families through this important forum that not only provides key information about NF but also offers the opportunity for NF families to gain understanding and strength through sharing their experiences, challenges, and concerns.
Neurofibromatosis Symposium: Family Day 2015
Saturday, August 29th, 2015
Schedule:
08:00-08:30am Register/Breakfast
08:30-10:00am Welcome/NF 101/Updates – Dr. Bruce Korf
10:00-10:30am Break
10:30-11:00am Clinical Trials Update – Dr. Alyssa Reddy
11:00-11:30am Research Studies – Ashley Turner
11:30-12:00pm Counseling Issues/Registry – Ashley Cannon
12:00-12:30pm Pain Management – Dr. James Weisberg
12:30-01:30pm Lunch / Patient and Family Roundtable
01:30-02:00pm Advocacy, Fundraising, Upcoming Events – Renie Moss
On July 17th- 19th, I attended the 4th International RASopathies Symposium in Seattle, Washington. The RASopathies are a group of medical genetic syndromes, including NF1, that have in common the fact that their underlying genetic alterations occur in a critical cellular signaling pathway called the RAS/MAPK pathway. Neurofibromatosis type 1 is caused by a genetic alteration in the gene that encodes for neurofibromin, a protein regulating activity of the RAS signaling pathway that also has a role in cell growth and division. As in NF1, the RAS pathway can be disturbed in a host of other syndromes including Noonan syndrome, cardiofaciocutaneous (CFC) syndrome, Legius syndrome, and Costello syndrome. All RASopathy syndromes affect multiple systems of the body; features such as cardiac disease, growth deficits, facial characteristics, bone and skin abnormalities, and learning and behavior problems are common. However, as with NF1, the presence and severity of these features varies widely among affected individuals.
The purpose of the RASopathies Symposium is to bring together scientists, clinicians, researchers, and affected families to facilitate a collaborative discussion focused on future research, development of therapies, and best clinical practices for RAS/MAPK pathway syndromes. Because NF1 was the first RASopathy to be identified, we in the NF scientific community are much further along than the other related syndromes in our capability to develop clinical trials focused on mechanism-based therapies. This is due in part to the fact that we’ve known about NF1 for a longer period of time and also because it is easier to define what success would look like in an NF patient. It is encouraging that the development of mechanism-based therapies that inhibit the over-activated RAS pathway and other RAS-connected pathways opens new avenues of therapeutic intervention for the many complications of the RAS disorders. Because neurofibromatosis has been a beacon in the realm of mechanism-based therapeutics, other RAS disorders are looking to the NF scientific community for examples in the development of effective treatments; we’re certainly hopeful that we can share valuable information based on our experience with NF and that this shared knowledge will facilitate research that will benefit those with the various RAS disorders.
Currently, Dr. Cannon is assisting with final preparations for the upcoming Neurofibromatosis Symposium to be held at the Finley Conference Center in the Kaul Human Genetics Building on Saturday, August 29th. Co-sponsored by UAB and the Children’s Tumor Foundation (CTF), this half-day, free event is designed to provide NF patients and their families with information about a range of NF-related topics including: an overview of neurofibromatosis; updates on clinical trials and other research advances; genetic counseling and the NF registry; pain management; a patient and family roundtable discussion; advocacy, fundraising, and upcoming events in the NF community; and a question-and-answer session. Breakfast, lunch, and childcare will be provided for the convenience of our families. While there is no cost to attend, reservations should be made by August 24th by emailing acannon@uab.edu. This is an invaluable opportunity for NF patients and families – especially those facing a new diagnosis – to gain information, support, and answers to questions about neurofibromatosis. Each year, we look forward to serving NF patients and their families through this important forum that not only provides key information about NF but also offers the opportunity for NF families to gain understanding and strength through sharing their experiences, challenges, and concerns.
