By: Bruce Korf Published Date: Aug 13

This month, our discussion continues about the newly released American College of Medical Genetics and Genomics (ACMG) clinical practice resource for adults with NF1.  The resource, written for general practitioners and other healthcare professionals, summarizes current knowledge of clinical care and proposes an approach to management for general practitioners and other healthcare professionals providing care to individuals with NF1.  I’d like to focus on a review of the ACMG recommendations in three areas: hypertension and vasculopathy; osteoporosis; and cutaneous neurofibromas.

Hypertension and Vasculopathy

The most common reason for hypertension, or high blood pressure, in individuals with NF1 is essential hypertension, which means that there is no known cause for why the high blood pressure is occurring.  This is similar to hypertension occurring in the general population.  Another cause of hypertension in individuals with NF1 is pheochromocytoma, a tumor of the adrenal gland discussed in last month’s blog that affects fewer than 5% of people with NF1. The tumor causes the irregular and excessive release of the hormones epinephrine and norepinephrine, causing symptoms of high blood pressure as well as rapid heart rate and palpitations, flushing, and excessive sweating. 

An important cause of hypertension in children and young adults with NF1 is renal artery stenosis, which is a narrowing of the artery that carries blood to the kidney. The kidneys control blood pressure by regulating the amount of water excreted from the body, and restriction in blood flow causes the kidneys to misinterpret this as low blood pressure in the body. In response, the kidneys release hormones that raise blood pressure and result in hypertension. It’s important to monitor blood pressure in people with NF1 beginning in childhood. If blood pressure is elevated, a vascular imaging study such as MRA (magnetic resonance arteriogram) is performed to diagnose the problem. If renal artery stenosis is found, it is treated with medication and sometimes surgery or stenting of the vessel to increase blood flow.

Vascular problems can occur in other areas of the body in people with NF1.  Moyamoya disease is a rare vascular disorder in which the internal carotid artery to the brain becomes blocked or narrowed, reducing blood flow to the brain.  In response to the blockage, which develops very slowly, tiny blood vessels open up in the brain in an attempt to restore blood flow. The word “moyamoya” means “puff of smoke” in Japanese (the condition was first described in Japan, among children who did not have NF1), which describes the appearance on an angiogram (where dye is injected into the artery and it is visualized by X-ray) of the cluster of blood vessels formed that compensate for the carotid artery blockage. Moyamoya disease significantly increases the risk of stroke and transient ischemic attack (TIA), a temporary reduction of blood flow to the brain.  Moyamoya occurs with increased frequency in individuals – usually children – with NF1, and is especially common among children exposed to radiation therapy to the brain for treatment of a brain tumor.

Other blood vessels can be narrowed in individuals with NF1, causing a weakening of the arterial wall and an increased risk of hemorrhage. However, screening for vascular problems in people with NF1 isn’t routinely performed unless there are instances of high blood pressure or TIA.  In these cases, a vascular imaging study would be performed to locate the vascular abnormality. 

Osteoporosis

Decreased bone mineral density and osteoporosis are more common in people with NF1 than the general population. Some studies have shown vitamin D deficiencies in people with NF1, which increases the risk of osteoporosis. A possible contributing factor to vitamin D deficiency may be that individuals with skin neurofibromas tend to cover up more often and not be exposed to enough sunlight as a result. Vitamin D deficiency is also common in the general population, and the practice resource recommends vitamin D supplementation to maintain regular levels. It’s important to note that supplementation should be done under the supervision of a physician to avoid toxicity that can occur with taking too much of the vitamin.  If osteoporosis is diagnosed, the treatments are the same as those for the general population, including the administration of medications to increase bone mineral density.

Cutaneous Neurofibromas

Cutaneous neurofibromas, benign tumors in or on the skin, are common in adults with NF1.  Numbers of tumors can be highly variable, with some individuals having very few and others having a wide distribution covering a large portion of the body. Cutaneous neurofibromas typically increase in number during puberty and continue to progress during adulthood. A substantial proportion of women develop them during pregnancy, and the neurofibromas typically don’t regress when the pregnancy is over. Studies indicate that quality of life for people with cutaneous neurofibromas can be significantly impaired, with major cosmetic concerns often arising in those with a large number and wide distribution of neurofibromas due to the potentially disfiguring aspect of the tumors. Also, the tumors may itch, cause pain, and can sometimes bleed. 

There is no known prevention of cutaneous neurofibromas, and the recommended treatment is surgical removal by a physician who has experience removing cutaneous neurofibromas.  Treatment with a specialized laser called the CO₂ laser has also shown success in removing cutaneous neurofibromas. Another treatment called electrodessication uses heat generated from electricity to remove the tumors. Anesthesia is often required if a large number of tumors are being removed at one time.  The risks of these treatments include scarring and regrowth of the neurofibromas.  Studies have shown that individuals treated with these approaches tend to be satisfied over a period of months following the procedure, but we do not have long term follow-up studies to know how long lasting the benefit might be.  

Here at UAB we are continuing our clinical trial targeting cutaneous neurofibromas using the investigational drug selumetinib, which has been shown to often be effective in reducing the growth of plexiform neurofibromas.  The trial is actively recruiting study participants at two study locations, UAB and the National Cancer Institute in Bethesda, Maryland. More information regarding the trial can be found at: www.clinicaltrials.gov(study number NCT02839720). 

