By: Bruce Korf Published Date: Aug 28

Before continuing our discussion from last month regarding a review of the pediatric NF clinical care guidelines, I’d like to mention that our annual UAB NF Symposium Family Day was held on Saturday, August 24, in the Bradley Lecture Center of the Children’s Harbor Building. Co-sponsored by the UAB Department of Genetics and the Children’s Tumor Foundation (CTF), this half-day, free event provides NF families and patients an opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. Also, the event offers a venue for families to establish a connection with others who are sharing the same journey, which can be especially meaningful for those who are newly diagnosed. The event was a great success, with more than 100 people registered.

Malignancies Related to NF1

In addition to optic gliomas, discussed in last month’s blog, the pediatric NF clinical care guidelines provide a review of the most commonly occurring malignancies in children with NF1; these include malignant peripheral nerve sheath tumors (MPNSTs), pheochromocytomas, and leukemia. MPNSTs represent one of the few life-threatening complications of the condition. These tumors are uncommon in children and occur mostly in teens and young adults, with the lifetime risk between 8% and 13% for those with NF1. Malignant peripheral nerve sheath tumors usually arise from pre-existing plexiform or nodular neurofibromas. Because MPNSTs can be difficult to treat, the focus is on early diagnosis. The clinical care guidelines indicate a possible diagnosis based on any one of the following: persistent unexplained pain, particularly if it progresses in intensity or wakes one from sleep; rapid growth of a tumor; and a change in a tumor from soft to hard.

If a malignancy is suspected based on clinical presentation, an MRI is usually performed. While MRI will not diagnose a malignancy, it can indicate unusually solid areas of a tumor where cells have deteriorated that are characteristic of a malignancy. Based on these results, a positron emission tomography (PET) scan with radiographic computed tomography (PET-CT) or magnetic resonance imaging (PET-MRI) may be performed to determine the tumor’s uptake of radioactive tracer material. Malignant tumors take up more of the radioactive material on the scan, indicating a possible malignancy, though a biopsy needs to be performed for pathological confirmation. Treatment of MPNSTs usually involves surgery, sometimes with accompanying radiation therapy.  Chemotherapy may be used, though if the tumor has spread this is often unsuccessful.

The guidelines also mention other, less commonly occurring pediatric malignancies in NF1, including astrocytomas, a type of malignant brain tumor; rhabdomyosarcoma, a malignant tumor that originates in the soft tissues of the body; pheochromocytoma, a tumor of the adrenal gland; and juvenile myelomonocytic leukemia, a rare type of blood cancer that occurs in young children.

Although pheochromocytoma affects fewer than 5% of people with NF1 and usually occurs in young adults, it’s an important tumor to recognize. A pheochromocytoma causes the irregular and excessive release of the hormones epinephrine and norepinephrine, resulting in symptoms of high blood pressure, rapid heart rate and palpitations, episodes of flushing, and excessive sweating. When these symptoms are present, a blood test is performed to assess the amounts of metabolic byproducts of epinephrine and norepinephrine present in the blood. A positive result requires a confirmatory 24-hour urine collection for measurement of the same substances. If laboratory results indicate a possible tumor, abdominal imaging is performed and other studies, including use of a radioactive tracer. Treatment is surgical and requires careful planning by an experienced surgical team.

>The clinical guidelines also note that breast cancer occurs more frequently in women with NF1 than in the general population, which should be kept in mind as females with NF1 progress into young adulthood. This risk, along with surveillance guidelines, has been discussed in a previous blog about the adult management guidelines.

Neurologic Issues

Migraine headaches are more common in people with NF1 than in the general population. In addition to the primary symptom of headache, migraines may also present with stomachache and nausea in children. The guidelines indicate that clinical judgement should be used in determining whether MRI is needed to determine other causes for headache. Indications for MRI could include: symptoms of increased intracranial pressure; a new neurologic deficit; or a new onset of seizures. Migraine in children with NF1 can usually be managed in the same way as similar headaches in the general population and may include lifestyle modification, the use of non-prescription medication and, in some cases, treatment with prescription medications.

The guidelines also mention that seizures are more common in people with NF1 than in the general population. This may be due, in part, to structural or vascular changes in the brains of people with NF1, and rarely indicate the presence of a tumor. The guidelines recommend brain MRI at the initial onset of seizure in those with NF1 and management by a physician who is experienced in the treatment of seizures.

By: Bruce Korf Published Date: Jun 28

It has been several months since Dr. Lane Rutledge, who was our colleague in the UAB NF Clinic, passed away unexpectedly, and her absence has been felt by those of us in the NF Clinic as well as by her patients. While patients with urgent issues are seen in the clinic right away, others may sometimes wait longer for an appointment than we would like. We’re currently working to expand NF Clinic capacity by integrating pediatric and adult neuro-oncology into the clinic to assist in following NF patients who have brain tumors, optic gliomas, and complex plexiform neurofibromas.  Fortunately, as more treatments have become available, particularly for plexiform neurofibromas, our NF Clinic is in a position to enroll many patients in clinical trials for certain treatments. Patients are sometimes surprised at the therapeutic options we now have at our disposal, and we’re pleased to be able to offer these new and promising clinical trials.

