Director's Blog
Multi-Year Research Grants Awarded to UAB Investigators Pursuing Genome-Guided Therapeutics
As many of you are by now aware, I need to start the New Year with the sad news that Dr. Lane Rutledge, who has taken care of NF patients and their families for decades, passed away suddenly just as the New Year was dawning. Dr. Rutledge was beloved by patients, family members, health providers, and staff, not to mention her family and the larger community. This was very evident at her memorial service, in which a large church was filled to capacity. It has also been evident in communications I have had from colleagues around the country. My sincere condolences go out to her family and close friends. I would also like to reassure her patients that we have been working so that clinical care will proceed seamlessly. I am taking care of immediate clinical needs, such as follow-up of imaging studies or urgent clinical problems. I am doing this together with Ms. Tammi Skelton, a nurse practitioner who works with me in NF Clinic and also had worked with Dr. Rutledge in clinic, so she knows many of Dr. Rutledge’s former patients. We are also expanding our NF Clinic capacity, working with Dr. Katie Metrock of pediatric oncology, who will follow children with NF who have brain tumors, optic gliomas, and complex plexiform neurofibromas. We cannot replace Dr. Rutledge but can honor her legacy by continuing to provide the highest quality of care possible for individuals with NF.
On a happier note, I’m pleased to share the recently announced news that several UAB investigators have received significant grants for NF-related preclinical research focused on restoring function to the mutated NF1 gene or its protein product. The multi-year research grants were awarded by the Gilbert Family Foundation, a private foundation established by Jennifer and Dan Gilbert of Detroit, MI, for the purpose of developing effective therapies that address the underlying genetic abnormalities in NF1. The foundation’s recent genomic therapy initiative awarded $12 million in multi-year research grants to several multi-disciplinary research teams identified through a rigorous, peer-reviewed process. UAB was awarded grants for four separate projects, which represents the largest number of grants awarded to any single institution. Other institutions with research teams receiving grants from the genome therapy initiative include: Duke University; Paris Descartes University; the University of California at Berkley; the University of California at San Diego; the University of Massachusetts; and Yale University.
A Focus on the Development of Genome-Guided Therapies
The majority of therapeutic approaches for NF1 have focused on blocking the Ras/MAPK signaling pathway that is hyperactive in cells that have lost NF1 function due to gene mutation. The NF1 gene encodes for a protein called neurofibromin, which regulates the activity of the Ras/MAPK cellular signaling pathway that helps to control cell growth and division. The development of therapies that target Ras signaling has been an important approach in developing NF treatments, with the discovery of the effectiveness of MEK inhibitors such as selumetinib in reducing the size of plexiform neurofibromas being the most exciting advance. Not all plexiform neurofibromas respond to MEK inhibitors, however, and none of the tumors completely disappears on treatment. We therefore have been seeking additional therapies, and the primary focus of the UAB NF Research Program has been to explore methods of restoring function to the mutated NF1 gene or gene product. Our research team at UAB introduced this area of NF research, which has now gained increased attention and focus from the NF scientific community. The four UAB projects that have received funding from this initiative represent preclinical research efforts that will help to accelerate the development of therapies that could restore full or partial function to the mutated NF1 gene or gene protein.
- The first project focuses on the identification of drug compounds capable of reading through a type of truncating mutation called a premature stop, or nonsense mutation, which affects 20% of individuals with NF1. This type of mutation inserts a signal that tells the protein production machinery in the cell to stop production of neurofibromin before the complete protein is made, resulting in a truncated and nonfunctioning protein. Drug compounds have been identified that have shown promise in overcoming the effects of premature stop mutations. The concept for this type of research was first developed by David Bedwell, Ph.D., chair of the UAB Department of Biochemistry and Molecular Genetics, who will serve as the principal investigator for the project. The focus will be on identifying and testing drug compounds capable of reading through premature stop mutations in the NF1 gene, with the goal of allowing cells to produce a full-length, functional neurofibromin protein.
