Director's Blog
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!
Responding to E-mailed Questions from Patients and Reviewing Diagnostic Criteria for Café-Au-Lait Spots and Groin Freckling
By: Bruce Korf
Published Date: May 07
On an almost daily basis, I receive e-mails from people in all parts of the U.S. and other countries asking clinical questions about NF. Most of the time, individuals who e-mail me have run across my name on social networking sites, such as a discussion board or a chat room devoted to the topic of NF. There is a robust network of NF-related discussion forums on the Internet, and they can serve as a valuable resource for patients and families in locating specialists who can provide a definitive diagnosis and treatment plan. In this blog, I’d like to address the general principles I follow in replying to patients’ questions via e-mail.
Because most of the people who contact me have questions about clinical features that might indicate NF – or they have already received a diagnosis and need a plan of treatment – my primary goal is to connect them with a qualified specialist in their area whenever possible, and I always stress in my response the importance of identifying a trusted clinician in the region. Fortunately, specialists can be found relatively easily in most major U.S. cities. For patients and families seeking assistance in locating a specialist, the Children’s Tumor Foundation (www.ctf.org) web site features a patient information tab that provides a list of specialists within the U.S.
However, finding a qualified NF specialist often can be challenging, especially for people in other countries. In many regions of the U.S., and in many other countries, there is not ready access to NF specialists, and some physicians with the clinical knowledge to make an NF diagnosis may lack experience in managing complications and developing a treatment plan. For these reasons, NF-related discussion boards and chat rooms have proven to be a valuable resource for patients and families seeking information and guidance.
Because I understand the importance of helping people gain access to accurate information about NF, I’m always glad to respond to any e-mailed questions I receive and consider it a privilege to communicate with patients who have NF-related concerns. However, I can’t provide specific medical advice to people whom I have not personally examined and whose records I have not reviewed. Many people who e-mail me often attach photos, for example of café-au-lait spots, usually taken with a cell phone. Most of these photos are difficult to interpret, and it’s important not to give advice based on the limited information provided in an e-mail or photo. Instead, I focus on providing general information about NF that is not specific to their situation – perhaps about the value of genetic testing or a review of different treatment approaches.
Regarding the numerous e-mailed questions I receive asking if a child with café-au-lait spots has NF, the majority describe children in whom a diagnosis of NF is not obvious. Parents of these children are usually distraught about the possibility of NF based on the presence café-au-lait spots, which may have been noticed by a pediatrician or other clinician. Frequently, I have the impression that most are healthy children with a few spots that don’t fulfill the diagnostic criteria requiring six or more café-au-lait spots. It is important to note that the vast majority of people with NF1 have this number of café-au-lait spots or more. Sometimes, infants can develop café-au-lait spots, but café-au-lait spots usually begin to appear in the first few weeks of life. By two years of age, a child with NF will have at least six café-au-lait spots, if they ever will. It’s important to note that a young child with six or more café-au-lait spots that are clear usually will have NF1 that can be confirmed with genetic testing. In my clinical experience, many children with between one and three spots usually don’t have NF.
There are some people with variant forms of NF who have fewer than six café-au-lait spots. Some of these individuals develop internal neurofibromas, but have few visible on the skin. Legius Syndrome is another condition that causes café-au-lait spots, although these individuals do not develop tumors; this is a benign condition that is much more rare than NF1, and genetic testing is required to confirm it. Also, there are other conditions that can produce café-au-lait spots, though most are rare. It should also be noted that some healthy people can have up to six spots with no other symptoms.
Freckling in the groin and under the arms is another feature used to confirm an NF1 diagnosis. While some parents may worry based on the presence of a few small freckles in these regions, it’s important to note that NF-related freckling appears between three and five years of age. Instead of a few tiny freckles in these regions, there are usually many freckles in the region, as if paint were spattered from a paint brush. Also, a café-au-lait spot that happens to appear under the arm or in the groin does not count as a skin fold freckle.
