Director's Blog
Upcoming NF Symposium at Children’s Harbor, Applications of New Gene Editing Technology, and a Review of the NF Extremities Exam
By: Bruce Korf
Published Date: Aug 22
Neurofibromatosis Symposium: Family Day 2016
Plans are finalized for the upcoming Neurofibromatosis Symposium to be held in the Bradley Lecture Center of the Children’s Harbor Building at Children’s of Alabama on Saturday, August 27th. This will be the first time the Symposium will be held in Children’s Harbor, a non-profit organization that supports seriously ill children and their families through educational and counseling services; we’re pleased that our NF Clinic has formed a collaboration with Children’s Harbor to enable our families to take advantage of the services they provide. Also known as NF Family Day, the NF Symposium is a half-day, free event, co-sponsored by UAB and the Children’s Tumor Foundation, that supports a key mission of our program in providing NF patients and their families with valuable information on a range of NF-related topics presented by clinical experts.
Janice Crow with Children’s Harbor will discuss the services offered by the organization and will be available to meet with parents one-on-one during the Symposium to discuss educational needs. Also, a tour of the facility will be available later in the day for those interested. Additional presentations during the Symposium will include an overview of NF1, NF2, and schwannomatosis as well as activities in the UAB NF Clinic; an update on clinical trials; developmental difficulties for children with NF; the natural history of dermal neurofibromas and upcoming clinical trials; and a review of advocacy, fundraising, and upcoming events. For the convenience of our families, breakfast, lunch, and childcare will be provided. Children participating in childcare in the Children’s Harbor facility will have access to a variety of activities including art projects, video games, and board games. While there is no cost to attend, reservations should be made by August 24th by emailing ashleycannon@uabmc.edu or calling 205-996-2916. The NF Symposium is an invaluable opportunity for NF patients and families, especially those facing a new diagnosis, to learn key information and answers to questions about neurofibromatosis. It also provides a unique forum for patients and families to connect with one another and gain understanding and strength through their shared experiences, challenges, and concerns. We look forward to serving our NF patients and families again this year through hosting this meaningful and informative event.
Neurofibromatosis Symposium: Family Day 2016
Saturday, August 27th, 2016
Schedule:
08:00-08:30 a.m. Register/Breakfast
08:30-8:45 a.m. Welcome – Dr. Bruce Korf
8:45-9:00 a.m. Children’s Harbor/Educational Assistance – Janice Crow
9:00-10:00 a.m. NF 101/Updates – Dr. Bruce Korf
10:00-10:30 a.m. Clinical Trials Update – Dr. Alyssa Reddy
10:30-10:45 a.m. Break
10:45-11:15 a.m. Developmental Difficulties – Dr. Michelle Kong
11:15 -11:45 a.m. Dermal Neurofibromas – Dr. Ashley Cannon
11:45-12:00 p.m. Advocacy, Fundraising, Upcoming Events – Renie Moss
12:00-12:30 p.m. Children’s Harbor Tour
12:30-1:30 p.m. Lunch
1:30 p.m. Closing Remarks
Applications of the CRISPR/Cas9 Gene Editing Technology
A question that frequently arises related to NF research is regarding the application of the gene editing technology CRISPR/Cas9 system. This technology allows investigators to “edit” the genome by targeting a particular gene sequence and changing it to something different. The technology has received a good deal of publicity lately, including a recent feature on the cover of TIME magazine.
The system has immediate application for creating models of disease. For example, if an investigator wants to create a mutation in mice or stem cell lines, the CRISPR/Cas9 enables targeting of the NF gene and introduction of a mutation. Our NF research program is currently using the technology for this purpose. The question is whether the technology could be used to restore the mutated gene back to normalcy. The challenge here is in targeting all the cells in the body. With a condition such as NF, in which the mutation causes the lack of production of a substance (neurofibromin) that affects growth of specific cells throughout the body, you would have to be sure to target every cell that could possibly form a neurofibroma. If you miss a cell that has the potential to form a neurofibroma, that particular cell could still grow into a tumor. For now, the technology does not enable correction of a mutation in every cell. There is much left to be learned about how the CRISPR/Cas9 system might be applied in the treatment of neurofibromatosis, however, so the possibility of it therapeutic use is in consideration.
NF Extremities Examination
Turning back to our previous discussion about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during an examination of the extremities. First, plexiform neurofibromas can affect the brachial plexus, a network of nerves that originate near the neck and shoulder and send signals from the spine to the arm and hand. Plexiforms can also affect the lumbar plexus, a network of nerves in the lower spine that send signals to the pelvis and legs. Some plexiform neurofibromas can cause infiltration of nerves in these areas that can compress the nerves and cause pain. In some cases, the presence of plexiform neurofibromas in these areas can cause a visible overgrowth of the extremity. In other cases, the problem presents with lower back pain. An MRI will confirm lumbar involvement. Due to the location in the body, these tumors are not surgically accessible; however, it is sometimes possible to perform surgery to help relieve pain. The other primary treatment option is pain management.
Another extremity-related problem that can occur is bone dysplasia, which is an abnormality of a long bone, usually involving the tibia in the leg but sometimes also affecting the fibula or even bones in the arm. This problem sometimes presents as a bowing of the leg in infancy, although it can be hard to diagnose that early because most infants have some normal leg bowing. By the time a child can stand, one can usually determine if this problem exists. An X-ray is performed to confirm dysplasia, and the child is referred to an orthopedist for treatment with a leg brace to prevent fracture. If the bone does fracture, it can be hard to treat. Also, surgery is difficult because the bone is not well formed. For this reason, prevention of fracture is important when this problem exists.
Plexiform neurofibromas can also affect any part of the foot or hand. While it’s not possible to surgically remove all of the tumor, surgery can be performed to remove a portion of the tumor (debulking surgery). Lastly, certain types of tumors discovered fairly recently, called glomus tumors, can occur under the nail beds of the fingers and toes in adults with NF. Although they are not easily visible, they are usually exquisitely painful with pressure applied at the tips of fingers and toes. Fortunately, they can be removed surgically to eliminate the associated pain. It’s important for NF clinicians and patients to be alert to this potential problem.
Plans are finalized for the upcoming Neurofibromatosis Symposium to be held in the Bradley Lecture Center of the Children’s Harbor Building at Children’s of Alabama on Saturday, August 27th. This will be the first time the Symposium will be held in Children’s Harbor, a non-profit organization that supports seriously ill children and their families through educational and counseling services; we’re pleased that our NF Clinic has formed a collaboration with Children’s Harbor to enable our families to take advantage of the services they provide. Also known as NF Family Day, the NF Symposium is a half-day, free event, co-sponsored by UAB and the Children’s Tumor Foundation, that supports a key mission of our program in providing NF patients and their families with valuable information on a range of NF-related topics presented by clinical experts.
Janice Crow with Children’s Harbor will discuss the services offered by the organization and will be available to meet with parents one-on-one during the Symposium to discuss educational needs. Also, a tour of the facility will be available later in the day for those interested. Additional presentations during the Symposium will include an overview of NF1, NF2, and schwannomatosis as well as activities in the UAB NF Clinic; an update on clinical trials; developmental difficulties for children with NF; the natural history of dermal neurofibromas and upcoming clinical trials; and a review of advocacy, fundraising, and upcoming events. For the convenience of our families, breakfast, lunch, and childcare will be provided. Children participating in childcare in the Children’s Harbor facility will have access to a variety of activities including art projects, video games, and board games. While there is no cost to attend, reservations should be made by August 24th by emailing ashleycannon@uabmc.edu or calling 205-996-2916. The NF Symposium is an invaluable opportunity for NF patients and families, especially those facing a new diagnosis, to learn key information and answers to questions about neurofibromatosis. It also provides a unique forum for patients and families to connect with one another and gain understanding and strength through their shared experiences, challenges, and concerns. We look forward to serving our NF patients and families again this year through hosting this meaningful and informative event.
Neurofibromatosis Symposium: Family Day 2016
Saturday, August 27th, 2016
Schedule:
08:00-08:30 a.m. Register/Breakfast
08:30-8:45 a.m. Welcome – Dr. Bruce Korf
8:45-9:00 a.m. Children’s Harbor/Educational Assistance – Janice Crow
9:00-10:00 a.m. NF 101/Updates – Dr. Bruce Korf
10:00-10:30 a.m. Clinical Trials Update – Dr. Alyssa Reddy
10:30-10:45 a.m. Break
10:45-11:15 a.m. Developmental Difficulties – Dr. Michelle Kong
11:15 -11:45 a.m. Dermal Neurofibromas – Dr. Ashley Cannon
11:45-12:00 p.m. Advocacy, Fundraising, Upcoming Events – Renie Moss
12:00-12:30 p.m. Children’s Harbor Tour
12:30-1:30 p.m. Lunch
1:30 p.m. Closing Remarks
Applications of the CRISPR/Cas9 Gene Editing Technology
A question that frequently arises related to NF research is regarding the application of the gene editing technology CRISPR/Cas9 system. This technology allows investigators to “edit” the genome by targeting a particular gene sequence and changing it to something different. The technology has received a good deal of publicity lately, including a recent feature on the cover of TIME magazine.