By: Bruce Korf Published Date: Jul 31

We’re continuing our discussion from last month’s blog of the newly released American College of Medical Genetics and Genomics (ACMG) clinical practice resource for adults with NF1. This document summarizes current knowledge of clinical care and proposes an approach to management for general practitioners and other healthcare professionals providing care to adults with NF1. Previously, I reviewed some of the recommendations related to malignant peripheral nerve sheath tumors (MPNST). Next, I’d like to focus on recommendations related to other types of tumors. 

Breast Cancer

In recent years, it has become clear that women with NF1 are at an increased risk for breast cancer, with the risk two to three times higher in women with NF1 than in those in the general population. The increased risk is greatest in women below age 40, with the earliest cases occurring around age 30. The increased risk of breast cancer in women with NF1 is not necessarily an expected outcome, as breast tissue is different from that usually affected by the NF phenotype, such as the tissue comprising neurofibromas.  

The risk of breast cancer in women with NF1 is not as high as the risk of breast cancer in women with mutations in the BRCA1or BRCA2genes; women with mutations in BRCA1or BRCA2have a much higher risk of both breast and ovarian cancer.  The reason for the increased risk of breast cancer in women with NF1 is not understood. Notably, mutations in the NF1gene have been found in the breast cancer tissue of women who do not have NF1. It is known that cancer is the result of the accumulation of genetic alterations that cause cells to behave abnormally. The fact that the NF1gene has been shown to be mutated in some common cancers, including breast cancer, might indicate that the NF1 mutation puts an individual one step closer to developing other cancers.  

A genetic panel of tests is often performed in women who have been diagnosed with breast cancer or have a family history of breast cancer, to detect mutations that might be associated with the cancer. The NF1 gene is now being tested as part of this panel, as well as other genes including BRAC1and BRCA2. We sometimes receive referrals to our clinic from women who have undergone genetic testing for a breast cancer diagnosis and have been found to have a mutation for NF1.There are three possible reasons for this finding: first, the individual has NF1 and the clinical features have gone unrecognized; second, the individual has a mosaic form of NF1 that is detected in the blood but may not be present in all cells of the body; third, genetic variants are sometimes found in testing that are not pathogenic, and are referred to as “variants of unknown significance,” and do not necessarily equate with having a condition such as NF.

Due to the increased risk of breast cancer in women with NF1, the National Comprehensive Cancer Network (NCCN), an organization that issues screening guidelines for various cancers, has recently recommended that women with NF1 be screened for breast cancer at an earlier age than the general population, with mammograms starting at age 30. Also, the NCCN recommends consideration of use of contrast enhanced breast MRI between the ages of 30 and 50. After this, the guidelines shift back to that of the general population.  Because it isn’t uncommon for women with NF1 to have neurofibromas around the beast, most commonly around the areola, some patients are concerned that neurofibromas in the breast may be mistaken for breast tumors during imaging. While this issue may sometimes make it more difficult to interpret masses in the breast, neurofibromas are clinically distinguishable from tumors in breast tissue. However, it is important for radiologists to know the NF history when reading imaging results for these patients.

Pheochromocytoma

A tumor of the adrenal gland called pheochromocytoma affects fewer than 5% of people with NF1, although it’s an important tumor to recognize. The adrenal glands produce the hormones epinephrine and norepinephrine that trigger the body’s fight-or-flight response to a perceived threat, causing an increase in heart rate and blood pressure. A pheochromocytoma causes the irregular and excessive release of these hormones, resulting in symptoms of high blood pressure, rapid heart rate and palpitations, episodes of flushing, and excessive sweating. 

When a patient presents with these symptoms, a blood test is done to measure plasma free metanephrines, which assesses the amounts of metabolic byproducts of epinephrine and norepinephrine present in the blood. A positive blood test result requires a confirmatory 24-hour urine collection for measurement of the same substances. If laboratory tests indicate the possibility of a tumor, abdominal imaging is performed to locate a possible tumor and may include CT scan and a form of PET scanning technology that can detect radioactive compounds taken up by a tumor.

Gastrointestinal Stromal Cell Tumors

Gastrointestinal stromal cell tumors (GISTs) are tumors of the GI tract that most commonly occur in the stomach or small intestine. Although rare, there is an increased risk of development of GIST in people with NF1. The primary symptoms of GISTs include abdominal pain and GI bleeding. These tumors are diagnosed using endoscopy, a procedure used to examine the digestive tract.  

By: Bruce Korf Published Date: May 29

NF Forum

In early May, I travelled to Atlanta to participate in the NF Forum, a bi-annual event sponsored by the Children’s Tumor Foundation (CTF). Held in different cities across the U.S. each year, the NF Forum is a national patient education and family gathering that features NF experts from around the country providing a series of keynote presentations, panels, and sessions on a variety of NF topics such as research advances and current clinical issues. The event included a meeting for clinic coordinators, physicians, genetic counselors, and other healthcare professionals, as well as a series of talks aimed at the NF patient community. I presented a talk on advances in NF treatment and provided an update on our research program’s current cutaneous neurofibroma clinical trial using an investigational drug.  The NF Forum is important for disseminating the most current information about NF and also provides NF patients and their families an opportunity to network and learn from one another.

Clinical Care Guidelines for Adults with NF1 

The American College of Medical Genetics and Genomics (ACMG) has recently spearheaded an effort to produce suggestions for clinical practice for adults with NF1. As part of this effort, the ACMG convened a panel of clinical experts to review current practice and published papers, and to use these to formulate guidelines for care of adults with NF1. Concluding many months of work, these guidelines were recently published in the journal Genetics in Medicineand are officially sponsored by the American College of Medical Genetics and Genomics (https://www.nature.com/articles/gim201828).  These consensus guidelines were written for the professional community, specifically general practitioners and other healthcare professionals providing care to adult patients with NF1.  Pediatric guidelines for NF1 produced by the American Academy of Pediatrics (AAP) have been available for many years. The American College of Medical Genetics and Genomics and the AAP have recently partnered in an effort to write updated pediatric guidelines, which are still in process. 