Neurofibromatosis Symposium: Family Day 2015
Saturday, August 29th, 2015
Schedule:
08:00-08:30am Register/Breakfast
08:30-10:00am Welcome/NF 101/Updates – Dr. Bruce Korf
10:00-10:30am Break
10:30-11:00am Clinical Trials Update – Dr. Alyssa Reddy
11:00-11:30am Research Studies – Ashley Turner
11:30-12:00pm Counseling Issues/Registry – Ashley Cannon
12:00-12:30pm Pain Management – Dr. James Weisberg
12:30-01:30pm Lunch / Patient and Family Roundtable
01:30-02:00pm Advocacy, Fundraising, Upcoming Events – Renie Moss
On July 17th- 19th, I attended the 4th International RASopathies Symposium in Seattle, Washington. The RASopathies are a group of medical genetic syndromes, including NF1, that have in common the fact that their underlying genetic alterations occur in a critical cellular signaling pathway called the RAS/MAPK pathway. Neurofibromatosis type 1 is caused by a genetic alteration in the gene that encodes for neurofibromin, a protein regulating activity of the RAS signaling pathway that also has a role in cell growth and division. As in NF1, the RAS pathway can be disturbed in a host of other syndromes including Noonan syndrome, cardiofaciocutaneous (CFC) syndrome, Legius syndrome, and Costello syndrome. All RASopathy syndromes affect multiple systems of the body; features such as cardiac disease, growth deficits, facial characteristics, bone and skin abnormalities, and learning and behavior problems are common. However, as with NF1, the presence and severity of these features varies widely among affected individuals.
The purpose of the RASopathies Symposium is to bring together scientists, clinicians, researchers, and affected families to facilitate a collaborative discussion focused on future research, development of therapies, and best clinical practices for RAS/MAPK pathway syndromes. Because NF1 was the first RASopathy to be identified, we in the NF scientific community are much further along than the other related syndromes in our capability to develop clinical trials focused on mechanism-based therapies. This is due in part to the fact that we’ve known about NF1 for a longer period of time and also because it is easier to define what success would look like in an NF patient. It is encouraging that the development of mechanism-based therapies that inhibit the over-activated RAS pathway and other RAS-connected pathways opens new avenues of therapeutic intervention for the many complications of the RAS disorders. Because neurofibromatosis has been a beacon in the realm of mechanism-based therapeutics, other RAS disorders are looking to the NF scientific community for examples in the development of effective treatments; we’re certainly hopeful that we can share valuable information based on our experience with NF and that this shared knowledge will facilitate research that will benefit those with the various RAS disorders.
Understanding Possible Explanations for Isolated Features of NF
By: Bruce Korf
Published Date: Jul 08
Frequently I receive questions, through both e-mails and individuals who are referred to my office, regarding patients who have one isolated feature of NF but do not have a confirmed diagnosis of neurofibromatosis. These isolated features most often occur in the form of either plexiform neurofibromas or optic gliomas, although they sometimes may include dermal neurofibromas or bone dysplasia. It is important to know that isolated features of NF can occasionally been seen in both children and adults who do not actually have the condition. I’d like to give a brief overview of how we evaluate patients with only one isolated feature of NF in the absence of other symptoms and provide some possible explanations of why this phenomenon may occur.
Some individuals develop plexiform neurofibromas – tumors that involve multiple branches of large nerves – in one isolated area of the body, such as the spine, with no other features of NF. The age of presentation varies, but it usually begins from the teenage years into adulthood, as the symptoms of a plexiform neurofibroma do not become apparent until adolescence. Isolated optic gliomas, tumors of the optic nerve, can also occur in children and adults who have no other features of NF. Unlike isolated plexiform neurofibromas, optic gliomas that occur in individuals who do not have NF are typically more aggressive tumors than those found in people who have neurofibromatosis. Some individuals also develop isolated dermal neurofibromas or bone dysplasia in the absence of other NF features and with no confirmed diagnosis of neurofibromatosis.
When we see someone in our clinic with an isolated feature of NF, we provide a comprehensive evaluation to make certain that subtle features of the condition are not present. In some cases, if possible, we obtain a tissue sample of the tumor, although this is often difficult due to the location of tumors, such as plexiform neurofibromas deep inside the body. Sometimes we obtain a blood sample for genetic testing; however, a negative result does not necessarily confirm that an individual does not have NF.
There are at least three possible explanations for the occurrence of isolated NF features in some individuals. The first is mosaicism, caused by a mutation in the NF1 gene that occurs early in embryonic development and that only affects certain cells in the body. As a result, individuals with mosaicism have features of NF1 that are limited to only one part of their body, such as neurofibromas or café-au-lait spots in a certain region. The only method of confirming mosaicism is to biopsy the lesion and do genetic testing on the tissue. A second possible explanation for the occurrence of isolated features of NF is that there could be other, still unknown mechanisms that cause tumors that occur in people with NF to also occur in individuals who do not have the condition.