The system has immediate application for creating models of disease. For example, if an investigator wants to create a mutation in mice or stem cell lines, the CRISPR/Cas9 enables targeting of the NF gene and introduction of a mutation. Our NF research program is currently using the technology for this purpose. The question is whether the technology could be used to restore the mutated gene back to normalcy. The challenge here is in targeting all the cells in the body. With a condition such as NF, in which the mutation causes the lack of production of a substance (neurofibromin) that affects growth of specific cells throughout the body, you would have to be sure to target every cell that could possibly form a neurofibroma. If you miss a cell that has the potential to form a neurofibroma, that particular cell could still grow into a tumor. For now, the technology does not enable correction of a mutation in every cell. There is much left to be learned about how the CRISPR/Cas9 system might be applied in the treatment of neurofibromatosis, however, so the possibility of it therapeutic use is in consideration.
NF Extremities Examination
Turning back to our previous discussion about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during an examination of the extremities. First, plexiform neurofibromas can affect the brachial plexus, a network of nerves that originate near the neck and shoulder and send signals from the spine to the arm and hand. Plexiforms can also affect the lumbar plexus, a network of nerves in the lower spine that send signals to the pelvis and legs. Some plexiform neurofibromas can cause infiltration of nerves in these areas that can compress the nerves and cause pain. In some cases, the presence of plexiform neurofibromas in these areas can cause a visible overgrowth of the extremity. In other cases, the problem presents with lower back pain. An MRI will confirm lumbar involvement. Due to the location in the body, these tumors are not surgically accessible; however, it is sometimes possible to perform surgery to help relieve pain. The other primary treatment option is pain management.
Another extremity-related problem that can occur is bone dysplasia, which is an abnormality of a long bone, usually involving the tibia in the leg but sometimes also affecting the fibula or even bones in the arm. This problem sometimes presents as a bowing of the leg in infancy, although it can be hard to diagnose that early because most infants have some normal leg bowing. By the time a child can stand, one can usually determine if this problem exists. An X-ray is performed to confirm dysplasia, and the child is referred to an orthopedist for treatment with a leg brace to prevent fracture. If the bone does fracture, it can be hard to treat. Also, surgery is difficult because the bone is not well formed. For this reason, prevention of fracture is important when this problem exists.
Plexiform neurofibromas can also affect any part of the foot or hand. While it’s not possible to surgically remove all of the tumor, surgery can be performed to remove a portion of the tumor (debulking surgery). Lastly, certain types of tumors discovered fairly recently, called glomus tumors, can occur under the nail beds of the fingers and toes in adults with NF. Although they are not easily visible, they are usually exquisitely painful with pressure applied at the tips of fingers and toes. Fortunately, they can be removed surgically to eliminate the associated pain. It’s important for NF clinicians and patients to be alert to this potential problem.
NF Clinic Genetics Counselor Receives Esteemed Scholars Award, Re-Cap of NF Forum, and What to Expect During an NF Genital Exam
By: Bruce Korf
Published Date: Jul 18
I’d like to begin with month’s blog with a special word of recognition for our NF Program Genetics Counselor, Ashley Cannon, MS, PhD, CGC, who has been named a 2016 recipient of the prestigious Francis S. Collins Scholars Program Award. Ashley is the first individual in our program to have received this significant honor, which is designed to attract the highest level of talent to the field of NF1 by providing salary and research support to advance rigorous clinical translational research that will lead to improved treatment options for NF1. The award is named in honor of Dr. Francis S. Collins, who led one of the teams that discovered the NF1 gene in 1990 and currently serves as the Director of the National Institutes of Health (NIH). It is Dr. Collins’ hope that the Scholars Award will encourage others to combine a career in patient care and research, as he did. Because Ashely is trained in and serves both as a genetic counselor and a neuroscientist, her work embodies the clinician-scientist role that Dr. Collins envisioned for the program. As a Collins Scholar, Ashley’s work will focus on two primary areas. In the patient care arena, she will utilize her training as a genetic counselor and a neuroscientist in working closely with patients to better understand the specific problems and challenges they face related to NF and develop methods to address these problems. In the area of research, she will be working on a clinical trial for dermal neurofibromas with the goal of developing new treatments. Our entire NF clinic team joins me in congratulating Ashley for this outstanding achievement, which is very exciting for our program.
In another special recognition of a dedicated individual in our local NF community, Renie Moss, tireless patient advocate, was recently presented with the Volunteer of the Year Award by the Children’s Tumor Foundation (CTF) during the CTF Volunteer Leadership Council Meeting in Austin, TX. Renie was recognized for her inspirational leadership and dedication to patient advocacy and increasing NF awareness nationwide as well as her unique spirit of caring and compassion for NF families. The NF community is very fortunate to have someone with Renie’s many talents dedicated to the cause of patient advocacy and education.
Re-Cap of NF Forum
Last month, 10 people from our NF program attended the annual NF Forum held in Austin, TX, which marks the largest group from our team to attend this meeting. The NF Forum is the largest worldwide meeting dedicated to NF, bringing together patients and families as well as more than 300 NF clinicians and scientists from around the world to discuss advances in patient care, treatment, and research. The meeting provides an invaluable collaborative environment in which to exchange ideas and research findings with international clinicians and scientists working in the field of NF. Several members of our team gave poster presentations summarizing research conducted as part of our NF research program. The meeting left all of us energized with new ideas and goals for our program. One of the most interesting aspects of this year’s meeting was learning about new animal models that have been developed using pigs instead of mice. The pig model replicates the features of NF1 more closely than the mouse model, providing significant research advantages. We’re currently establishing a collaboration with one of the groups that developed the pig model and are hoping to incorporate these models into our research in the near future.
NF Genital Exam
In continuing our discussion of what to expect during an NF exam, I’d like to briefly review issues that could be detected during a genital exam. The most relevant potential problem we’re looking for is evidence of early or delayed puberty. As clinicians, we’re looking for changes such as the appearance of pubic hair and an early growth spurt as indicators of precocious (early) puberty. Sometimes, precocious puberty occurs for no known reason, but usually it is associated with optic nerve tumors (optic glioma) that involve the nearby hypothalamus that controls hormonal production in the brain. If signs of precocious puberty are found, we use MRI to check for the presence of an optic glioma and obtain hormonal studies. We also arrange for referral to a pediatric endocrinologist. Early puberty is difficult for children both emotionally and psychologically, and it causes them to be significantly taller than their peers at a very young age, but, because of premature closure of the growth plate, ultimate height attainment is shorter than normal. Precocious puberty can be successfully treated hormonally; if there is an optic glioma, sometimes that, too, requires treatment, though if there is no impairment of vision or evidence of progression, the optic pathway tumor may not require treatment. Aside from precocious puberty, signs of puberty can also occur later than normal. If delayed puberty is suspected based on a lack of physical indicators such as pubic hair and an adolescent growth spurt, we would also perform hormonal testing and refer to an endocrinologist.
In some people with NF, plexiform neurofibromas can affect the genital region, sometimes causing an overgrowth of the genitalia in males and females. Surgical treatment can be performed in these cases to help manage the problem. In women, plexiform neurofibromas can also sometimes impinge on the uterus and cause issues during pregnancy that might require surgical treatment, though sometimes these are too large to be amenable to surgical resection.
In another special recognition of a dedicated individual in our local NF community, Renie Moss, tireless patient advocate, was recently presented with the Volunteer of the Year Award by the Children’s Tumor Foundation (CTF) during the CTF Volunteer Leadership Council Meeting in Austin, TX. Renie was recognized for her inspirational leadership and dedication to patient advocacy and increasing NF awareness nationwide as well as her unique spirit of caring and compassion for NF families. The NF community is very fortunate to have someone with Renie’s many talents dedicated to the cause of patient advocacy and education.
Re-Cap of NF Forum
Last month, 10 people from our NF program attended the annual NF Forum held in Austin, TX, which marks the largest group from our team to attend this meeting. The NF Forum is the largest worldwide meeting dedicated to NF, bringing together patients and families as well as more than 300 NF clinicians and scientists from around the world to discuss advances in patient care, treatment, and research. The meeting provides an invaluable collaborative environment in which to exchange ideas and research findings with international clinicians and scientists working in the field of NF. Several members of our team gave poster presentations summarizing research conducted as part of our NF research program. The meeting left all of us energized with new ideas and goals for our program. One of the most interesting aspects of this year’s meeting was learning about new animal models that have been developed using pigs instead of mice. The pig model replicates the features of NF1 more closely than the mouse model, providing significant research advantages. We’re currently establishing a collaboration with one of the groups that developed the pig model and are hoping to incorporate these models into our research in the near future.
NF Genital Exam
In continuing our discussion of what to expect during an NF exam, I’d like to briefly review issues that could be detected during a genital exam. The most relevant potential problem we’re looking for is evidence of early or delayed puberty. As clinicians, we’re looking for changes such as the appearance of pubic hair and an early growth spurt as indicators of precocious (early) puberty. Sometimes, precocious puberty occurs for no known reason, but usually it is associated with optic nerve tumors (optic glioma) that involve the nearby hypothalamus that controls hormonal production in the brain. If signs of precocious puberty are found, we use MRI to check for the presence of an optic glioma and obtain hormonal studies. We also arrange for referral to a pediatric endocrinologist. Early puberty is difficult for children both emotionally and psychologically, and it causes them to be significantly taller than their peers at a very young age, but, because of premature closure of the growth plate, ultimate height attainment is shorter than normal. Precocious puberty can be successfully treated hormonally; if there is an optic glioma, sometimes that, too, requires treatment, though if there is no impairment of vision or evidence of progression, the optic pathway tumor may not require treatment. Aside from precocious puberty, signs of puberty can also occur later than normal. If delayed puberty is suspected based on a lack of physical indicators such as pubic hair and an adolescent growth spurt, we would also perform hormonal testing and refer to an endocrinologist.