There are two major types of guidelines: evidence-based and consensus guidelines. Evidence-based guidelines are considered more authoritative and are developed through a formal process that involves gathering published, peer-reviewed results of clinical research and reviewing evidence about why a certain approach or treatment is or is not effective.  Evidence-based guidelines carry a great deal of weight, especially with insurance carriers. However, for NF1, our panel didn’t feel that evidence-based guidelines were an option at this point in time.  The primary reason is that there have been very few large, randomized clinical trials for management of NF1 due to the relatively small numbers of individuals with the condition and the significant variability in symptoms and complications. It is easier to conduct large clinical trials for common conditions such as diabetes and cardiovascular disease.  Another obstacle is that a thorough review of evidence is a time-consuming and expensive process, beyond the reach of the organizations sponsoring the guideline development at this time.

Consensus guidelines, like those written for NF1, are developed by convening a group of clinical experts who provide their opinions based on clinical experience as well as a review of evidence from the literature. These guidelines summarize current knowledge of clinical care and propose an approach to diagnosis and management. Because the consensus guidelines for NF1 are intended for general practitioners, they provide guidance in identifying specific problems but don’t address treatment, which would be managed by a specialist. For example, the guidelines address the identification of patients showing signs of a malignant tumor, but they don’t specify how to treat the malignant tumor. 

Guidelines for Malignant Peripheral Nerve Sheath Tumors 

In the next few months, I’ll try to discuss some of the recommendations of the adult guideline panel, and, when it is available, the pediatric guidelines.  To start, I’ll cover one of the issues addressed in the clinical care guidelines, the occurrence of malignant peripheral nerve sheath tumors (MPNST). These malignancies occur in about 10% of people with NF1 and represent one of the few life-threatening complications of the condition. MPNSTs occur mostly in teens and young adults with NF1. Malignant peripheral nerve sheath tumors usually arise from pre-existing plexiform or nodular neurofibromas. Atypical neurofibromas, which have distinctive clinical and pathological features, may be a precursor to the development of an MPNST and appear as homogenous nodules that, if superficial, have a firm consistency when palpated. 

Because MPNSTs are very difficult to treat, the focus is on early diagnosis. The clinical care guidelines for NF1 indicate a possible diagnosis based on any one of the following: persistent unexplained pain; rapid growth of a tumor; a change in a tumor from soft to hard; and the use of PET scanning to determine increased uptake of the radioactive tracer. The use of whole body MRI may be of value as a screening tool in helping to identify atypical neurofibromas so they can be followed or surgically removed to prevent their progression to MPNSTs. However, the utility of this approach requires further study at this time.

By: Bruce Korf Published Date: Apr 24

Re-Cap of Successful NF Symposium

Another successful and informative UAB NF Symposium, also known as NF Family Day, was held earlier this month in the Bradley Lecture Center of the Children’s Harbor Building. Co-sponsored by UAB and the Children’s Tumor Foundation (CTF), this half-day, free event provided an opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics from clinical experts. We were pleased to host more than 70 attendees from several states, including as far away as Colorado. A special program of activities was provided for the children in attendance by NF Clinic staff as well as students in the UAB Genetic Counseling and Biomedical Sciences Programs. For the first time, this year’s event featured a keynote speaker from outside the UAB community, New York University neuro-oncologist Kaleb Yohay, M.D., who gave a presentation about the role of alternative medicine in the management of NF. This topic is of great interest to many of our patients, who often ask about the possible benefits of alternative medicine treatments. While alternative medicine is not known to be effective in shrinking tumors or slowing their growth, in some cases there could be some benefits in managing symptoms of NF that can impact quality of life. UAB Professor of Pediatrics and Director of Neuro-Oncology Alyssa Reddy, M.D., provided an update of NF-related clinical trials currently in progress, and I gave a presentation about recommended clinical management for all three forms of neurofibromatosis. In addition to serving as a forum for educating NF patients, families, and the community about important NF-related topics, the event also provides a means for establishing a connection with other NF families who are sharing the same journey. Several NF patients and family members shared how they came to be diagnosed and their personal experiences of managing care for themselves or loved ones. 

Frequency of NF Clinic Visits

Next, I’d like to address a question that patients frequently ask, which is how often should an individual with NF be seen in a specialty NF clinic? I generally recommend that children be seen in clinic on a regular basis, usually once a year.  The rationale for recommending clinic visits for children annually is to help in the identification of any NF-related problems during a period of rapid change as a child develops.  In early childhood, there is uncertainty about how NF will evolve, with the potential for the development of complications such as optic glioma, scoliosis, and bone dysplasia.  For this reason, I recommend that children should be seen once a year by both an NF specialist and a pediatric ophthalmologist.  Of course, if there are recognized problems, it may be appropriate to see a child more than once a year; that should be decided by the physician, together with the family.  