A third possible explanation is related to the specific “two-hit” genetic mechanism that causes the development of tumors in people with NF1. All persons have two copies of the gene, one inherited from each parent. In individuals with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the mutated gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation. For a neurofibroma to develop in someone with NF1, a random genetic mutation must occur to the other copy of the NF1 gene in the tissue that will become the neurofibroma, café-au-lait spot, or other lesion; this is referred to as the “second-hit” mutation. Although an extremely rare occurrence, it is also possible for some individuals to acquire two random NF mutations, affecting each inherited copy of the NF1 gene, in a cell that could become a neurofibroma or other lesion. This two-hit mutation – similar to lightning striking twice in the same place – could result in the development of an isolated feature of NF in the absence of other signs of the condition.
On another topic, there are two things to report regarding the UAB NF Program. First, Dr. Ashley Cannon has joined the program as genetic counselor and clinical research coordinator. Dr. Cannon has unique training both as a neuroscientist and genetic counselor; she will be seeing patients with me in clinic and also involved in many of our research studies and clinical trials. Second, we will be hosting our annual NF Symposium this summer on Saturday, August 29. As in the past, the focus will be on educating patients and families about NF and highlighting research progress. We have assembled a group of speakers both from UAB and from the Children’s Tumor Foundation who will participate. If interested in knowing more about the symposium please contact Dr. Cannon at acannon@uab.edu. We look forward to seeing as many families as possible at this event!
Some individuals develop plexiform neurofibromas – tumors that involve multiple branches of large nerves – in one isolated area of the body, such as the spine, with no other features of NF. The age of presentation varies, but it usually begins from the teenage years into adulthood, as the symptoms of a plexiform neurofibroma do not become apparent until adolescence. Isolated optic gliomas, tumors of the optic nerve, can also occur in children and adults who have no other features of NF. Unlike isolated plexiform neurofibromas, optic gliomas that occur in individuals who do not have NF are typically more aggressive tumors than those found in people who have neurofibromatosis. Some individuals also develop isolated dermal neurofibromas or bone dysplasia in the absence of other NF features and with no confirmed diagnosis of neurofibromatosis.
When we see someone in our clinic with an isolated feature of NF, we provide a comprehensive evaluation to make certain that subtle features of the condition are not present. In some cases, if possible, we obtain a tissue sample of the tumor, although this is often difficult due to the location of tumors, such as plexiform neurofibromas deep inside the body. Sometimes we obtain a blood sample for genetic testing; however, a negative result does not necessarily confirm that an individual does not have NF.
There are at least three possible explanations for the occurrence of isolated NF features in some individuals. The first is mosaicism, caused by a mutation in the NF1 gene that occurs early in embryonic development and that only affects certain cells in the body. As a result, individuals with mosaicism have features of NF1 that are limited to only one part of their body, such as neurofibromas or café-au-lait spots in a certain region. The only method of confirming mosaicism is to biopsy the lesion and do genetic testing on the tissue. A second possible explanation for the occurrence of isolated features of NF is that there could be other, still unknown mechanisms that cause tumors that occur in people with NF to also occur in individuals who do not have the condition.
A third possible explanation is related to the specific “two-hit” genetic mechanism that causes the development of tumors in people with NF1. All persons have two copies of the gene, one inherited from each parent. In individuals with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the mutated gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation. For a neurofibroma to develop in someone with NF1, a random genetic mutation must occur to the other copy of the NF1 gene in the tissue that will become the neurofibroma, café-au-lait spot, or other lesion; this is referred to as the “second-hit” mutation. Although an extremely rare occurrence, it is also possible for some individuals to acquire two random NF mutations, affecting each inherited copy of the NF1 gene, in a cell that could become a neurofibroma or other lesion. This two-hit mutation – similar to lightning striking twice in the same place – could result in the development of an isolated feature of NF in the absence of other signs of the condition.
On another topic, there are two things to report regarding the UAB NF Program. First, Dr. Ashley Cannon has joined the program as genetic counselor and clinical research coordinator. Dr. Cannon has unique training both as a neuroscientist and genetic counselor; she will be seeing patients with me in clinic and also involved in many of our research studies and clinical trials. Second, we will be hosting our annual NF Symposium this summer on Saturday, August 29. As in the past, the focus will be on educating patients and families about NF and highlighting research progress. We have assembled a group of speakers both from UAB and from the Children’s Tumor Foundation who will participate. If interested in knowing more about the symposium please contact Dr. Cannon at acannon@uab.edu. We look forward to seeing as many families as possible at this event!