In some people with NF, plexiform neurofibromas can affect the genital region, sometimes causing an overgrowth of the genitalia in males and females. Surgical treatment can be performed in these cases to help manage the problem. In women, plexiform neurofibromas can also sometimes impinge on the uterus and cause issues during pregnancy that might require surgical treatment, though sometimes these are too large to be amenable to surgical resection.
Upcoming NF Symposium, Enhanced Patient Exam Procedure, and a Review of the NF Abdominal Exam
By: Bruce Korf
Published Date: Jun 09
Planning the Upcoming NF Symposium
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the NF Community Advisory Board was developed last year with the objective of providing input and direction regarding patient information, education, support, and coordination of care. Comprised of NF patients and family members, the Board meets four times a year. During the Board’s second meeting of the year held last month, plans were discussed for the upcoming NF Symposium scheduled for August 27th. Also known as NF Family Day, this half-day, free event co-sponsored by UAB and the Children’s Tumor Foundation (CTF), provides valuable information to NF patients and families through a series of presentations given by clinical experts on a range of NF-related topics. The Board was very helpful in offering suggestions for this year’s Symposium, which will be held for the first time in the Children’s Harbor Family Center at Children’s of Alabama. Children’s Harbor is a non-profit organization that supports seriously ill children and their families through educational and counseling services. Although the previous NF Symposia have been held at the Kaul Building in the UAB Medical District, the Children’s Harbor Building offers better facilities and parking for this type of event. Also, our NF Clinic has formed a collaboration with Children’s Harbor so that our NF patients and families can take advantage of the educational and counseling services they provide.
Enhanced Patient Exam Procedure in the NF Clinic
We’re pleased to announce the addition of Tammy Skelton, MSN, CRNP, NP-C, a certified nurse practitioner, to our team of specialists in the UAB NF Clinic. Tammy is enhancing patient care by performing preliminary patient examinations after our certified genetic counselor, Ashley Cannon, MS, PhD, CGC, collects or reviews a patient’s history. After I review the history and notes from Tammy’s preliminary examination, I perform a more focused exam and talk to the patient/family. We then confer as a team regarding next steps. The feedback from our Community Advisory Board on this new procedure has been very positive. Our goal is to reduce the backlog of patients waiting to be seen in the clinic by streamlining the examination process. By having Tammy perform preliminary exams, we’re able to see more patients in clinic and spend more focused time with them. We’re hoping our NF patients and families will be pleased and that the new procedure will make us more accessible.
On another note, a team from our NF Program will be attending the Neurofibromatosis Conference in mid-June in Austin, Texas. We’re presenting several abstracts and participating in a series of workshops and presentations. Stay tuned for a re-cap of this important meeting in next month’s blog.
Review of the NF Abdominal Exam
To continue our discussion of what occurs during the typical NF examination, this month we will consider the abdominal portion of the exam. Because the abdomen is covered by a large expanse of skin, neurofibromas are usually very visible in this area; sometimes they are obvious, and other times they can be seen using a pen light to illuminate the skin from the side. We’re also looking for masses, although it’s not very common to feel a mass through the skin. While the liver and spleen can be palpated, these organs aren’t usually involved in NF.
The two main abdominal-related concerns in people with NF are episodes of nausea and sometimes vomiting, which tend to occur mostly in children, as well as the lower GI problem of constipation. Children with NF have a tendency to develop migraine headaches, and I find that stomachaches, nausea, and occasional vomiting are common presentations of migraines in children. Sometimes treating children for migraines can be effective in resolving gastrointestinal symptoms. Constipation also seems to be more common in people with NF, probably because the condition affects the nerves in the intestine.
It’s rare that a tumor is the cause of a GI problem. Although plexiform neurofibromas can occur in the abdomen, they are usually too deep to palpate and are mostly asymptomatic. Tumors can also occur in the wall of the intestine, but these are usually also asymptomatic, though sometimes they can cause obstruction or bleeding. Gastrointestinal stromal cell tumors are more common in people with NF1 than in the general population. They present with abdominal pain and bleeding in the GI tract. It’s important that an individual with abdominal pain and blood in the stool be evaluated for this potential problem. Lastly, some people with NF may develop a specific type of tumor on the adrenal gland called pheochromocytoma. The most common presentation is high blood pressure, which is caused by increased secretion of the hormones epinephrine and norepinephrine. Some people may also experience episodes of skin flushing and a racing heart. If symptoms are present, a blood test is performed to determine the presence of elevated hormone levels. If this is confirmed, a 24-hour urine collection is performed to further detect the presence of increased hormones followed by a scan to identify the tumors. If they are found during a scan, careful surgical removal is required as the treatment.
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the NF Community Advisory Board was developed last year with the objective of providing input and direction regarding patient information, education, support, and coordination of care. Comprised of NF patients and family members, the Board meets four times a year. During the Board’s second meeting of the year held last month, plans were discussed for the upcoming NF Symposium scheduled for August 27th. Also known as NF Family Day, this half-day, free event co-sponsored by UAB and the Children’s Tumor Foundation (CTF), provides valuable information to NF patients and families through a series of presentations given by clinical experts on a range of NF-related topics. The Board was very helpful in offering suggestions for this year’s Symposium, which will be held for the first time in the Children’s Harbor Family Center at Children’s of Alabama. Children’s Harbor is a non-profit organization that supports seriously ill children and their families through educational and counseling services. Although the previous NF Symposia have been held at the Kaul Building in the UAB Medical District, the Children’s Harbor Building offers better facilities and parking for this type of event. Also, our NF Clinic has formed a collaboration with Children’s Harbor so that our NF patients and families can take advantage of the educational and counseling services they provide.
Enhanced Patient Exam Procedure in the NF Clinic
We’re pleased to announce the addition of Tammy Skelton, MSN, CRNP, NP-C, a certified nurse practitioner, to our team of specialists in the UAB NF Clinic. Tammy is enhancing patient care by performing preliminary patient examinations after our certified genetic counselor, Ashley Cannon, MS, PhD, CGC, collects or reviews a patient’s history. After I review the history and notes from Tammy’s preliminary examination, I perform a more focused exam and talk to the patient/family. We then confer as a team regarding next steps. The feedback from our Community Advisory Board on this new procedure has been very positive. Our goal is to reduce the backlog of patients waiting to be seen in the clinic by streamlining the examination process. By having Tammy perform preliminary exams, we’re able to see more patients in clinic and spend more focused time with them. We’re hoping our NF patients and families will be pleased and that the new procedure will make us more accessible.
On another note, a team from our NF Program will be attending the Neurofibromatosis Conference in mid-June in Austin, Texas. We’re presenting several abstracts and participating in a series of workshops and presentations. Stay tuned for a re-cap of this important meeting in next month’s blog.
Review of the NF Abdominal Exam
To continue our discussion of what occurs during the typical NF examination, this month we will consider the abdominal portion of the exam. Because the abdomen is covered by a large expanse of skin, neurofibromas are usually very visible in this area; sometimes they are obvious, and other times they can be seen using a pen light to illuminate the skin from the side. We’re also looking for masses, although it’s not very common to feel a mass through the skin. While the liver and spleen can be palpated, these organs aren’t usually involved in NF.
The two main abdominal-related concerns in people with NF are episodes of nausea and sometimes vomiting, which tend to occur mostly in children, as well as the lower GI problem of constipation. Children with NF have a tendency to develop migraine headaches, and I find that stomachaches, nausea, and occasional vomiting are common presentations of migraines in children. Sometimes treating children for migraines can be effective in resolving gastrointestinal symptoms. Constipation also seems to be more common in people with NF, probably because the condition affects the nerves in the intestine.
It’s rare that a tumor is the cause of a GI problem. Although plexiform neurofibromas can occur in the abdomen, they are usually too deep to palpate and are mostly asymptomatic. Tumors can also occur in the wall of the intestine, but these are usually also asymptomatic, though sometimes they can cause obstruction or bleeding. Gastrointestinal stromal cell tumors are more common in people with NF1 than in the general population. They present with abdominal pain and bleeding in the GI tract. It’s important that an individual with abdominal pain and blood in the stool be evaluated for this potential problem. Lastly, some people with NF may develop a specific type of tumor on the adrenal gland called pheochromocytoma. The most common presentation is high blood pressure, which is caused by increased secretion of the hormones epinephrine and norepinephrine. Some people may also experience episodes of skin flushing and a racing heart. If symptoms are present, a blood test is performed to determine the presence of elevated hormone levels. If this is confirmed, a 24-hour urine collection is performed to further detect the presence of increased hormones followed by a scan to identify the tumors. If they are found during a scan, careful surgical removal is required as the treatment.
Sources of Variability in NF and What to Expect During an NF Chest Examination
By: Bruce Korf
Published Date: May 03
In previous blogs, I’ve discussed to the fact that NF is a highly variable condition that can manifest differently among affected individuals. For example, two people within the same family can have very different symptoms of the condition. It’s an enigma as to why such a high degree of variability exists within NF. However, we do have a general understanding of three probable sources of variability that could provide a framework for determining, through further research, the extent to which complications of NF are predictable.
Sources of Variability Among People with NF
The first possible source of variability is the specific genetic mutation associated with NF in an individual. More than 3,000 mutations have been identified in the NF1 gene, and there a few examples in which a specific mutation can be correlated to certain NF symptoms. The UAB Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene. While it is probable that certain mutations do predict specific NF symptoms, it’s also very likely that most mutations don’t predict the specific NF features or the course of the condition.