Annual review in an NF Clinic can also be recommended for adults with NF.  Again, the exact frequency of visits depends on the nature of the clinical problems facing the individual.  Some have active problems that require more frequent follow-up; others have been stable for a long period of time, with little change from year-to-year.  In the latter instance, one can debate whether annual follow-up is really necessary.   I can’t say that a rigid annual schedule is critical for all adults with NF1 if nothing is changing clinically.  There are, however, advantages to regular follow-up. First, sometime these visits provide an opportunity to review symptoms that may have been present for a while, but weren’t severe enough to warrant a special visit.  Probably most of these are not medically significant, but sometimes complaints such as pain require further investigation to rule out problems such as malignant change of a neurofibroma.  We do occasionally see people with NF after a gap of many years who have developed significant complications that ideally would have been identified earlier.  A second reason to consider annual follow-up is to stay up-to-date on new advances in the field.  For example, we now have access to clinical trials and even prescription medications that didn’t exist even a few years ago.  The field is changing rapidly, and there is value to staying in touch, as something that couldn’t be treated years ago may well be treatable going forward. A third reason is to provide updated education on NF, including things to look for that might be a sign of progression of the condition.  NF can be a complicated condition, so hearing about the major signs repeatedly over a period of years can be helpful.  Finally, regular – not too frequent, but regular – visits provide a way to stay in touch with the medical team, so that they are familiar with a person’s history if problems do eventually arise.

Our goal is to help patients to be more proactive about their own care and encourage them to stay in touch with their NF care team through tools such as the UAB patient portal when concerns arise.  Also, we’re currently working to develop an educational app that will help patients better understand their condition and signs of potential problems.   The key for successfully managing NF is to remain vigilant about potential problems as much as possible. 

By: Bruce Korf Published Date: Mar 21

Identifying Areas for Improving Patients’ Clinic Experience

A primary focus of our NF Clinic this year is conducting a careful evaluation of our internal systems to identify areas for improvement. To that end, we have begun a series of internal discussions about process improvements in the clinic with the goal of making the experience of our patients as positive as possible. While we feel that our clinic provides the highest level of care comparable to or better than specialty clinics anywhere in the world, we’re continually interested in identifying areas where we can improve the experience of our patients. Providing comprehensive care for NF patients involves multiple appointments with many specialists as well as coordination of a variety of laboratory and imaging tests. In addition, obtaining insurance preauthorizations requires significant behind-the-scenes work from our staff.

Because of this complexity of care, our ongoing focus is to provide the most streamlined and stress-free experience possible for our patients – and we know that we have to go some distance to achieve this goal. We feel that helping patients to become more engaged in their care is an important way to give them more control and enhance their overall experience. One way we’re doing this is to encourage patients to use the online UAB Patient Portal, which allows secure messaging of clinical information for pediatric and adult patients. This important tool helps to streamline care by expediting and increasing communication between patients and the clinical care team. Although we send electronic invitations to all patients for the portal, not everyone registers to use it because the invitation is sometimes not recognized or the instructions aren’t well understood. We’re focused on increasing usage of the online patient portal system by walking patients through the portal registration process while they are in clinic, as we feel all of our patients can benefit from this care management tool. Additionally, we’re attempting to minimize the number of no-show appointments in our clinic through appointment verifications and other measures.  When a patient doesn’t arrive for an appointment, this represents a slot we could have offered to someone else who was hoping to be seen sooner.   We welcome comments regarding additional ways we can improve our patients’ experience, and we look forward to maintaining our commitment to providing the highest level of patient-centered care.

Atypical Neurofibromas and Malignant Peripheral Nerve Sheath Tumors

Next, I’d like to address the issue of atypical neurofibromas and their potential to become  malignant peripheral nerve sheath tumors (MPNST), probably the most feared complication of NF1. Occurring in about 10% of people with NF1, the malignant peripheral nerve sheath tumor can develop from a pre-existing plexiform neurofibroma. Diagnosis usually requires imaging, and in some cases use of a radioactive tracer (PET scan), and, ultimately, surgical biopsy of the tumor. Surgical resection is the most effective treatment, as these tumors are not sensitive to standard chemotherapy or radiation.  The best way to prevent serious complications resulting from these tumors is to identify them as early as possible and consider surgical resection if this can be done safely.

Atypical neurofibromas, which have distinctive clinical and pathological features, may be a precursor to the development of a malignant peripheral nerve sheath tumor. They usually appear as homogenous nodules that, when palpated, have a firm consistency that is unlike plexiform neurofibromas, which are usually soft or spongy to the touch. Biopsies of atypical neurofibromas tend to show densely packed cells and may show dividing cells, whereas non-malignant neurofibromas typically are less dense.  There is evidence that atypical neurofibromas may be early precursors to a malignant peripheral nerve sheath tumors, so vigilance is important, which may include biopsy or surgical resection.  Whole body MRI is beginning to emerge as a method that may be helpful in identifying atypical neurofibromas, and we are exploring the utilization of whole body MRI for this purpose.

By: Bruce Korf Published Date: Feb 13 The start of 2018 also marked my 15-year anniversary at UAB, having begun my tenure as Chairman of the Department of Genetics and Director of the UAB NF Program on January 2^nd, 2003. At that time, the Department of Genetics consisted of only two full-time faculty members, subsequently merging with another department and increasing to 15 faculty. Today, the UAB Department of Genetics has grown to include 35 distinguished faculty members who continue to make significant contributions in clinical care, education, and research. Our program has also grown in scope over the past 15 years, with expanded patient care and initiatives in research and education. As part of a reorganization into adult and pediatric clinics, NF patients are now served at two distinct locations, including Children’s of Alabama and The Kirklin Clinic.  The NF Clinical Trials Consortium, for which UAB serves as the National Coordinating Center, is now in its third five-year funding cycle and is actively engaged in developing multiple new clinical trials for all forms of NF. In addition, our program has successfully secured NIH grants in genomic medicine focused on integrating genomics into diagnostic and therapeutic decision-making.  The department has three clinical laboratories, one of which – the Medical Genomics Laboratory – performs the most scientifically reliable and highest volume of NF genetic testing in the world. We also have an ongoing commitment to patient education through our annual support of key events such as the NF Symposium, NF Walk, and Rare Disease Genomics Symposium.