Because NF-related features such as café-au-lait spots and groin and underarm freckling are sometimes over-interpreted and often a source of unnecessary anxiety, it’s important to identify an experienced clinician who can make a recommendation about diagnosis and the use of genetic testing for NF based on the presence of specific clinical criteria. My continued objective in responding to e-mailed questions is to provide patients with accurate information about NF and assist them in identifying an experienced, trusted clinician who can provide additional information and guidance.
Because most of the people who contact me have questions about clinical features that might indicate NF – or they have already received a diagnosis and need a plan of treatment – my primary goal is to connect them with a qualified specialist in their area whenever possible, and I always stress in my response the importance of identifying a trusted clinician in the region. Fortunately, specialists can be found relatively easily in most major U.S. cities. For patients and families seeking assistance in locating a specialist, the Children’s Tumor Foundation (www.ctf.org) web site features a patient information tab that provides a list of specialists within the U.S.
However, finding a qualified NF specialist often can be challenging, especially for people in other countries. In many regions of the U.S., and in many other countries, there is not ready access to NF specialists, and some physicians with the clinical knowledge to make an NF diagnosis may lack experience in managing complications and developing a treatment plan. For these reasons, NF-related discussion boards and chat rooms have proven to be a valuable resource for patients and families seeking information and guidance.
Because I understand the importance of helping people gain access to accurate information about NF, I’m always glad to respond to any e-mailed questions I receive and consider it a privilege to communicate with patients who have NF-related concerns. However, I can’t provide specific medical advice to people whom I have not personally examined and whose records I have not reviewed. Many people who e-mail me often attach photos, for example of café-au-lait spots, usually taken with a cell phone. Most of these photos are difficult to interpret, and it’s important not to give advice based on the limited information provided in an e-mail or photo. Instead, I focus on providing general information about NF that is not specific to their situation – perhaps about the value of genetic testing or a review of different treatment approaches.
Regarding the numerous e-mailed questions I receive asking if a child with café-au-lait spots has NF, the majority describe children in whom a diagnosis of NF is not obvious. Parents of these children are usually distraught about the possibility of NF based on the presence café-au-lait spots, which may have been noticed by a pediatrician or other clinician. Frequently, I have the impression that most are healthy children with a few spots that don’t fulfill the diagnostic criteria requiring six or more café-au-lait spots. It is important to note that the vast majority of people with NF1 have this number of café-au-lait spots or more. Sometimes, infants can develop café-au-lait spots, but café-au-lait spots usually begin to appear in the first few weeks of life. By two years of age, a child with NF will have at least six café-au-lait spots, if they ever will. It’s important to note that a young child with six or more café-au-lait spots that are clear usually will have NF1 that can be confirmed with genetic testing. In my clinical experience, many children with between one and three spots usually don’t have NF.
There are some people with variant forms of NF who have fewer than six café-au-lait spots. Some of these individuals develop internal neurofibromas, but have few visible on the skin. Legius Syndrome is another condition that causes café-au-lait spots, although these individuals do not develop tumors; this is a benign condition that is much more rare than NF1, and genetic testing is required to confirm it. Also, there are other conditions that can produce café-au-lait spots, though most are rare. It should also be noted that some healthy people can have up to six spots with no other symptoms.
Freckling in the groin and under the arms is another feature used to confirm an NF1 diagnosis. While some parents may worry based on the presence of a few small freckles in these regions, it’s important to note that NF-related freckling appears between three and five years of age. Instead of a few tiny freckles in these regions, there are usually many freckles in the region, as if paint were spattered from a paint brush. Also, a café-au-lait spot that happens to appear under the arm or in the groin does not count as a skin fold freckle.
Because NF-related features such as café-au-lait spots and groin and underarm freckling are sometimes over-interpreted and often a source of unnecessary anxiety, it’s important to identify an experienced clinician who can make a recommendation about diagnosis and the use of genetic testing for NF based on the presence of specific clinical criteria. My continued objective in responding to e-mailed questions is to provide patients with accurate information about NF and assist them in identifying an experienced, trusted clinician who can provide additional information and guidance.