Another factor that likely plays a role in the variability of NF is an individual’s genetic background. Because individuals express genetic variants across the genome, it’s likely that there are other genes that can influence the manifestations of NF. Evidence for this phenomenon can be seen in mouse models. When the NF1 gene is introduced into genetically distinct strains of mice, the manifestations of NF can be very different. It seems likely that an individual’s distinct genetic background can help to determine the symptoms of NF that he or she experiences. It is difficult to design human studies to look for this phenomenon, however, due to the need to determine phenotypes (symptoms) and perform genetic sequencing on hundreds of patients, though efforts are underway to try to address this issue.
We are reasonably certain there is also a random nature to some of the physical manifestations of NF. Each individual is born with two copies of the NF1 gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or in most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. This “second-hit” mutation seems to be a random event that leads to a specific complication, such as a neurofibroma. It is possible that there may be factors in a person’s genetic background that increase the likelihood of a “second-hit”mutation.
NF Chest Examination
Turning back to our discussion in the previous blog about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during a chest examination. Because people with NF have an increased risk of congenital heart defects, the chest exam includes listening for a specific type of heart murmur associated with pulmonic stenosis. This condition causes a narrowing of the pulmonary valve, interfering with blood flow from the heart to the lungs. However, the condition is not as common in NF as in other RAS pathway disorders.
While the lungs are not commonly affected in NF, some adults may experience emphysema-like changes thought to be related to NF. It is also possible for neurofibromas to develop in the chest, which can interfere with inflation of the lungs and with breathing. Occasionally, we can feel a nodular neurofibroma at the base of the neck or near the collarbone. Some people develop plexiform neurofibromas deep inside the chest, although we usually don’t see plexiform neurofibromas in the lungs or heart muscle. The only treatment for plexiform neurofibromas is surgical removal, which is reserved for cases in which important structures are affected.
Sometimes a bony deformation of the chest wall, called pectus excavatum, can occur in people with NF. The condition causes a depression in the breast bone and usually doesn’t result in problems or require treatment unless it interferes with lung inflation and breathing. In these cases, surgical treatment can be offered. Another condition, called pectus carinatum, causes the chest wall to bulge out, probably due to disproportionate rib cage growth. In most cases, the condition doesn’t require treatment.
In some people with NF, spinal tumors can become large enough that they can push on the lungs, which may require surgical removal of the tumors if breathing is affected. Also, people with NF are at increased for developing abnormal tissue growth inside of blood vessels, including major arteries in the heart and lungs. This condition weakens the vessel wall and leads to narrowing and possible rupture, which is a serious emergency. Sudden onset of severe chest or abdominal pain is a symptom that this condition may be present, indicating the need for diagnostic testing, though many other things can lead to pain other than vascular rupture.
NF Awareness Month
Finally, I’d like to remind everyone that May is NF Awareness Month. The Children’s Tumor Foundation has developed a number of activities to inform the public about NF [http://www.ctf.org/NFawareness], and there will be events here in Birmingham as well. Keep an eye on our Facebook page [https://www.facebook.com/uabnfprogram/], as well as the Neurofibromatosis Alabama page [https://www.facebook.com/Neurofibromatosis-Alabama-Childrens-Tumor-Foundation-203255213153983/] for further details.
Sources of Variability Among People with NF
The first possible source of variability is the specific genetic mutation associated with NF in an individual. More than 3,000 mutations have been identified in the NF1 gene, and there a few examples in which a specific mutation can be correlated to certain NF symptoms. The UAB Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene. While it is probable that certain mutations do predict specific NF symptoms, it’s also very likely that most mutations don’t predict the specific NF features or the course of the condition.
Another factor that likely plays a role in the variability of NF is an individual’s genetic background. Because individuals express genetic variants across the genome, it’s likely that there are other genes that can influence the manifestations of NF. Evidence for this phenomenon can be seen in mouse models. When the NF1 gene is introduced into genetically distinct strains of mice, the manifestations of NF can be very different. It seems likely that an individual’s distinct genetic background can help to determine the symptoms of NF that he or she experiences. It is difficult to design human studies to look for this phenomenon, however, due to the need to determine phenotypes (symptoms) and perform genetic sequencing on hundreds of patients, though efforts are underway to try to address this issue.
We are reasonably certain there is also a random nature to some of the physical manifestations of NF. Each individual is born with two copies of the NF1 gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or in most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. This “second-hit” mutation seems to be a random event that leads to a specific complication, such as a neurofibroma. It is possible that there may be factors in a person’s genetic background that increase the likelihood of a “second-hit”mutation.
NF Chest Examination
Turning back to our discussion in the previous blog about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during a chest examination. Because people with NF have an increased risk of congenital heart defects, the chest exam includes listening for a specific type of heart murmur associated with pulmonic stenosis. This condition causes a narrowing of the pulmonary valve, interfering with blood flow from the heart to the lungs. However, the condition is not as common in NF as in other RAS pathway disorders.
While the lungs are not commonly affected in NF, some adults may experience emphysema-like changes thought to be related to NF. It is also possible for neurofibromas to develop in the chest, which can interfere with inflation of the lungs and with breathing. Occasionally, we can feel a nodular neurofibroma at the base of the neck or near the collarbone. Some people develop plexiform neurofibromas deep inside the chest, although we usually don’t see plexiform neurofibromas in the lungs or heart muscle. The only treatment for plexiform neurofibromas is surgical removal, which is reserved for cases in which important structures are affected.
Sometimes a bony deformation of the chest wall, called pectus excavatum, can occur in people with NF. The condition causes a depression in the breast bone and usually doesn’t result in problems or require treatment unless it interferes with lung inflation and breathing. In these cases, surgical treatment can be offered. Another condition, called pectus carinatum, causes the chest wall to bulge out, probably due to disproportionate rib cage growth. In most cases, the condition doesn’t require treatment.
In some people with NF, spinal tumors can become large enough that they can push on the lungs, which may require surgical removal of the tumors if breathing is affected. Also, people with NF are at increased for developing abnormal tissue growth inside of blood vessels, including major arteries in the heart and lungs. This condition weakens the vessel wall and leads to narrowing and possible rupture, which is a serious emergency. Sudden onset of severe chest or abdominal pain is a symptom that this condition may be present, indicating the need for diagnostic testing, though many other things can lead to pain other than vascular rupture.
NF Awareness Month
Finally, I’d like to remind everyone that May is NF Awareness Month. The Children’s Tumor Foundation has developed a number of activities to inform the public about NF [http://www.ctf.org/NFawareness], and there will be events here in Birmingham as well. Keep an eye on our Facebook page [https://www.facebook.com/uabnfprogram/], as well as the Neurofibromatosis Alabama page [https://www.facebook.com/Neurofibromatosis-Alabama-Childrens-Tumor-Foundation-203255213153983/] for further details.
Re-Cap of Meetings in Washington, DC, for Renewed NF Research Funding and a Review of What to Expect During an NF Neck Exam
By: Bruce Korf
Published Date: Mar 29
Highlights of CDMRP Meetings
At the beginning of March, I spent a day in Washington, DC, meeting with congressional legislative aids to discuss the importance of continued NF research funding for the Congressionally Directed Medical Research Programs (CDMRP). The CDMRP was established in 1992 to support novel approaches in biomedical research to benefit the American public and the military. The program is funded by the Department of Defense (DoD) through the annual Defense Appropriations Act. However, funds for the program are not included in the DoD’s annual budget and must instead be renewed each year during the congressional budget approval cycle based on response to requests by consumer advocates and those affected by the condition. Our primary purpose in meeting with congressional aids was to explain the relevance and impact of NF research and the need for a continued investment that will lead to breakthrough treatments and improvements in patient care.
In addition to neurofibromatosis research, a wide range of biomedical research projects are funded by the CDMRP, including breast and ovarian cancer, autism, multiple sclerosis, and spinal cord injury, to name only a few. We emphasized during our meetings that NF research has implications for bone and wound healing, medical issues important to the military. Also, we discussed the fact that NF genetics research is yielding information that is applicable to several other areas of medicine. For example, it has been established that the NF1 gene is one of the most commonly altered genes in cancer. Some may wonder if these research projects could be funded through the National Institutes of Health (NIH), the nation’s largest government-funded medical research agency. While the NIH does fund important basic and translational research relevant to NF, it’s difficult for the NIH to direct funding to a specific condition, as the CDMRP has the flexibility to do. In fact, a hallmark of the CDMRP is filling critical research gaps by funding high-impact projects that would be not be feasible for other agencies. For example, the NF Clinical Trials Consortium – funded by a grant that integrates research at more than 17 sites coordinated by UAB – was developed 10 years ago in response to a funding need identified by the CDMRP for NF-related clinical trials. In this way, the CDMRP complements the work of the NIH by filling a critical niche. We found the congressional aids with whom we met to be supportive of continued NF funding for the CDMRP primarily because the program has a substantial return on investment. It also has the unique capability to leverage funds for high-impact research that might not otherwise receive needed support.
NF Neck Examination
Continuing our discussion about what to expect during an NF exam, I’d like to discuss issues that may be identified during a neck examination. The most common feature we look for on the neck is neurofibromas, benign nerve sheath tumors that appear on or under the skin. In children, neurofibromas can be sometimes difficult to distinguish from lymph nodes, which can usually be palpated in the neck; however, an experienced NF clinician can usually make this distinction.