New Role as Chief Genomics Officer and Continued Role as Director of NF Program

Along with the significant growth our program has experienced over the past 15 years, the field of genomic medicine has continued to evolve since the completion of the Human Genome Project in 2003 that successfully sequenced the complete human genome. Since that time, our understanding of the role of genes in health and disease has greatly expanded, leading to the rapid growth of genomic medicine to provide individualized clinical care to patients. Genomic medicine uses an individual’s genetic profile to guide decisions about  prevention, diagnosis, and treatment.  UAB Medicine has committed to advancing research into genomic medicine through two initiatives aimed at collecting health data from participants to determine the impact of lifestyle, environment, and genomic profiles on a variety of health conditions.  UAB has launched the Alabama Genomic Health Initiative (https://www.uabmedicine.org/aghi) in collaboration with HudsonAlpha Institute for Biotechnology. We have been actively involved in recruiting participants in support of this initiative’s goal to enroll 10,000 individuals in our state over the next five years to determine how genomic information correlates with health status and risk of disease.  We are also the hub of a regional network as part of the NIH All of Us research program (https://allofus.nih.gov), which ultimately will recruit 1 million volunteers across the country.  Local enrollment in this program will begin soon.

In support of UAB Medicine’s commitment to implement precision medicine across all clinical programs, I have recently been appointed to the new role of Chief Genomics Officer for UAB Medicine, with the responsibility for establishing clinical programs in genomic medicine across the UAB Health System. This role also involves providing training and education to clinicians in the use of clinical tools to enable the use of genomic information in making diagnosis and treatment decisions. Because of this new role, I’ve stepped away from my position as Chairman of the Department of Genetics, as relinquishing the administrative responsibilities involved in that position will allow more time for me to focus on these new initiatives. I’ll continue to serve as a professor in the Department of Genetics and will also continue in concurrent positions as Associate Director for Rare Diseases in the UAB Hugh Kaul Precision Medicine Institute and as Co-Director of the UAB-Hudson/Alpha Center for Genomic Medicine.  From the perspective of the NF Program, nothing changes, as I’ll continue to direct the program, with ongoing involvement in clinical trials and research initiatives in developing genomic therapies. Also, I will continue to see patients in the NF Clinic with a continued commitment to maintaining the highest standards of clinical care.

2018 NF Symposium/NF Family Day Coming in April

The annual UAB NF Symposium, also known as NF Family Day, is scheduled for Saturday, April 7^th, in the Bradley Lecture Center of the Children’s Harbor Building. This year’s keynote speaker will be New York University neuro-oncologist Kaleb Yohay, M.D., who will give a presentation about the role of alternative medicine in the treatment of NF. This annual event serves as a forum for NF patients and families to hear a series of presentations about a range of NF-related topics from clinical experts and also provides a means for establishing connections with other NF families. Event registration information is coming soon; for more information, please contact Ashley Cannon at ashleycannon@uabmc.edu  or Renie Moss and rpmoss@uab.edu. 

Newly Identified NF Mutation/Phenotype Correlation

Previously, I’ve discussed the ongoing efforts of the UAB Medical Genomics Laboratory to determine correlations between physical manifestations of NF (phenotype) and specific mutations in the NF1 gene (genotype). More than 3,000 mutations have been identified in the NF1 gene, and there are a few examples in which a specific mutation can be correlated to certain NF symptoms.  The January issue of the American Journal of Human Genetics (Am J Hum Genet. 2018 Jan 4;102(1):69-87. doi: 10.1016/j.ajhg.2017.12.001. Epub 2017 Dec 28.) features a paper from the UAB group and multiple collaborators, led by Dr. Ludwine Messiaen, that identifies a cluster of mutations in the NF1 gene that are associated with a relatively severe set of NF complications. This represents an example of a correlation between specific mutations and certain manifestations of NF.  It is known that most NF mutations turn off the gene, thereby destroying its function; there is no particular phenotype associated with these mutations, except the typical features of NF.   However, there are a handful of mutations where there is some ability to predict the phenotype. Identifying a correlation between a mutation and phenotype can be clinically valuable because certain complications can be anticipated with the potential of managing the condition more effectively. Also, a correlation provides information about how the gene works and may lead to answers regarding why some mutations result in a large burden of internal tumors but not many cutaneous neurofibromas, such as the mutations described in the recently published paper. With more than 3,000 NF gene mutations representing the largest repository in the world, the UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., is in the best position for determining additional mutation/phenotype correlations. In 2016, using the repository of mutations and a catalogue of phenotypes (symptoms) in NF1 patients, Dr. Messiaen and her colleagues identified only the third genotype/phenotype correlation so far found for NF1. Some of these newly identified mutations are being reproduced in animal models, such as mice, rats and pigs, to observe the manifestations of NF correlated with these mutations. Also, we are developing a cell culture system that will help us to determine the way specific mutations alter function within the cell.   These studies will help us to classify the ability of specific mutations to cause NF1, and also will provide a system to test new approaches to treatment.