- The next project, conducted by UAB investigator Bob Kesterson, Ph.D., in conjunction with researchers at Yale University, will utilize the CRISPR/Cas9 gene editing system to perform gene editing in NF1 animal models with mutations found in human patients. Dr. Kesterson’s previous research has used the CRISPR/Cas9 system to introduce human NF mutations into animal model systems. As part of the current project, the CRISPR/Cas9 will be used to directly correct the mutations that cause NF1 in a model system for the purpose of generating preclinical data that could serve as the foundation for clinical trials of genomic therapeutics that utilize gene editing.
- The third project, conducted by UAB investigator Deeann Wallis, Ph.D., in conjunction with researchers from the Royal Holloway University of London, focuses on correcting NF mutations in model systems using a technique called exon skipping, which causes cells to skip over mutations in the genetic code while still producing a functional protein. A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. The purpose of this project is to identify exons within the NF1 gene mutation that can be skipped while still maintaining function of the gene, allowing these mutations to be bypassed.
- The fourth project, led by UAB investigator Andre Leier, Ph.D., in conjunction with researchers from the University of California, San Diego, uses ribozyme therapy in NF1 mouse models with patient-specific mutations. Ribozymes are molecules that can be used to edit messenger RNA, allowing investigators to remove one end of the messenger RNA containing the faulty gene in order to correct the mutation.
We are excited by the opportunity pursue these projects and grateful for the support of the Gilbert Family Foundation. I hope to have the opportunity to provide updates in the months and years to come on the progress of these and other research projects underway in the UAB NF Program.
A Re-Cap of the 2018 NF Conference in Paris
In early November, several colleagues from the UAB NF Program attended the 2018 NF Conference in Paris. The annual NF Conference is an international meeting of NF scientists and clinicians that is usually held in the U.S. and is organized by the Children’s Tumor Foundation. This year CTF partnered, for the first time, with colleagues in Europe to further promote international scientific collaboration. As a result, the meeting attracted a larger international audience and was possibly the largest NF research meeting in history. Estimated attendance was approximately 900, which is far larger than the usual NF Conference attendance. The large attendance in part reflects the growing recognition of the importance of NF to our understanding of fundamental biological processes, particularly the initiation and progression of cancer, as well as the maturity of the techniques that are now available to investigate NF.
Regional Highlights
The most prestigious national award presented annually by CTF is the Friedrich von Recklinghausen Award, named for the German physician who first described ‘von Recklinghausen’s disease,’ now known as neurofibromatosis type 1. We extend our most sincere congratulations to Director of the UAB Medical Genomics Laboratory Ludwine Messiaen, Ph.D., named the 2018 recipient of the Friedrich von Recklinghausen Award, presented to individuals in the professional neurofibromatosis community who have made significant and lifelong contributions to neurofibromatosis research or clinical care.
Dr. Messiaen’s recognition with this award can be attributed to the numerous contributions she has made to the field of NF research. She became the first scientist to establish a practical, reproducible, and valid mutation testing method for the routine molecular diagnosis of NF1. Under Dr. Messiaen’s direction, the UAB Medical Genomics Laboratory is viewed in the medical and scientific communities as the gold standard and world leader of genetic testing for all forms of NF and has identified upwards of 3,000 distinct pathogenic NF1 mutations. Using this vast catalogue of variants, Dr. Messiaen has published numerous studies of genotype/phenotype correlations, providing information about the expected course of NF1 with a specific type of NF1 mutation. This information is helpful for both clinicians and patients in gaining a better understanding of the symptoms that are likely to be most prominent with a specific type of NF1 mutation. While this is not possible for every mutation, for some it is possible.
In addition to these achievements, Dr. Messiaen discovered a new genetic cause of schwannomatosis, specifically mutations in a gene designated LZTR1. This discovery has opened the way toward diagnostic testing and new approaches to study the biology of schwannomatosis. Most importantly, the UAB Medical Genomics Laboratory under Dr. Messiaen’s leadership has maintained an unparalleled commitment to serving clinicians and patients, always going the extra mile to assist clinicians and provide whatever support and help is needed regarding the process of mutation testing and validation.