Plexiform neurofibromas, which involve large branches of multiple nerves, can cause significant problems in the neck. In some people, they grow aggressively and can compress the airway and other structures in the neck. While it is possible for plexiform neurofibromas to encase the carotid artery and jugular vein, usually the blood flow is unimpaired.
Another problem associated with plexiform neurofibromas in the neck is possible compression of the spinal nerves as they exit the spinal cord, causing pain or weakness in one or both arms. For this reason, an NF exam should include monitoring of patients for pain and neurologic function in the arms. It’s also possible for plexiform neurofibromas to grow into the vertebral foramen, the gap between vertebral bones where nerve roots connect to the spinal cord. Surgical removal is the only treatment option for plexiform neurofibromas, which can be difficult in the neck due to the risk of damage to vessels and nerves that could cause serious bleeding and other problems. Because of these significant risks, we reserve surgery for critical cases in which important structures in the neck are affected.
Some people with NF develop narrowing of the major arteries, which commonly occurs in one or both kidneys. The reduced blood flow caused by the narrowing signals the kidneys to release hormones that result in high blood pressure, which is a significant health risk. During each NF exam, blood pressure is closely monitored to ensure this problem isn’t developing. Narrowing can also occur in one or both of the carotid arteries, the major arteries in the neck supplying blood flow to the brain. As this condition gradually develops, collateral blood vessels are formed to compensate for reduced blood flow to the brain. Although most people with carotid artery narrowing don’t experience significant symptoms, certain conditions, such as dehydration, significantly increase the risk of stroke in these individuals. We don’t routinely perform imaging tests to screen for this issue, although we’re alert to any symptoms a patient may be experiencing that could indicate this problem. When this problem is recognized we usually recommend starting a mild blood thinner, typically baby aspirin. In symptomatic cases, there are surgical approaches that can restore blood flow to the brain.
At the beginning of March, I spent a day in Washington, DC, meeting with congressional legislative aids to discuss the importance of continued NF research funding for the Congressionally Directed Medical Research Programs (CDMRP). The CDMRP was established in 1992 to support novel approaches in biomedical research to benefit the American public and the military. The program is funded by the Department of Defense (DoD) through the annual Defense Appropriations Act. However, funds for the program are not included in the DoD’s annual budget and must instead be renewed each year during the congressional budget approval cycle based on response to requests by consumer advocates and those affected by the condition. Our primary purpose in meeting with congressional aids was to explain the relevance and impact of NF research and the need for a continued investment that will lead to breakthrough treatments and improvements in patient care.
In addition to neurofibromatosis research, a wide range of biomedical research projects are funded by the CDMRP, including breast and ovarian cancer, autism, multiple sclerosis, and spinal cord injury, to name only a few. We emphasized during our meetings that NF research has implications for bone and wound healing, medical issues important to the military. Also, we discussed the fact that NF genetics research is yielding information that is applicable to several other areas of medicine. For example, it has been established that the NF1 gene is one of the most commonly altered genes in cancer. Some may wonder if these research projects could be funded through the National Institutes of Health (NIH), the nation’s largest government-funded medical research agency. While the NIH does fund important basic and translational research relevant to NF, it’s difficult for the NIH to direct funding to a specific condition, as the CDMRP has the flexibility to do. In fact, a hallmark of the CDMRP is filling critical research gaps by funding high-impact projects that would be not be feasible for other agencies. For example, the NF Clinical Trials Consortium – funded by a grant that integrates research at more than 17 sites coordinated by UAB – was developed 10 years ago in response to a funding need identified by the CDMRP for NF-related clinical trials. In this way, the CDMRP complements the work of the NIH by filling a critical niche. We found the congressional aids with whom we met to be supportive of continued NF funding for the CDMRP primarily because the program has a substantial return on investment. It also has the unique capability to leverage funds for high-impact research that might not otherwise receive needed support.
NF Neck Examination
Continuing our discussion about what to expect during an NF exam, I’d like to discuss issues that may be identified during a neck examination. The most common feature we look for on the neck is neurofibromas, benign nerve sheath tumors that appear on or under the skin. In children, neurofibromas can be sometimes difficult to distinguish from lymph nodes, which can usually be palpated in the neck; however, an experienced NF clinician can usually make this distinction.
Plexiform neurofibromas, which involve large branches of multiple nerves, can cause significant problems in the neck. In some people, they grow aggressively and can compress the airway and other structures in the neck. While it is possible for plexiform neurofibromas to encase the carotid artery and jugular vein, usually the blood flow is unimpaired.
Another problem associated with plexiform neurofibromas in the neck is possible compression of the spinal nerves as they exit the spinal cord, causing pain or weakness in one or both arms. For this reason, an NF exam should include monitoring of patients for pain and neurologic function in the arms. It’s also possible for plexiform neurofibromas to grow into the vertebral foramen, the gap between vertebral bones where nerve roots connect to the spinal cord. Surgical removal is the only treatment option for plexiform neurofibromas, which can be difficult in the neck due to the risk of damage to vessels and nerves that could cause serious bleeding and other problems. Because of these significant risks, we reserve surgery for critical cases in which important structures in the neck are affected.
Some people with NF develop narrowing of the major arteries, which commonly occurs in one or both kidneys. The reduced blood flow caused by the narrowing signals the kidneys to release hormones that result in high blood pressure, which is a significant health risk. During each NF exam, blood pressure is closely monitored to ensure this problem isn’t developing. Narrowing can also occur in one or both of the carotid arteries, the major arteries in the neck supplying blood flow to the brain. As this condition gradually develops, collateral blood vessels are formed to compensate for reduced blood flow to the brain. Although most people with carotid artery narrowing don’t experience significant symptoms, certain conditions, such as dehydration, significantly increase the risk of stroke in these individuals. We don’t routinely perform imaging tests to screen for this issue, although we’re alert to any symptoms a patient may be experiencing that could indicate this problem. When this problem is recognized we usually recommend starting a mild blood thinner, typically baby aspirin. In symptomatic cases, there are surgical approaches that can restore blood flow to the brain.
New Discoveries in the UAB Medical Genomics Laboratory, Animal Model Progress, and NF-Related Features of the Head
By: Bruce Korf
Published Date: Mar 07
In previous blogs, I’ve referred to the leading-edge work conducted in the UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D. Viewed in the medical and scientific communities as the gold standard for NF genetic testing, the laboratory has identified mutations in more than 8,000 unrelated NF1 patients and has identified more than 3,000 NF1 mutations. A recent UAB School of Medicine web site article highlights the groundbreaking work of Dr. Messiaen and her colleagues in determining correlations between specific NF1 mutations and symptoms of the disorder (http://www.uab.edu/medicine/news/latest/item/956-uab-researchers-work-to-unravel-the-complex-genetic-disease-neurofibromatosis-type-1). Using the database of more than 3,000 different NF1 mutations and a catalogue of phenotypes (symptoms) in NF1 patients, Dr. Messiaen led a team of 74 researchers and clinicians from 58 centers (from 24 U.S. states and 8 non-U.S. countries) in identifying only the third genotype/phenotype correlation ever found for NF1. The details of this and other recent investigations conducted by Dr. Messiaen’s team were published last year in the journals Human Mutation (http://www.ncbi.nlm.nih.gov/pubmed/26178382) and The American Journal of Human Genetics (http://www.ncbi.nlm.nih.gov/pubmed/26189818).
This finding is significant in giving patients and clinicians a better understanding of the expected course of the disease, including the symptoms that are likely to be most prominent, with a specific type of NF1 mutation. As we’ve discussed previously, there is broad clinical variability in the expression of NF among individual patients, and the course of the disease is often difficult to predict. This uncertainty can be anxiety-provoking and unsettling for families of children facing a diagnosis of NF1. Dr. Messiaen’s continued efforts in developing, utilizing and expanding the laboratory’s extensive mutation database to identify additional genotype/phenotype correlations will help to explain the causes of variability of expressions of NF and provide a greater degree of clarity and predictability for patients and clinicians about the expected course of the disease.
Our NF research program is continuing to accelerate the development of new animal models of NF mutations. Recently, we have been in discussions with various groups about developing models of individual mutations. Our goal remains to create models that allow us to test or develop new drugs that will restore function to the mutated gene or gene product. We will soon have completed our first mouse model preclinical trial of one new approach to therapy, and expect to launch others in the upcoming months.
I’d like to continue our discussion, featured in the previous few blogs, briefly reviewing specific NF features and symptoms clinicians may identify during a patient examination. When conducting an exam of the head, the most obvious NF-related feature is often the presence of neurofibromas, soft benign tumors that develop on or under the skin. These are not usually seen in young children but typically appear during adolescence and continue to develop throughout life. Because skin neurofibromas are harmless, the primary concern may be cosmetic in individuals who have a significant distribution of neurofibromas on the face and neck. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another tumor that can occur on the face is a plexiform neurofibroma, a type of tumor that involves multiple branches of small or large nerves. Some children with NF1 develop a plexiform neurofibroma behind an eye, which may show up as a swelling of the upper eyelid in the early years of life. These can grow rapidly in childhood and cause significant disfigurement and interference with vision. Approximately 2% to 3% of people with NF1 develop orbital plexiform neurofibromas. Treatment involves surgical removal when possible, although surgery is complex and challenging due to the location of these tumors and the involvement of cranial nerves. Because recurrence after surgical removal is common, close follow-up with an experienced NF clinician as well as an ophthalmologist and plastic surgeon is important.