By: Bruce Korf Published Date: Dec 18 Highlights in Patient Care and Education and Plans for Upcoming Year

As the year draws to a close, I’d like to highlight significant accomplishments and events in the UAB NF Program during 2017 and provide a preview of plans for the upcoming year in patient care, education, and research.  It has been more than a year since the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District as part of a reorganization into adult and pediatric clinics, and the change continues to reap benefits.  Patients seem to be pleased with the new facilities and improved logistics, including more convenient parking. The most significant benefit for our patients is the streamlined, integrated care that is provided in the new clinic locations that enable imaging, lab tests, and consultations with a range of specialists to occur in one location. We’re pleased that our patients are benefitting from this new structure and that our hopes seem to have been realized for improved convenience and integration of care. 

As part of our ongoing commitment to patient education and support, our program co-sponsored, with the Children’s Tumor Foundation (CTF), another successful NF Symposium at the Children’s Harbor Building at Children’s of Alabama in August. Also known as NF Family Day, this annual event serves as a forum for NF patients and families to hear a series of presentations on a range of NF topics from clinical experts as well as  provides a meaningful opportunity for NF families to connect with others sharing the same journey. Our program was also pleased to again support the 4^th Annual Alabama NF Walk held last month in Veteran’s Park in Hoover. Held in cities across the nation, the NF Walk is an important fundraising event 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.

Another highlight for our program this year was our participation in the Rare Disease Genomics Symposium, held in March at UAB, which is an event designed to share information about the role of genomics in the diagnosis and treatment of rare diseases with healthcare practitioners who are non-genetic specialists. While the event was not specific to neurofibromatosis, NF1 is a rare disorder that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders.  The Symposium serves as an important forum for increasing awareness of rare disorders and educating faculty and clinicians at UAB and in the community about the role of genomic medicine in the diagnosis and management of rare diseases.  This year’s Symposium featured a panel discussion led by parents of children with rare diseases as well as an art exhibit showcasing works that depict people with genetic conditions in a humanistic way.  Next year, the Symposium will be a two-day event with the first day designed for professionals and the second day focused on families.

In addition to lending our continued support to the NF Symposium, NF Walk, and Rare Disease Genomics Symposium during the upcoming year, we also plan to increase patient engagement through continuing work begun this year on the development of a smart phone app.  This app will allow patients to become more involved in several aspects of their care and enhance their interaction and experience with the clinic.

Re-Cap of 2017 Research Initiatives and a Preview of 2018

The UAB NF Research program has been actively engaged in basic and preclinical research as well as clinical trials focused on identifying and developing effective therapies for people with NF. Our primary research focus is the development of therapeutics targeted at specific mutations. The UAB Medical Genomics Laboratory is a world leader in genetic testing and medical diagnosis of NF, performing the most scientifically reliable, leading-edge genetic testing currently available for the diagnosis and characterization of mutations for NF1, NF2, and schwannomatosis, with the highest volume of NF genetic testing in the world. The Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene.  This research could provide a framework for determining the extent to which complications of NF are predictable.

Continuing our efforts in the development of animal models, we have developed several additional mouse models with specific NF mutations, some of which have been identified in our own patients. This offers the possibility of a personalized medicine approach to treatment that will remain an increased area of focus for our program in the upcoming year. These models enable our scientists to study the NF disease process as well as the effectiveness of potential drug treatments. Also in the area of preclinical research, we have developed a method of expressing the NF1 gene in a cellular system. This was accomplished by deleting the normal NF1 genes in these cells and replacing them with a mutated gene, allowing us to investigate the effects of a mutation on cells. A scientific poster summarizing our development of this model won first prize at the annual NF Conference last June.  We expect that the model system will yield further information about the NF disease process that will help guide the development of targeted therapeutics.

Additionally, we are conducting a clinical trial targeting cutaneous neurofibromas using the investigational drug called selumetinib. Cutaneous neurofibromas, which are common in adults with NF1, are benign tumors on or in the skin. This trial is actively recruiting study participants, and more information regarding the trial can be found at: www.clinicaltrials.gov (study number NCT02839720).

In support of our continued focus on the development of genome-guided therapies, we have also responded to several RFAs for research funding focused on genome-guided therapeutics with an emphasis on identifying approaches that will allow function to be restored to a non-functional gene or gene product. Our research program was the first to concentrate in this area several years ago, and now this approach is gaining increased attention from others in the scientific community.

Finally, last year we applied for renewal of our Department of Defense grant to fund the NF Clinical Trials Consortium.  This grant was approved, and the Consortium is now into its third five-year funding cycle.  We are in process of developing multiple new clinical trials for all forms of NF, including NF1, NF2, and schwannomatosis, and expect to be announcing the launch of the first trials very soon in the new year.

In summary, this has been a very busy year in the UAB NF Program, and next year promises to be at least as active.  I am grateful to our many supporters, and to the patients and families we serve for their confidence in our care.  I wish everyone a very restful and happy holiday season and look forward to reporting on our progress in the New Year! 

By: Bruce Korf Published Date: Nov 08 American Society of Human Genetics Meeting and Alabama NF Walk

Last month, several colleagues from UAB attended the American Society of Human Genetics meeting in Orlando (ASHG). The ASHG is the primary worldwide professional membership organization for human genetics with the mission of advancing genetics research by promoting the exchange of research findings at annual meetings, advocating for research support, and enhancing genetics education for current and future professionals in the field.  Several faculty members from the UAB NF research program gave poster presentations at the meeting, including NF Program Genetic Counselor Ashley Cannon, PhD, MS, CGC, and Associate Professor of Genetics Deeann Wallis-Schultz, PhD, as well as several other members of our research team. These presentations served as an opportunity to bring attention to our role as a national leader in advancing innovative NF research initiatives.