Measurement Technique for Dermal Neurofibromas Validated at UAB Expands Possibilities for Clinical Trials
By: Bruce Korf
Published Date: Apr 03
In continuing our discussion from the previous blog regarding how the focus of a clinical trial is determined, I’d like to address the treatment and research of two distinctive features of NF that are of significant concern to patients – dermal neurofibromas and plexiform neurofibromas. A frequent question from patients related to neurofibromas is: Why do clinical trials focus on plexiform neurofibromas, while there are no clinical trials in progress for dermal neurofibromas? Many patients feel that dermal neurofibromas are an underappreciated feature of NF.
The basis for focusing on plexiform neurofibromas thus far in clinical trials centers on three issues: first, complications of plexiforms are often more serious than for dermal neurofibromas and can sometimes be life-threatening; second, the several mouse models for testing drug effectiveness in plexiform neurofibromas are better established than the model currently available for dermal neurofibromas; and the technology for measuring dermal neurofibromas is not as advanced as for plexiforms, making it more difficult to determine the effectiveness of a specific drug on tumor growth. The good news is that the UAB NF Program has worked with collaborators recently to establish the validity of a measurement technique for dermal neurofibromas, and this method will enable the development of future clinical trials focused on testing the effectiveness of drugs in slowing or reversing the growth of these types of tumors.
In providing a more thorough explanation about the future of clinical trials for dermal neurofibromas, it’s first helpful to understand the significant differences between dermal and plexiform neurofibromas. Dermal neurofibromas are soft, benign tumors that develop under the skin. These tumors typically appear after puberty and grow slowly over a period of time. While they are variable in size and number, dermal neurofibromas can be disfiguring in some patients, causing embarrassment and problems with self-esteem. In fact, the unpredictability of dermal neurofibromas can be the most daunting aspect of this NF feature; some individuals have few or none, while others’ bodies may be completely covered. Many women with NF1 experience increased growth of neurofibromas during pregnancy, suggesting that hormonal changes may be related to their development.
The treatment approach for dermal neurofibromas is dependent on the number and location of tumors, although the most common approach is to leave them alone due to their benign nature and the low risk of medical problems. The most common treatment is surgical removal of individual tumors using either conventional plastic surgery, laser treatment, or a procedure called electrodessication that uses an electrical current to remove a large number of tumors at one time. While these treatments can be effective, each can leave scarring and none of the options prevents additional tumor development.
Plexiform neurofibromas are congenital tumors that often first appear in infancy or early childhood as a soft swelling under the skin. Affecting about 50% of people with NF1, these tumors are frequently larger and usually involve multiple branches of large nerves. Depending on their location, plexiform neurofibromas can lead to abnormal bone growth or pressure on nerves, blood vessels, or organs. For example, plexiform neurofibromas along the spine can compress the spinal cord, leading to weakness, pain, and sometimes paralysis. Surgical removal can reduce the overall size of the tumor, although it will not stop the tumor from growing.
Because the symptoms of plexiforms can be urgent and potentially life-threatening, this feature has been given greater priority over dermal neurofibromas in clinical trials. Plexiform and dermal neurofibromas are similar at the cellular level, however, so the hope is that some treatments for plexiforms may also be effective for dermal neurofibromas.
Until recently, the challenge in testing the effectiveness of specific drugs for the treatment of dermal neurofibromas has centered on the difficulty of obtaining accurate measurements of these tumors. Unlike plexiforms that grow quickly and can be measured relatively easily with imaging studies, the slower growth rate and configuration of dermal neurofibromas make them difficult to measure accurately.
In collaboration with a research group in Brazil, scientists in the UAB NF Program have tested a measurement method over the past several years that recently has been validated as providing an accurate estimate of dermal neurofibromas (Publication). Using adhesive paper frames with a 10 cm x 10 cm window cut-out, a group of patients’ dermal tumors were documented and measured by attaching the paper frame to a specific region identified by a physical landmark that was photographed; this procedure allowed us to measure growth of dermal neurofibromas over a period of time.
This recently validated measurement technique for dermal neurofibromas has opened the door to conducting clinical trials focused on testing medications to treat this feature that is problematic for so many NF patients. We are now exploring the possibility of conducting a small, independent pilot trial to determine the effectiveness of a treatment for dermal neurofibromas. Also, we have plans to design a secondary arm of a clinical trial for plexiform neurofibromas that would test the effectiveness of the medication on dermal neurofibromas. As a secondary endpoint within this trial, individuals with plexiform neurofibromas would undergo measurements of dermal neurofibromas over a period of time to determine if the medication has had an effect on slowing the growth.