In some cases, distinctive facial features may be present in people with NF. An example of a feature that may be noted by a clinician is palpebral fissures – the longitudinal opening between the eyelids – which slant downward from the midline to the lateral area. While many people with NF share this feature, it doesn’t appear in everyone with NF. There also may be slight drooping of the upper eyelids. Other NF features on the head include scalp neurofibromas, which can become painful and sometimes bleed, usually in adults. Also, some people with NF retain a soft spot on the head, usually behind the left ear, that doesn’t completely close during the normal process of skull bone fusion that begins in early childhood. While this feature is uncommon, it may be noted by an experienced clinician during an examination. It is a benign feature that usually does not require treatment.
This finding is significant in giving patients and clinicians a better understanding of the expected course of the disease, including the symptoms that are likely to be most prominent, with a specific type of NF1 mutation. As we’ve discussed previously, there is broad clinical variability in the expression of NF among individual patients, and the course of the disease is often difficult to predict. This uncertainty can be anxiety-provoking and unsettling for families of children facing a diagnosis of NF1. Dr. Messiaen’s continued efforts in developing, utilizing and expanding the laboratory’s extensive mutation database to identify additional genotype/phenotype correlations will help to explain the causes of variability of expressions of NF and provide a greater degree of clarity and predictability for patients and clinicians about the expected course of the disease.
Our NF research program is continuing to accelerate the development of new animal models of NF mutations. Recently, we have been in discussions with various groups about developing models of individual mutations. Our goal remains to create models that allow us to test or develop new drugs that will restore function to the mutated gene or gene product. We will soon have completed our first mouse model preclinical trial of one new approach to therapy, and expect to launch others in the upcoming months.
I’d like to continue our discussion, featured in the previous few blogs, briefly reviewing specific NF features and symptoms clinicians may identify during a patient examination. When conducting an exam of the head, the most obvious NF-related feature is often the presence of neurofibromas, soft benign tumors that develop on or under the skin. These are not usually seen in young children but typically appear during adolescence and continue to develop throughout life. Because skin neurofibromas are harmless, the primary concern may be cosmetic in individuals who have a significant distribution of neurofibromas on the face and neck. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another tumor that can occur on the face is a plexiform neurofibroma, a type of tumor that involves multiple branches of small or large nerves. Some children with NF1 develop a plexiform neurofibroma behind an eye, which may show up as a swelling of the upper eyelid in the early years of life. These can grow rapidly in childhood and cause significant disfigurement and interference with vision. Approximately 2% to 3% of people with NF1 develop orbital plexiform neurofibromas. Treatment involves surgical removal when possible, although surgery is complex and challenging due to the location of these tumors and the involvement of cranial nerves. Because recurrence after surgical removal is common, close follow-up with an experienced NF clinician as well as an ophthalmologist and plastic surgeon is important.
In some cases, distinctive facial features may be present in people with NF. An example of a feature that may be noted by a clinician is palpebral fissures – the longitudinal opening between the eyelids – which slant downward from the midline to the lateral area. While many people with NF share this feature, it doesn’t appear in everyone with NF. There also may be slight drooping of the upper eyelids. Other NF features on the head include scalp neurofibromas, which can become painful and sometimes bleed, usually in adults. Also, some people with NF retain a soft spot on the head, usually behind the left ear, that doesn’t completely close during the normal process of skull bone fusion that begins in early childhood. While this feature is uncommon, it may be noted by an experienced clinician during an examination. It is a benign feature that usually does not require treatment.
New Year’s Resolutions for the NF Program and Common Skin Issues Detected During an NF Clinic Visit
By: Bruce Korf
Published Date: Jan 19
With the beginning of a new year, I’d like to follow the time-honored tradition of outlining a few key New Year’s resolutions for the UAB NF Program in 2016 that will continue to build on our commitment to excellence in patient care, research, and education. First, we continue our important mission of finding and developing new, life-changing therapies for people with NF by expanding and enhancing our program’s innovative research efforts during the upcoming year. As part of this effort, we are actively recruiting an additional faculty member to join our drug discovery initiatives. Also, we continue to make significant progress in animal model development that will allow us to test the effectiveness of potential NF medications more quickly and efficiently. To accomplish this objective, a graduate student in our program has developed new animal models with NF features that develop more rapidly than previous animal models that have neurofibromas, which are often slow-growing. We believe these new models hold promise in allowing for more expeditious drug testing efforts that will enable us to test more medications more quickly.
Also, as part of our ongoing drug discovery efforts in 2016, we continue to test the effectiveness of potential new drug therapies for NF1 using specialized types of cells derived from individuals with the NF1 gene mutation, called induced pluripotent stem (iPS) cells. Using cells from a biopsy taken from either skin or a neurofibroma of a patient with NF1, we can create iPS cells by manipulations that cause them to behave like undifferentiated cells. These patient-specific cell lines can be used to test the effectiveness of potential new drug therapies for NF1. An additional research goal for this year is to launch a clinical trial for skin neurofibromas in 2016. We are currently following patients and collecting data on the growth and progression of their neurofibromas, which is a necessary step before the clinical trial can begin.
In a recent blog post, I mentioned that we have plans to remake a video that was produced while I was Boston more than 10 years ago featuring a counseling session with a family regarding the new diagnosis of NF1 in a child (called “Understanding NF1,” available at (www.understandingnf1.org). Based on that post, we received a response from a family interested in participating and the project is now moving forward. Our Community Advisory Board, which held their initial meeting last October, will meet this spring with the overall objective of providing valuable input and direction regarding patient information, education, support, and coordination of care in our NF Clinic. Based on feedback from the Board, we are currently developing several projects for new approaches to patient education. Also, the Community Advisory Board will play a key role in helping to organize this year’s NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included.
In continuing our discussion from last month’s blog regarding important issues NF clinicians are focused on during a patient evaluation, I’d like to briefly review what we look for on the skin during an NF clinic visit. While NF1 includes many features, the appearance of multiple flat, brown spots called café-au-lait spots is the most common sign. These spots, which have flat margins and distinct borders, commonly appear in the first few months of life and may continue to increase in number through age two, though they often fade in adulthood. The coloring of café-au-lait spots is typically at least a shade darker than the general pigmentation of the skin. Anyone can have one or two café-au-lait spots without having NF1; however, most people with NF have at least six and most have many more. It’s important to understand that the presence of this feature only suggests the possibility of NF1. Legius Syndrome is another condition that causes café-au-lait spots, although this is a benign condition that does not cause the development of tumors and is much more rare than NF1
Freckling in the skin fold regions is another common NF1 feature that we look for during an exam. This distinctive freckling appears between three and five years of age and most commonly occurs in the groin region, under the arms, at the base of the neck, and under the breasts in women. Unlike typical freckling that occurs on sun-exposed areas of the skin, NF-related freckling manifests as many freckles in the region, as if paint were spattered from a brush. In addition to freckling, we also look for neurofibromas, soft benign tumors that develop under the skin. Although we occasionally see these in young children, the more visible neurofibromas appear later in childhood or adolescence and continue to develop throughout life, especially during pregnancy in women. While the size of neurofibromas can vary, the average size is that of a pencil eraser, though some can be larger or smaller. Skin neurofibromas are generally harmless, although they can be a significant cosmetic concern for individuals who have many neurofibromas distributed over large areas of the body such as the face, neck, and arms. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another skin condition that can be detected during an NF exam is a type of lesion called nevus anemicus, which can be associated with NF1. These lesions appear as a flat white patch on the skin, often on the chest or back. They are irregular in shape and sharply marginated. Usually present at birth or early childhood, the lesions seem to be caused by the incomplete formation of blood vessels in the skin and are harmless. Lastly, we sometimes see children with skin nodules called xanthogranulomas that occur more frequently in people with NF1. These appear as small, yellowish-orange bumps on the skin, especially at the hairline, in infants or very young children. Because xanthogranulomas regress spontaneously, they don’t require any special treatment. An experienced NF clinician can provide information and guidance about the clinical significance of the various skin conditions detected during an examination.
Also, as part of our ongoing drug discovery efforts in 2016, we continue to test the effectiveness of potential new drug therapies for NF1 using specialized types of cells derived from individuals with the NF1 gene mutation, called induced pluripotent stem (iPS) cells. Using cells from a biopsy taken from either skin or a neurofibroma of a patient with NF1, we can create iPS cells by manipulations that cause them to behave like undifferentiated cells. These patient-specific cell lines can be used to test the effectiveness of potential new drug therapies for NF1. An additional research goal for this year is to launch a clinical trial for skin neurofibromas in 2016. We are currently following patients and collecting data on the growth and progression of their neurofibromas, which is a necessary step before the clinical trial can begin.
In a recent blog post, I mentioned that we have plans to remake a video that was produced while I was Boston more than 10 years ago featuring a counseling session with a family regarding the new diagnosis of NF1 in a child (called “Understanding NF1,” available at (www.understandingnf1.org). Based on that post, we received a response from a family interested in participating and the project is now moving forward. Our Community Advisory Board, which held their initial meeting last October, will meet this spring with the overall objective of providing valuable input and direction regarding patient information, education, support, and coordination of care in our NF Clinic. Based on feedback from the Board, we are currently developing several projects for new approaches to patient education. Also, the Community Advisory Board will play a key role in helping to organize this year’s NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included.