Scientific Perspective
Several reports were provided during the conference regarding various clinical trials. Physicians from the National Cancer Institute (NCI) reported the results of a clinical trial indicating that selumetinib has continued to show efficacy in reducing the size of plexiform neurofibromas. The NCI clinical trial, which included a larger group of patients than previously studied, indicated that selumetinib was effective in reducing the size of plexiform neurofibromas in approximately 70% of patients with NF1. A trial of another type of drug called cabozantinib is also showing success in reducing the size of plexiform neurofibromas, through a mechanism different from selumetinib. There is now evidence that various approaches to treatment are gaining traction in treating plexiform neurofibromas, which was not the case a short time ago.
After four days of meetings, there was an interesting closing session of the conference entitled “NF: Past, Present, and Future,” providing reflections on how NF research has grown over the years. I’ve been engaged in the field for 35 years now, and those of us who began our work more than three decades ago could never have imagined where it would take us. We have been privileged to experience a remarkable evolution in the field of NF research during that timespan, and the ground that has been covered in the field is staggering. It was encouraging to see many young investigators present at the meeting and to know that the opportunities they face are very different from when the field was in its infancy 35 or more years ago. The work these young investigators are doing gives us great hope that that the pace of discovery for new and promising NF treatments will continue to accelerate.
Highlights of Visit with Australian NF Team and Advice for Locating an Experienced NF Program
I recently returned from a visit to Melbourne, Australia, where I met with the NF team affiliated with the Royal Children’s Hospital and the Murdoch Children’s Research Institute. The NF Clinical Trials Consortium has benefitted from a long-term collaboration with the Australian NF team; during this trip, I met with the group of investigators who conducted the clinical trial evaluating the effectiveness of lovastatin in improving cognitive problems in people with NF1. Lovastatin is a widely-used cholesterol-lowering drug; in previous mouse studies, it was shown to improve learning in the mouse NF1 model, perhaps based on interference with Ras binding to the cell membrane. Based on the results of these studies, some parents of children with NF1 asked for prescriptions of lovastatin for their children. While lovastatin is a relatively safe medication, there are side effects to be considered when prescribing it, especially for children.
The clinical trial evaluating the effectiveness of lovastatin for learning problems in NF1, known as the STARS study, was conducted through the NF Clinical Trials Consortium. Serving as the lead investigators, the Australian research group had responsibility for study design, recruitment of many of the participants, and data evaluation. The STARS study showed that lovastatin was not an effective treatment for learning problems in NF1. This finding was important because it demonstrated that it’s not appropriate to expose a child with NF1 to the side effects of this medication if the goal is to improve cognitive function. During my visit, the research team also shared information about other exciting work in which they are engaged related to neurocognitive issues in NF1, as well as other areas.
Also during my visit, I was honored to speak at an event held by the Australian NF patient advocacy group, the Children’s Tumour Foundation. This organization is similar to the Children’s Tumor Foundation in the U.S., as it serves as a major source of patient advocacy for NF in adults and children in Australia. The event had robust attendance and featured numerous speakers from around the region. I was also grateful to have the opportunity to connect with Australian NF families to discuss their challenges and concerns, which are much the same as those faced by NF families in the U.S. and elsewhere in the world. My discussions with these families are a reminder that NF is an international condition that affects individuals and families in a similar way regardless of race, ethnicity, or socioeconomic status.
As I mentioned in the previous blog, the 2018 NF Conference will be held in Paris in November, which is the first time this international conference has been held outside the U.S. Our group from UAB will be well represented at the conference, with plans to provide several poster presentations and at least one platform presentation summarizing our drug discovery initiatives and progress in clinical trials. Our lab work is focused on restoring function to the mutated NF1 gene or gene product; we’ve recently obtained renewed funding to advance these projects to the next stage, and I’ll discuss these developments in a future blog.