We still do not know when there will be effective treatments for the various aspects of neurofibromatosis. Those with dermal neurofibromas should know that this aspect of the condition is not being ignored, and I am hopeful that clinical trials for dermal tumors will become a reality soon.
The basis for focusing on plexiform neurofibromas thus far in clinical trials centers on three issues: first, complications of plexiforms are often more serious than for dermal neurofibromas and can sometimes be life-threatening; second, the several mouse models for testing drug effectiveness in plexiform neurofibromas are better established than the model currently available for dermal neurofibromas; and the technology for measuring dermal neurofibromas is not as advanced as for plexiforms, making it more difficult to determine the effectiveness of a specific drug on tumor growth. The good news is that the UAB NF Program has worked with collaborators recently to establish the validity of a measurement technique for dermal neurofibromas, and this method will enable the development of future clinical trials focused on testing the effectiveness of drugs in slowing or reversing the growth of these types of tumors.
In providing a more thorough explanation about the future of clinical trials for dermal neurofibromas, it’s first helpful to understand the significant differences between dermal and plexiform neurofibromas. Dermal neurofibromas are soft, benign tumors that develop under the skin. These tumors typically appear after puberty and grow slowly over a period of time. While they are variable in size and number, dermal neurofibromas can be disfiguring in some patients, causing embarrassment and problems with self-esteem. In fact, the unpredictability of dermal neurofibromas can be the most daunting aspect of this NF feature; some individuals have few or none, while others’ bodies may be completely covered. Many women with NF1 experience increased growth of neurofibromas during pregnancy, suggesting that hormonal changes may be related to their development.
The treatment approach for dermal neurofibromas is dependent on the number and location of tumors, although the most common approach is to leave them alone due to their benign nature and the low risk of medical problems. The most common treatment is surgical removal of individual tumors using either conventional plastic surgery, laser treatment, or a procedure called electrodessication that uses an electrical current to remove a large number of tumors at one time. While these treatments can be effective, each can leave scarring and none of the options prevents additional tumor development.
Plexiform neurofibromas are congenital tumors that often first appear in infancy or early childhood as a soft swelling under the skin. Affecting about 50% of people with NF1, these tumors are frequently larger and usually involve multiple branches of large nerves. Depending on their location, plexiform neurofibromas can lead to abnormal bone growth or pressure on nerves, blood vessels, or organs. For example, plexiform neurofibromas along the spine can compress the spinal cord, leading to weakness, pain, and sometimes paralysis. Surgical removal can reduce the overall size of the tumor, although it will not stop the tumor from growing.
Because the symptoms of plexiforms can be urgent and potentially life-threatening, this feature has been given greater priority over dermal neurofibromas in clinical trials. Plexiform and dermal neurofibromas are similar at the cellular level, however, so the hope is that some treatments for plexiforms may also be effective for dermal neurofibromas.
Until recently, the challenge in testing the effectiveness of specific drugs for the treatment of dermal neurofibromas has centered on the difficulty of obtaining accurate measurements of these tumors. Unlike plexiforms that grow quickly and can be measured relatively easily with imaging studies, the slower growth rate and configuration of dermal neurofibromas make them difficult to measure accurately.
In collaboration with a research group in Brazil, scientists in the UAB NF Program have tested a measurement method over the past several years that recently has been validated as providing an accurate estimate of dermal neurofibromas (Publication). Using adhesive paper frames with a 10 cm x 10 cm window cut-out, a group of patients’ dermal tumors were documented and measured by attaching the paper frame to a specific region identified by a physical landmark that was photographed; this procedure allowed us to measure growth of dermal neurofibromas over a period of time.