Our program was again pleased to support the 4^th Annual Alabama NF Walk, which occurred on November 5^th in Veteran’s Park in Hoover. Held in cities across the nation, the walk serves as a key fundraising event 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 walk raised over $30,000 and gathered individuals and families from Alabama as well as surrounding states. To learn more about the Alabama Walk visit: https://join.ctf.org/hoover/events/2017-alabama-nf-walk/e130144.

Muscle Involvement in NF1  

An area of interest that we haven’t discussed previously is whether there is a direct involvement of muscle in NF1.  The primary manifestation of NF1 involves nerves affected by the growth of tumors. Because nerves control muscles, one might expect some muscle weakness due to impairment of a nerve by neurofibroma growth.  For example, a plexiform neurofibroma located on a spinal nerve could result in weakness of muscle innervated by that nerve.

There is, however, evidence now that there can be muscle involvement that is not related to a nerve sheath tumor.  Many children with NF1 exhibit low muscle tone, which usually becomes apparent between the ages of 2 and 5. Low muscle tone results in muscles that feel looser or more lax than normal, although muscle strength is typically within normal limits. Some children with low muscle tone tire more easily as a result of the condition. Also, the bellies of some children may protrude and give the appearance of a potbelly. This protrusion is due to abdominal and spinal muscles that are laxer than normal, not as a result of being overweight in most cases.  Low muscle tone should not affect one side more than the other, and the problem usually gradually improves by adolescence. However, these individuals retain relatively poor coordination compared to their peers.

For a long time it was assumed that low muscle tone in children with NF1 could be due to a central nervous system problem related to neurological pathways to the muscles. In recent years, increased attention to this issue has resulted in studies of muscles in individuals with NF1, which have shown some abnormalities of the function of muscle cells themselves. These findings suggest that something may be occurring in muscle cells, although it is not known in what ways the NF1 gene is affecting the muscle.

Parents of children affected by low muscle tone often ask if anything can be done to improve the condition. Physical therapy is often the recommended approach for improving the muscle tone and strength. It is a safe and useful way to define the current level of muscle function and provide opportunities to gain strength and improve overall coordination when a child is young. There are ongoing studies focused on developing more specific treatments for low muscle tone. While these are promising for the future, physical therapy is the only current option for improvement of motor function, though in many children this improves only very gradually over a period of years.

By: Bruce Korf Published Date: Oct 10 This month, I’d like to address an issue that often arises in the minds of parents whose children have been newly diagnosed with NF1. These parents often ask when they should be concerned about an issue or symptom that they notice in their child. I don’t think parents should assume the task of being their child’s doctor and become hypervigilant about every potential issue. Instead, parents have the important role and responsibility of nurturing and caring for their child. However, it’s natural for parents to experience anxiety about possible complications of NF1, and we do want parents to be alert to any potentially serious complication that may develop. The key is in separating everyday aches and pains from important symptoms, and the central question becomes:  What are the complications that, if detected early, would allow for better outcomes for children with NF1?

Optic Glioma

A tumor of the optic pathway, or optic glioma, occurs in approximately 15% of children with NF1. These tumors usually occur early in life, between the ages of 18 to 24 months. While more than half of children with optic glioma have no symptoms, some children experience vision loss, usually between the ages of 2 to 6 years. Because very young children don’t complain of vision loss, the early presentation of these problems can be subtle. Some signs of possible visual impairment include: tripping over objects or having difficultly navigating physical obstacles; becoming fearful of walking down stairs; and holding objects closer than normal or sitting closer to a screen, such as a television or computer. While we recommend yearly eye exams for children with NF1, parents who recognize these possible signs of vision loss should make an appointment for an evaluation with an NF specialist or pediatric ophthalmologist.

Physical Growth

A physical feature that is common for children with NF1 is that head size tends to be larger than average. However, a sign of concern would be if the size of the head crossed percentile lines as it grew or became noticeably larger in a relatively short period of time. Also, vomiting and lethargy could be a sign of obstructive hydrocephalus, a condition of increased brain fluid pressure that is rare, but more common in people with NF1 and usually occurs in childhood or young adulthood.

Also regarding physical growth, some degree of short stature is common among children with NF1. Slow weight gain is also common, although falling off the growth curve or crossing percentile lines are a cause for concern that requires further evaluation. In some cases, a brain stem tumor or optic glioma can affect the functioning of the hypothalamus where appetite is controlled, resulting in weight loss.

Plexiform Neurofibromas

These tumors, which occur deep in the body and involve large branches of multiple nerves, are usually noticed in the first year of life. They appear as a painless soft tissue swelling of the arm, leg, or around one or both eyes or on the face. Plexiform neurofibromas are believed to be congenital in most cases, although they are not easy to see at birth. Swelling of the upper eyelid in the early years of life could be a sign of a plexiform neurofibroma around the eye, which can grow rapidly in childhood and cause significant disfigurement and interference with vision.  Enlargement of an arm or leg can also be an early sign of plexiform neurofibroma.   

Bone Dysplasia

This problem is an abnormality of a long bone, usually involving the tibia in the leg but also sometimes affecting the fibula as well as bones in the arms. Bone dysplasia sometimes presents as bowing of a leg in infancy, although this can be difficult to detect early because most infants have some normal leg bowing. By the time a child can stand, one can usually determine if dysplasia is present. An X-ray is performed to confirm the problem, and the child is referred to an orthopedist for treatment with a leg brace to prevent fracture. If a fracture does occur, it can be difficult to treat, which makes early detection of this problem important.