In continuing our discussion from last month’s blog regarding important issues NF clinicians are focused on during a patient evaluation, I’d like to briefly review what we look for on the skin during an NF clinic visit. While NF1 includes many features, the appearance of multiple flat, brown spots called café-au-lait spots is the most common sign. These spots, which have flat margins and distinct borders, commonly appear in the first few months of life and may continue to increase in number through age two, though they often fade in adulthood. The coloring of café-au-lait spots is typically at least a shade darker than the general pigmentation of the skin. Anyone can have one or two café-au-lait spots without having NF1; however, most people with NF have at least six and most have many more. It’s important to understand that the presence of this feature only suggests the possibility of NF1. Legius Syndrome is another condition that causes café-au-lait spots, although this is a benign condition that does not cause the development of tumors and is much more rare than NF1
Freckling in the skin fold regions is another common NF1 feature that we look for during an exam. This distinctive freckling appears between three and five years of age and most commonly occurs in the groin region, under the arms, at the base of the neck, and under the breasts in women. Unlike typical freckling that occurs on sun-exposed areas of the skin, NF-related freckling manifests as many freckles in the region, as if paint were spattered from a brush. In addition to freckling, we also look for neurofibromas, soft benign tumors that develop under the skin. Although we occasionally see these in young children, the more visible neurofibromas appear later in childhood or adolescence and continue to develop throughout life, especially during pregnancy in women. While the size of neurofibromas can vary, the average size is that of a pencil eraser, though some can be larger or smaller. Skin neurofibromas are generally harmless, although they can be a significant cosmetic concern for individuals who have many neurofibromas distributed over large areas of the body such as the face, neck, and arms. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.
Another skin condition that can be detected during an NF exam is a type of lesion called nevus anemicus, which can be associated with NF1. These lesions appear as a flat white patch on the skin, often on the chest or back. They are irregular in shape and sharply marginated. Usually present at birth or early childhood, the lesions seem to be caused by the incomplete formation of blood vessels in the skin and are harmless. Lastly, we sometimes see children with skin nodules called xanthogranulomas that occur more frequently in people with NF1. These appear as small, yellowish-orange bumps on the skin, especially at the hairline, in infants or very young children. Because xanthogranulomas regress spontaneously, they don’t require any special treatment. An experienced NF clinician can provide information and guidance about the clinical significance of the various skin conditions detected during an examination.
Animal Model Research Update, Plans for Adult and Pediatric NF Clinics, and the Focus of Exams in an NF Clinic
By: Bruce Korf
Published Date: Dec 11
As the year draws to a close, I’d like to provide a brief update on the NF Program’s research progress in the important area of animal model development. Animal models allow scientists to study the process of specific diseases and often serve as an important foundation of drug research before clinical trials can begin in humans. Our research program is continuing work on a mouse model we developed with a specific type of gene mutation, called a premature stop mutation, that is responsible for ~20% of NF1 cases. A mouse clinical trial is currently in progress with the objective of determining whether certain medications are effective in overcoming the stop mutation by either shrinking existing tumors in the mice or delaying or preventing tumor growth. In addition to the premature stop mutation model, we have also expanded the number of mutations for which we’re developing animal models, with an overall goal of establishing a library of animal models that can be used to test the efficacy of potential medications. We’re using the new gene editing approach called the CRISPR/Cas9 system, which allows investigators to “edit” the genome and quickly introduce mutations into these model systems. Although the results of our research initiatives can’t be released until they have been peer-reviewed and published (and a set of papers are now in preparation), it’s important to know that significant progress is being made in the development of animal models that are allowing us to test new drug therapies that hold promise in restoring function to genes with specific types of mutations.
In other developments, we are anticipating that by early 2016, the NF Clinic will be separated into adult and pediatric clinics located at two distinct sites: the adult clinic will be located in the Kirklin Clinic at UAB, while the pediatric clinic will be at the downtown Children’s Hospital of Alabama location. Both of these facilities provide more convenient patient parking than our current NF Clinic location in the Hugh Kaul Human Genetics building. Most importantly, the new locations will allow for a more seamless integration with the range of other medical specialties involved in the multidisciplinary approach to care that we provide to our NF patients.
Lastly, I’d like to briefly discuss some of the important issues that we, as NF clinicians, are focused on during a patient evaluation by highlighting three main points: the value of NF patients being followed by NF specialists; the purpose of annual follow-up exams; and a brief explanation of what NF clinicians are looking for during an NF exam. First, we understand that most patients have a primary care physician and we try to work together with these providers. Primary care physicians play an integral role in the healthcare continuum by providing recommended screenings, risk assessments, and vaccinations, for example. Our goal as NF clinicians is to serve as consultants by providing support and assistance. NF is a progressive disorder, and an NF clinician has experience in detecting changes in NF patients before significant problems develop and in recognizing NF-related problems when they do occur. We occasionally see patients with NF-related problems whose diagnosis was delayed, which can make the problem more difficult to manage.
Once a patient is established in an NF Clinic, exams at one-year intervals are a convenient and useful benchmark for clinicians to stay in touch with patients and detect any NF-related problems that may be developing. Also, the state of knowledge in the NF field changes significantly from year to year, especially with the progress in clinical trials and other research, and we want our patients to benefit from new treatment advances or opportunities to participate in research. The emphasis of annual exams varies depending on many factors, including the age of the patient, the type of NF involved, and the complications the patient is currently experiencing. As NF clinicians, we follow people with all forms of NF at all ages, from birth to advanced age; the problems a clinician looks for in an NF patient vary with all these factors. For example, we keep a close watch on the formation of optic nerve tumors in children with NF1 because they are more common in pediatric patients, while we’re not as concerned about this issue in adults. In general, an annual exam focuses on keeping track of known problems, identifying new signs or symptoms, and anticipating likely future issues. In an NF clinic, exams are performed by experts who can detect problems early and customize care to the needs of individual patients and their life stage.
In other developments, we are anticipating that by early 2016, the NF Clinic will be separated into adult and pediatric clinics located at two distinct sites: the adult clinic will be located in the Kirklin Clinic at UAB, while the pediatric clinic will be at the downtown Children’s Hospital of Alabama location. Both of these facilities provide more convenient patient parking than our current NF Clinic location in the Hugh Kaul Human Genetics building. Most importantly, the new locations will allow for a more seamless integration with the range of other medical specialties involved in the multidisciplinary approach to care that we provide to our NF patients.
Lastly, I’d like to briefly discuss some of the important issues that we, as NF clinicians, are focused on during a patient evaluation by highlighting three main points: the value of NF patients being followed by NF specialists; the purpose of annual follow-up exams; and a brief explanation of what NF clinicians are looking for during an NF exam. First, we understand that most patients have a primary care physician and we try to work together with these providers. Primary care physicians play an integral role in the healthcare continuum by providing recommended screenings, risk assessments, and vaccinations, for example. Our goal as NF clinicians is to serve as consultants by providing support and assistance. NF is a progressive disorder, and an NF clinician has experience in detecting changes in NF patients before significant problems develop and in recognizing NF-related problems when they do occur. We occasionally see patients with NF-related problems whose diagnosis was delayed, which can make the problem more difficult to manage.
Once a patient is established in an NF Clinic, exams at one-year intervals are a convenient and useful benchmark for clinicians to stay in touch with patients and detect any NF-related problems that may be developing. Also, the state of knowledge in the NF field changes significantly from year to year, especially with the progress in clinical trials and other research, and we want our patients to benefit from new treatment advances or opportunities to participate in research. The emphasis of annual exams varies depending on many factors, including the age of the patient, the type of NF involved, and the complications the patient is currently experiencing. As NF clinicians, we follow people with all forms of NF at all ages, from birth to advanced age; the problems a clinician looks for in an NF patient vary with all these factors. For example, we keep a close watch on the formation of optic nerve tumors in children with NF1 because they are more common in pediatric patients, while we’re not as concerned about this issue in adults. In general, an annual exam focuses on keeping track of known problems, identifying new signs or symptoms, and anticipating likely future issues. In an NF clinic, exams are performed by experts who can detect problems early and customize care to the needs of individual patients and their life stage.
Successful 2nd Annual Alabama NF Walk and Update on Newly Formed NF Community Advisory Board
By: Bruce Korf
Published Date: Nov 16
I’m pleased to report that the 2nd annual Alabama NF Walk, held on October 18th in Veterans Park in Hoover, was a huge success both in terms of fundraising and attendance. The purpose of the event is to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults. This year’s NF Walk raised more than $73,000 and registered more than 400 participants, a significant accomplishment for this important event that was launched in our area only one year ago by Birmingham resident Renie Moss, a dedicated patient advocate and mother of two children with NF. Through the tireless efforts of the Moss family, as well as other Birmingham families who have been affected by NF, the Alabama NF Walk has become a significant fundraising event in our area that supports critical NF research focused on the development of breakthrough treatments.
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the newly formed NF Community Advisory Board held its first meeting at the Kaul Human Genetics Building last month. Comprised of NF patients and family members, the primary purpose of the Board is to provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets the needs of our community. Due to the collective expertise and experience of our NF Clinic specialists and staff, I’m confident that our patients are receiving the highest level of NF care available. However, we also want to ensure that our patients have the best possible experience in our Clinic with respect to patient information, education, support, and coordination of care. The Board, which will meet three or four times a year, will maintain an emphasis on community outreach and education regarding NF and the clinical and research programs available at UAB. In addition, the Board will serve an integral role in helping to organize the NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included. Other goals for the group include identifying any needs that are currently not being addressed by our NF program and offering advice to our program leadership to help make the NF Clinic as strong and responsive as possible. Also, the Board will explore the development of smart phone and tablet apps to assist patients in documenting and storing information about their own care that can also be shared with clinicians to expedite communication and enhance patient care. These and other initiatives will serve to improve our patients’ experience in the Clinic and ensure that our NF program continues to maintain our commitment to meeting patients’ needs in every area.