This recently validated measurement technique for dermal neurofibromas has opened the door to conducting clinical trials focused on testing medications to treat this feature that is problematic for so many NF patients. We are now exploring the possibility of conducting a small, independent pilot trial to determine the effectiveness of a treatment for dermal neurofibromas. Also, we have plans to design a secondary arm of a clinical trial for plexiform neurofibromas that would test the effectiveness of the medication on dermal neurofibromas. As a secondary endpoint within this trial, individuals with plexiform neurofibromas would undergo measurements of dermal neurofibromas over a period of time to determine if the medication has had an effect on slowing the growth.
We still do not know when there will be effective treatments for the various aspects of neurofibromatosis. Those with dermal neurofibromas should know that this aspect of the condition is not being ignored, and I am hopeful that clinical trials for dermal tumors will become a reality soon.
Birmingham Family Affected by NF Recognized at CTF BeNeFit II Gala in Detroit, and Frequently Asked Patient Questions Regarding NF Clinical Trials
By: Bruce Korf
Published Date: Jan 06
The previous year drew to a close with the recognition of an inspirational family affected by NF who has shown unique courage, determination, and leadership in facing the challenges so familiar to other NF families. On November 22, 2014, a well-known Birmingham family in the NF community – Renie and Philip Moss and their children, Philip and Helen – received the prestigious Strength and Honor Award at the Children’s Tumor Foundation (CTF) BeNeFit II in Detroit, Michigan. The well-deserved recognition of this special family is based on their leadership role in establishing the Alabama chapter of CTF and their ongoing, tireless dedication to NF-related education, fundraising, and outreach. With more than 1,100 people in attendance, the superhero-themed gala raised approximately $3 million for CTF, the major source of patient advocacy and research support for all forms of NF in both adults and children. A brief video of the Moss family’s story and Renie’s and Philip’s reflections of the gala and the Strength and Honor Award can be found on the CTF web site.
As a new year begins, we at UAB continue our commitment to advancing and facilitating research for all forms of neurofibromatosis. In support of this commitment, UAB serves as the national coordinating center for the NF Clinical Trials Consortium, a collaborative group of 17 medical centers across the country (and one in Australia) dedicated to conducting clinical trials of the most promising drug therapies for all forms of neurofibromatosis. During the NF Clinical Trials Consortium steering committee meeting held last month in Baltimore, discussions were held regarding selection criteria for topics of upcoming clinical trials. Frequently, two specific questions that arise from NF patients regarding clinical trials are: Why are the entry criteria for clinical trials so strict?; and Why aren’t more clinical trials conducted for more features of NF?
Regarding the first question, it is understandable that many NF patients are interested in participating in clinical trials to assist in advancing research and to receive drug therapies that might be beneficial in treating a specific feature of NF. The purpose of a clinical trial is to conduct a test of a specific medication to determine if it has a potential benefit. It’s important to understand that clinical trials must be conducted according to strict protocols, and in the case of new drugs, the trials are monitored by the FDA. Also, data have to be collected with strict adherence to the protocols to ensure that results are valid and usable. If a trial proves to be effective, a specific drug could be made available to a wide number of people, instead of just the few individuals who participated in a specific trial. Strict entry criteria must be maintained to ensure the validity and reliability of the clinical trial, which in the long run benefits the entire NF community. These criteria include: A confirmed diagnosis of NF; the confirmed presence of the NF characteristic(s) being investigated in the trial; and the absence of a prohibitive medical history, such as reduced kidney or liver function or other medical conditions that could compromise the study results or endanger the study participant. Because of these strict entry criteria, some NF patients are not eligible for a certain clinical trial. While this can be disappointing for these patients, it is important to remember that accepting only those patients into the trial who fit the specific criteria ensures the reliability of the trial and safeguards the potential of making a specific beneficial drug available to larger number of NF patients.