Guidelines for Finding an Experienced NF Program
Following on the conversation I had with patients and families in Australia, a commonly asked question from individuals and families affected by NF is: How do I find an experienced NF program? Sometimes this is a challenging task, especially for people who don’t live near large cities or major academic centers. For those who do live near major academic medical centers, it’s important to know that most of these centers have practitioners who are experienced in managing NF, although they may or may not have a dedicated NF clinic.
An important resource for locating an experienced clinician or clinic is to check the “Find a Doctor” list of NF clinics that is maintained and regularly updated on the Children’s Tumor Foundation (CTF) web site (www.ctf.org/understanding-nf/find-a-doctor). To be placed on this list, clinics much submit initial information, as well as annual renewal information to remain on the list. As part of the renewal process, NF clinics are asked whether their program is engaged in clinical research, whether they see both adult and pediatric patients, and how care transitions from adult to pediatric patients are managed. Providing a continuum of care for pediatric and adult patients can be challenging if NF programs don’t have clinicians with experience in treating both children and adults. Other important questions in evaluating the quality of an NF program include:
- How many patients are seen in the clinic?
- Does the clinic provide access to a consistent group of clinicians?
- What is the capacity to coordinate care with other specialties?
- Is the NF program participating in clinical studies and publishing the results?
- Is the NF program participating in national and international NF conferences?
These measures are indicators of a program’s commitment to providing the highest level of NF care and also serve as the hallmark of a center of excellence for an NF clinic.
Upcoming NF Conference and a Final Review of the ACMG Clinical Practice Resource
In early November, several colleagues from the UAB NF Program will attend the 2018 NF Conference in Paris organized by the Children’s Tumor Foundation. Although the meeting is usually held in the U.S., CTF has partnered this year with the European NF Conference to further promote and encourage international scientific collaboration. Established in the 1980s, the annual NF Conference represents the largest meeting of NF scientists and clinicians and serves as the global forum for several hundred participants from diverse scientific and clinical backgrounds to encourage collaboration and advance research for all forms of NF. Our UAB group will present at least one platform presentation, as well as several poster presentations, summarizing our drug discovery initiatives and progress in clinical trials. We look forward to participating in this important scientific meeting and will review highlights of the event in a subsequent blog post.
Psychiatric and Neurocognitive Issues
In this last installment of our review of the ACMG practice resource, I’d like to first discuss some psychiatric and neurocognitive issues associated with NF in adults. It is well recognized that cognitive problems occur in at least 50% of children with NF, including learning disabilities and attention-deficit disorder (ADD). However, less attention is paid to cognitive problems in adults with NF, although many individuals have neurocognitive issues that persist beyond childhood. One of the most common psychiatric problems in adults with NF1 is depression, which is sometimes related to cosmetic disfigurement or chronic medical problems, but this probably is not the only explanation; it’s uncertain whether NF1 has a primary effect on brain function that increases the risk of depression. Because of the prevalence of depression in people with NF, it’s important to pay attention to signs of depression that might include: irritable mood; feelings of sadness or emptiness; overeating or loss of appetite; changes in sleep patterns; difficulty concentrating; persistent fatigue; feelings of guilt or helplessness; and suicidal thoughts. Neurocognitive problems such as learning disabilities and attention-deficit disorder (ADD), which are common in children with NF1, often persist into adulthood. More research is needed to determine how these problems affect adults with NF1, as most studies have focused on the pediatric population. Clinicians are advised to be aware of the potential for neurocognitive and psychiatric problems in adults with NF1.
Headache, Polyneuropathy, and Glomus Tumors
Another common problem in adults with NF1 is headache, which is often a component of migraine. These headaches, usually throbbing in character, seem to be more common in people with NF1 than in the general population. They can last several hours and cause extreme sensitivity to light and noise. While over-the-counter medications can be effective in treating occasional migraines, prescription medications are sometimes required to manage frequent migraine headaches. This includes not only medications to treat an ongoing headache, but also medications that can help to prevent them. Because the occurrence of headache in people with NF1 is underreported and underappreciated, clinicians should be vigilant in discussing headache frequency and treatment options with patients.