One final point: More than 10 years ago, while I was still in Boston, we produced a video of a counseling session with a family regarding the new diagnosis of NF1 in a child. It can be viewed online at www.understandingnf1.org. We have gotten a lot of good feedback about the video over the years, as many families have found it helpful to understand the many issues that arise with a new diagnosis of NF1. A lot has happened in NF research – genetic testing and clinical trials, for example – since the video was done, and therefore I’d like to redo it and include this new information. The couple who were featured in the video actually do have a child with NF1, though this was not really their first time hearing about it. It works best to have a couple with a young child who has been diagnosed in the relatively recent past. If anyone reading this would like to consider working with us on this, please let me know (bkorf@uabmc.edu).
As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the newly formed NF Community Advisory Board held its first meeting at the Kaul Human Genetics Building last month. Comprised of NF patients and family members, the primary purpose of the Board is to provide valuable feedback to ensure the NF Clinic is functioning in a way that best meets the needs of our community. Due to the collective expertise and experience of our NF Clinic specialists and staff, I’m confident that our patients are receiving the highest level of NF care available. However, we also want to ensure that our patients have the best possible experience in our Clinic with respect to patient information, education, support, and coordination of care. The Board, which will meet three or four times a year, will maintain an emphasis on community outreach and education regarding NF and the clinical and research programs available at UAB. In addition, the Board will serve an integral role in helping to organize the NF Symposium for patients and families, including providing insight and guidance about topics and speakers to be included. Other goals for the group include identifying any needs that are currently not being addressed by our NF program and offering advice to our program leadership to help make the NF Clinic as strong and responsive as possible. Also, the Board will explore the development of smart phone and tablet apps to assist patients in documenting and storing information about their own care that can also be shared with clinicians to expedite communication and enhance patient care. These and other initiatives will serve to improve our patients’ experience in the Clinic and ensure that our NF program continues to maintain our commitment to meeting patients’ needs in every area.
One final point: More than 10 years ago, while I was still in Boston, we produced a video of a counseling session with a family regarding the new diagnosis of NF1 in a child. It can be viewed online at www.understandingnf1.org. We have gotten a lot of good feedback about the video over the years, as many families have found it helpful to understand the many issues that arise with a new diagnosis of NF1. A lot has happened in NF research – genetic testing and clinical trials, for example – since the video was done, and therefore I’d like to redo it and include this new information. The couple who were featured in the video actually do have a child with NF1, though this was not really their first time hearing about it. It works best to have a couple with a young child who has been diagnosed in the relatively recent past. If anyone reading this would like to consider working with us on this, please let me know (bkorf@uabmc.edu).
Upcoming 2nd Annual Alabama NF Walk and Understanding the Role of NF Genetic Testing
By: Bruce Korf
Published Date: Oct 12
Plans are in place for the 2nd annual Alabama NF Walk in Birmingham to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both adults and children. This year’s event will be held on Sunday, October 18th, at 1 p.m. in Veterans Park located in Hoover. For more information or to register, visit the following page on the CTF web site: www.nfwalk.org/alabama. Last year’s inaugural NF Walk was a landmark event for our city and a huge success, raising more than $50,000 for CTF. Birmingham resident Renie Moss, a dedicated patient advocate and mother of two children with NF, spearheaded our local NF Walk last year in conjunction with CTF. Working with other Birmingham families who have been affected by NF, the Moss family continues to play an integral role in organizing and publicizing this important event that supports critical NF research focused on the development of breakthrough treatments.
Next, I’d like to discuss the role of genetic testing in diagnosing NF and explain when it can be useful. The UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., offers clinical genetic testing for all forms of neurofibromatosis and Legius syndrome, as well as a group of related disorders collectively referred to as the “rasopathies.” In 2003, Dr. Messiaen launched the first routine, reliable, and affordable clinical genetic test for NF1 that has the capability to detect more than 95% of the mutations in persons who fulfill diagnostic criteria. Prior to the development of this test, it was difficult to perform testing for NF1 because of the vast number and diversity of the mutations involved, of which there are thousands. Because of her pioneering efforts, the UAB Medical Genomics Laboratory run by Dr. Messiaen is viewed in the medical and scientific communities as the gold standard for NF genetic testing. The laboratory offers the most scientifically reliable, leading-edge genetic testing currently available for the diagnosis and characterization of mutations in NF1, NF2, and schwannomatosis and performs the highest volume of neurofibromatosis genetic testing in the world. The laboratory has performed more than 7,000 NF1 tests and has identified more than 3,000 different NF1 mutations. Dr. Messiaen and her colleagues were also able to discover a new gene, designated LZTR1, responsible for some cases of schwannomatosis.
Several factors are involved in determining when genetic testing can be useful to patients with neurofibromatosis. In most cases, a diagnosis of NF1 is made clinically, based on the presence of two or more of the seven NIH criteria for the disorder. In some cases, however, a clinical diagnosis of NF1 may be inconclusive or needs to be confirmed, and here genetic testing can be very helpful. For example, if a child has café-au-lait spots and no other clinical features, genetic testing can be used to confirm an NF diagnosis and also to rule out Legius syndrome (which can cause the appearance of café-au-lait spots but not the tumors that are characteristic of NF1).
In addition, there are some cases in which particular mutations predict certain features of NF; for example, a whole gene deletion predicts a more severe course of the disorder and there are a few other mutations that predict a mild course. People who have an unusual presentation, including either isolated or severe features, can also benefit from genetic testing to determine if an NF1 mutation is involved. Finally, identification of an NF1 mutation can make it possible to offer prenatal testing to determine if the mutation has been passed on to a fetus who is at risk based on the mother or father being affected.
One additional interesting point on genetic testing for NF has recently emerged. There is evidence that individuals with NF1 are at increased risk of breast cancer – not to the extent of those with mutations in genes such as BRCA1 or BRCA2, but still at a greater risk than the general population. For this reason, many companies offering genetic testing to persons diagnosed with breast cancer are including a test for NF1 on their genetic testing panel, and a few examples of people with unexpected NF1 mutations have been found. Some of these are likely to be people who actually have neurofibromatosis but had never realized they were affected. Others may have few signs or symptoms, making the finding a real surprise. It remains to be seen how this is explained, and it represents a new area of research in neurofibromatosis genetic testing.
Next, I’d like to discuss the role of genetic testing in diagnosing NF and explain when it can be useful. The UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., offers clinical genetic testing for all forms of neurofibromatosis and Legius syndrome, as well as a group of related disorders collectively referred to as the “rasopathies.” In 2003, Dr. Messiaen launched the first routine, reliable, and affordable clinical genetic test for NF1 that has the capability to detect more than 95% of the mutations in persons who fulfill diagnostic criteria. Prior to the development of this test, it was difficult to perform testing for NF1 because of the vast number and diversity of the mutations involved, of which there are thousands. Because of her pioneering efforts, the UAB Medical Genomics Laboratory run by Dr. Messiaen is viewed in the medical and scientific communities as the gold standard for NF genetic testing. The laboratory offers the most scientifically reliable, leading-edge genetic testing currently available for the diagnosis and characterization of mutations in NF1, NF2, and schwannomatosis and performs the highest volume of neurofibromatosis genetic testing in the world. The laboratory has performed more than 7,000 NF1 tests and has identified more than 3,000 different NF1 mutations. Dr. Messiaen and her colleagues were also able to discover a new gene, designated LZTR1, responsible for some cases of schwannomatosis.
Several factors are involved in determining when genetic testing can be useful to patients with neurofibromatosis. In most cases, a diagnosis of NF1 is made clinically, based on the presence of two or more of the seven NIH criteria for the disorder. In some cases, however, a clinical diagnosis of NF1 may be inconclusive or needs to be confirmed, and here genetic testing can be very helpful. For example, if a child has café-au-lait spots and no other clinical features, genetic testing can be used to confirm an NF diagnosis and also to rule out Legius syndrome (which can cause the appearance of café-au-lait spots but not the tumors that are characteristic of NF1).
In addition, there are some cases in which particular mutations predict certain features of NF; for example, a whole gene deletion predicts a more severe course of the disorder and there are a few other mutations that predict a mild course. People who have an unusual presentation, including either isolated or severe features, can also benefit from genetic testing to determine if an NF1 mutation is involved. Finally, identification of an NF1 mutation can make it possible to offer prenatal testing to determine if the mutation has been passed on to a fetus who is at risk based on the mother or father being affected.
One additional interesting point on genetic testing for NF has recently emerged. There is evidence that individuals with NF1 are at increased risk of breast cancer – not to the extent of those with mutations in genes such as BRCA1 or BRCA2, but still at a greater risk than the general population. For this reason, many companies offering genetic testing to persons diagnosed with breast cancer are including a test for NF1 on their genetic testing panel, and a few examples of people with unexpected NF1 mutations have been found. Some of these are likely to be people who actually have neurofibromatosis but had never realized they were affected. Others may have few signs or symptoms, making the finding a real surprise. It remains to be seen how this is explained, and it represents a new area of research in neurofibromatosis genetic testing.