Some NF patients find it frustrating that the complications they are experiencing may not be the subject of a clinical trial and often ask how the focus of a clinical trial is determined. This is an important question, and it should be emphasized that we are interested in conducting clinical trials for all forms of NF. Because financial resources for conducting clinical trials are limited, with the minimum average cost of a trial in the hundreds of thousands of dollars, decisions regarding the focus of a clinical trial are made according to specific criteria. We are also mindful of the fact that the NF patient community is relatively small, and we want to make sure that clinical trials are done for the most promising treatments, so that we don’t overwhelm the community with trials that have little chance of working. Generally, features that are potentially life-threatening are given greater priority, such as plexiform neurofibromas and malignancies. The NF Clinical Trials Consortium Steering Committee determines the focus of a clinical trial based on the following criteria: The degree to which a specific feature of NF is problematic or life-threatening; the availability of a drug that might be effective (based on previous animal model studies); and the prevalence and availability of patients with the NF feature. The recommendations of the Steering Committee are then reviewed by an external scientific review panel and also by an external oversight committee appointed by the Department of Defense, which is the sponsor for the Consortium.
In using specific definable criteria for selecting the focus of clinical trials and the participants to whom drug therapies are administered, we’re ensuring that the results of these important studies are valid, reliable, and can ultimately be used to identify the most promising drug therapies for all forms of neurofibromatosis.
As a new year begins, we at UAB continue our commitment to advancing and facilitating research for all forms of neurofibromatosis. In support of this commitment, UAB serves as the national coordinating center for the NF Clinical Trials Consortium, a collaborative group of 17 medical centers across the country (and one in Australia) dedicated to conducting clinical trials of the most promising drug therapies for all forms of neurofibromatosis. During the NF Clinical Trials Consortium steering committee meeting held last month in Baltimore, discussions were held regarding selection criteria for topics of upcoming clinical trials. Frequently, two specific questions that arise from NF patients regarding clinical trials are: Why are the entry criteria for clinical trials so strict?; and Why aren’t more clinical trials conducted for more features of NF?
Regarding the first question, it is understandable that many NF patients are interested in participating in clinical trials to assist in advancing research and to receive drug therapies that might be beneficial in treating a specific feature of NF. The purpose of a clinical trial is to conduct a test of a specific medication to determine if it has a potential benefit. It’s important to understand that clinical trials must be conducted according to strict protocols, and in the case of new drugs, the trials are monitored by the FDA. Also, data have to be collected with strict adherence to the protocols to ensure that results are valid and usable. If a trial proves to be effective, a specific drug could be made available to a wide number of people, instead of just the few individuals who participated in a specific trial. Strict entry criteria must be maintained to ensure the validity and reliability of the clinical trial, which in the long run benefits the entire NF community. These criteria include: A confirmed diagnosis of NF; the confirmed presence of the NF characteristic(s) being investigated in the trial; and the absence of a prohibitive medical history, such as reduced kidney or liver function or other medical conditions that could compromise the study results or endanger the study participant. Because of these strict entry criteria, some NF patients are not eligible for a certain clinical trial. While this can be disappointing for these patients, it is important to remember that accepting only those patients into the trial who fit the specific criteria ensures the reliability of the trial and safeguards the potential of making a specific beneficial drug available to larger number of NF patients.
Some NF patients find it frustrating that the complications they are experiencing may not be the subject of a clinical trial and often ask how the focus of a clinical trial is determined. This is an important question, and it should be emphasized that we are interested in conducting clinical trials for all forms of NF. Because financial resources for conducting clinical trials are limited, with the minimum average cost of a trial in the hundreds of thousands of dollars, decisions regarding the focus of a clinical trial are made according to specific criteria. We are also mindful of the fact that the NF patient community is relatively small, and we want to make sure that clinical trials are done for the most promising treatments, so that we don’t overwhelm the community with trials that have little chance of working. Generally, features that are potentially life-threatening are given greater priority, such as plexiform neurofibromas and malignancies. The NF Clinical Trials Consortium Steering Committee determines the focus of a clinical trial based on the following criteria: The degree to which a specific feature of NF is problematic or life-threatening; the availability of a drug that might be effective (based on previous animal model studies); and the prevalence and availability of patients with the NF feature. The recommendations of the Steering Committee are then reviewed by an external scientific review panel and also by an external oversight committee appointed by the Department of Defense, which is the sponsor for the Consortium.
In using specific definable criteria for selecting the focus of clinical trials and the participants to whom drug therapies are administered, we’re ensuring that the results of these important studies are valid, reliable, and can ultimately be used to identify the most promising drug therapies for all forms of neurofibromatosis.