Another problem addressed in the ACMG practice resource is polyneuropathy, which is an impairment of multiple nerves that affects approximately 2% to 3% of people with NF1. This condition usually presents as numbness or tingling in the hands and feet. While it doesn’t usually cause pain, it can predispose an individual to injury due to the lack of feeling in the extremities. Also, some adults with NF1 may experience severe pain with pressure applied to the tips of fingers and toes due to the presence of glomus tumors that occur under the nail beds. Most people with this problem don’t associate the pain with NF and therefore don’t seek treatment. Fortunately, these tumors can be successfully removed surgically, eliminating the pain. Therefore, it is important for clinicians and patients to recognize this type of pain so that surgery can be performed if needed. Pain related to NF can occur anywhere in the body, often, but not always, due to a tumor. As we have discussed in the past, sometimes pain can be a sign of malignant change, so it is important to report persistent pain to a physician for further evaluation.
Pregnancy and Contraception
Women with NF often report a progression of cutaneous neurofibromas during pregnancy. This also occurs in both males and females during puberty, resulting in speculation about a possible hormonal link to the growth of neurofibromas. Because oral contraceptives contain a combination of progesterone and estrogen, many women with NF are concerned about whether it’s safe to take oral contraceptives. There is no clear evidence that oral contraceptives contribute to the growth of neurofibromas in women with NF, though the issue is difficult to study, especially given the various formulations in use. A woman with NF needs to balance the potential risks and benefits of oral contraceptive use, and should discuss the question with her physician. As to other risks of pregnancy, problems such as high blood pressure, pre-eclampsia and fluid balance problems may occur more often in women with NF, although these problems require further study. These risks warrant close monitoring during pregnancy by an obstetrician who is familiar with NF.
Another common pregnancy-related concern is whether epidurals administered prior to delivery are safe for women with NF. Although there are few studies related to the safety of epidurals in women with NF, the general feeling is that the procedure is not dangerous. While some people may be concerned about the presence of spinal neurofibromas, the ACMG group did not feel that it is necessary to perform imaging for spinal neurofibromas prior to the administration of anesthesia unless there are specific concerns about the presence of tumors (as from prior imaging or clinical signs).
Lastly, a couple in which one partner has NF1 needs to be aware of the 50% risk of transmission the NF1gene change to any offspring. This risk should be considered in family planning along with the fact that the wide variability of NF, even within families, means there is no way to predict the severity of NF in an individual. It is possible to do prenatal diagnosis of NF1, which first requires identifying the genetic mutation in the mother or father. The first method involves obtaining a fetal tissue sample through amniocentesis at 15-18 weeks of pregnancy to determine if the child has the genetic change. Another method involves chorionic villus sampling at 10-12 of pregnancy to identify the genetic change. A genetic counselor, who has specialized training in medical genetics and counseling, can provide information about specific tests available to couples regarding genetic risks and options to manage those risks.
A Review of ACMG Clinical Practice Resource Related to Hypertension and Vasculopathy, Osteoporosis, and Cutaneous Neurofibromas
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).
A Discussion of ACMG Clinical Practice Resource Related to Tumors Associated with NF1
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.
Highlights of the NF Forum and a Discussion of Newly Published Clinical Care Guidelines for NF1
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.
Highlights of NF Symposium and a Discussion of the Frequency of NF Clinic Visits
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.
A Focus on Improving Our Patients’ Experience and the Relationship Between Atypical Neurofibromas and Malignant Peripheral Nerve Sheath Tumors
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.
New Role as UAB Medicine’s Chief Genomics Officer, Upcoming NF Family Day, and Newly Identified Mutation/Phenotype Correlation in NF
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 7th, 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.