Developmental and Cognitive Issues

Some children with NF1 exhibit low muscle tone, which results in muscles that are less firm and seem weaker than normal.   This problem tends to improve over time, but it may evolve into some degree of poor coordination in adolescence and adulthood. Also, learning problems are present in approximately 50% of children with NF1, although this issue may not become apparent until the child has reached school age.  Children with NF1 may exhibit problems in maintaining attention, hyperactive behavior, and social immaturity.  In some, speech articulation may be affected.  Sudden onset developmental delay is not common in children with NF1.  If a child is failing to reach developmental milestones or displays signs of learning or cognitive problems, this is a cause for concern and further evaluation. 

Headache

I have mentioned the occurrence of headaches in children with NF1 in previous blogs.  Most typically these occur intermittently and may be associated with nausea, stomach aches, and vomiting.  These signs are suggestive of migraine, which seems to be more common in children with NF1 than in the general population.  Another cause of headaches in children with NF1 is Chiari malformation, in which the base of the brain extends below the foramen magnum, which is the space in the skull where the spinal cord connects to the brainstem.  This is also more common in children with NF1 than in the general population.  Many parents of children with NF1 and headaches worry that the headaches could be a sign of brain tumor.  For a brain tumor to cause headaches it requires that the tumor cause increased fluid pressure in the brain.  If this does happen, the headaches are usually severe, may wake the child from sleep, and are associated with severe vomiting.  A careful physical exam would reveal increased pressure on the optic nerve visible in an eye exam, and would be followed up with an MRI scan.  Fortunately, I find that this is an uncommon cause of headaches in children with NF1.

By: Bruce Korf Published Date: Sep 11 In news related to the UAB NF Program, I’d like to mention that that Department of Defense NF Research Program has issued a request for grant applications (RFAs) from investigators to support innovative, high-impact NF research.  Several of our faculty members have submitted proposals, and more updates will follow as the process moves forward.

Pain Related to NF1

In this month’s post, I think it would be helpful to discuss the issue of pain in the context of NF, other than headaches, which have been covered previously. Individuals with neurofibromatosis type 1, the most common form of NF, can sometimes experience pain related to the presence of neurofibromas, benign tumors that can grow on nerves throughout the body.  While neurofibromas are not typically painful, some people have pain associated with these tumors that may take a variety of forms. Cutaneous neurofibromas, which appear on the surface of the skin, can sometimes result in pain due to an event that causes pressure on the tumor, such as hair brushing.  These tumors can also become infected, which can be painful.  Subcutaneous neurofibromas, occurring under the skin, can be nodular and are usually pea-sized to marble-sized. Though not typically painful most of the time, they can be tender to the touch or pressure such as hair brushing or lying down. Subcutaneous neurofibromas on the scalp can also serve as trigger points for headaches by internally pressing on nerves and surrounding structures, causing pain.

Plexiform neurofibromas occur deep inside the body and are usually not painful unless causing pressure on internal structures. There are instances in which they can press on nerve roots, resulting in significant pain. Some individuals with NF1 develop a condition call dural ecstasia in which there is a ballooning of the membranes surrounding the spinal cord that can put pressure on surrounding nerves, resulting in pain in the lower back or legs.   This can be a very difficult condition to treat surgically, and may result in chronic pain.

Some adults with NF1 may also experience exquisite pain with pressure applied at the tips of fingers and toes due to the presence of glomus tumors that occur under the nail beds. Fortunately, this pain can be eliminated by removing these tumors surgically; however, many adults don’t associate this pain with NF and therefore don’t seek treatment. It’s important for patients and clinicians to be alert to this type of pain so that surgery can be performed if needed.

Malignant peripheral nerve sheath tumors, which occur in 10% of people with NF1, cause a nagging, unremitting pain that becomes worse over time. It’s important to recognize this type of pain so that an imaging study, such as an MRI and PET scan, can be performed to identify the tumor and recognize its malignant potential.  For this reason, people with NF should be alert to any unexplained and persistent pain.

Pain Related to NF2 and Schwannomatosis

Chronic pain can occur in individuals with neurofibromatosis type 2 due to nerve root compression by one of the two types of tumors associated with the condition, meningiomas and schwannomas.

People with schwannomatosis, the third distinct type of NF, usually experience excruciating pain, which is a hallmark of the condition. Surgical removal of schwannomas usually relieves pain, although surgery is not always feasible due to the location of the tumors. Interestingly, the pain tends to be out of proportion with the number and size of tumors. Small tumors can be surprisingly painful, which may indicate there is something inherent in the tumor that causes pain.

Pain Management and Signs to Seek Treatment

In mild instances of NF-related pain, over-the-counter medications, such as Ibuprofen, are usually indicated and can be effective. Pain due to nerve compression or dysfunction sometimes responds to the medicine gabapentin or other similar medications.  Also, pain management programs can be helpful in dealing with chronic pain for which there is not a treatment option available. These programs have extensive experience in helping patients achieve symptom relief while avoiding addictive drugs when possible.

In conclusion, it’s important for individuals with NF to understand the signs of when to seek treatment for pain, including: chronic or nagging pain that gets worse over time; neurofibromas that become noticeably larger; pain with pressure applied to the tips of fingers and toes; and localized pain, which may be an indication of nerve root compression.