Pediatric Clinical Care Guidelines for Optic Pathway Gliomas

Continuing our review of the newly published pediatric NF clinical care resource, the next issue to cover is the optic pathway glioma, which is a tumor that occurs in 15% of children with NF1 and usually presents before six years of age.  Optic gliomas can involve one or both optic nerves or the optic chiasm, the area where optic nerves meet in front of the brain.  Although optic glioma is the most common central nervous system-associated tumor in children with NF1, most optic gliomas are non-progressive and do not require treatment. The guidelines emphasize the consensus recommendation of annual eye exams with a pediatric ophthalmologist for children with NF1 beginning at the time of diagnosis, and these exams should be performed more frequently or repeated if there is a concern.

Because a small percentage of optic pathway gliomas can lead to vision loss or precocious puberty, there has been significant discussion among NF clinicians about whether early detection is beneficial. The practice guidelines at this point recognize that there is controversy about neuroimaging as a baseline screening test for optic gliomas. Baseline neuroimaging is viewed as optional unless symptoms are present. The practice guidelines provide a useful table regarding indications for neuroimaging in children with NF1, including the following:

• Focal sensory or motor symptoms confined to one area of the body;
• New onset of seizures in the brain, although these are not common in NF;
• Headaches; these are common in NF but if especially severe may be an indication for neuroimaging;
• Signs of increased intracranial pressure, such as severe headache, lethargy, and vomiting.
• Stroke-like symptoms, including vision problems, numbness, and tingling. These symptoms could indicate a vascular event, such as a transient ischemic attack.
• Declining visual acuity. Because children typically don’t report this problem, it would be suspected based on increased clumsiness, tripping, or difficulty with hand/eye coordination.
• Precocious puberty, which includes breast development and the onset of menses in girls and the development of pubic, underarm, or facial hair in boys as well as accelerated growth in girls and boys. This condition could indicate the presence of an optic pathway glioma with contiguous involvement of the hypothalamus.
• Head and neck plexiform neurofibromas increasing in size or the development of new pain;
• Decline in cognitive function over time;
• Significant difference in arm or leg length.

The guidelines also discuss characteristic MRI findings that can occur in children with NF1, including T2 hyperintensities. Also known as “unidentified bright objects,” these benign lesions are visible on MRI predominantly in the basal ganglia, brainstem, and cerebellum. They typically appear in young children between the ages of two and 10 years of age and eventually regress and disappear. If the lesions enhance with contrast on MRI, this could indicate the presence of a low-grade glioma, though these also can be very slowly progressive or may not progress at all. The practice guidelines recommend clinical monitoring for symptoms such as headache, hydrocephalus, or cranial nerve dysfunction in the setting of glioma found by MRI.

By: Bruce Korf Published Date: May 28

In the next few blog posts, I’d like to review the newly released pediatric NF guidelines that were published in the journal Pediatrics (Vol.143, Issue 5) as a joint venture between the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG). These guidelines serve as an update to previous AAP guidelines regarding health supervision for pediatric patients with NF1, with additional input from the ACMG.

These are consensus guidelines developed by a group of clinical experts, of which I was a part, who provided their opinions based on clinical experience as well as a review of evidence from the literature. While evidence-based guidelines are developed through a formal review of published, peer-reviewed clinical research, consensus-based guidelines summarize current knowledge of clinical care and propose an approach to diagnosis and management.

Diagnosis and Differential Diagnosis

The first component of the new guidelines is diagnosis and differential diagnosis of NF1 in pediatric patients. It’s important to point out that this was not an effort to revise the diagnostic criteria, which were established in 1987 by the NIH consensus of experts, although there is currently an effort underway under the aegis of the Children’s Tumor Foundation to review these criteria.

The first feature usually seen in children with NF1 is multiple café-au-lait spots. These usually have relatively sharp borders that are clear and distinct from surrounding skin and are sometimes referred to as “typical” café-au-lait spots. It is possible for some children with NF1 to have some café- au-lait spots that are “atypical” in appearance, which means they may be highly variable in shape, size, degree of pigmentation, and distinctness of the margins. However, if all of the spots are atypical in appearance, this is less likely to be associated with NF1.

The guidelines also mention a differential diagnosis of other conditions with café-au-lait spots that can appear similar to NF1, including Legius syndrome, which is a benign condition that does not cause the development of tumors and is much rarer than NF1.  Legius syndrome should be considered in any child (or adult for that matter) who has café-au-lait spots and skin fold freckles but no other signs of NF1.  The guidelines also mention that some fair-skinned people can have up to six café-au-lait spots, although these individuals don’t seem to have any underlying medical condition.

Two additional conditions are discussed in the guidelines that can sometimes be associated with NF1. The first is juvenile xanthogranuloma, which occurs more in children with NF1 than in the general population. These small, yellowish bumps are seen in a some children with NF1 in the early years of life, after which time they gradually regress.  They can be anywhere on the body, but seem especially common around the hairline.   Because these bumps are benign, there is no need to monitor them. Although there was a previous suggestion in the clinical literature about an association with leukemia, there is not good evidence to support this in children with NF1. I tend to be reassuring with parents whose children develop juvenile xanthogranulomas that these are benign.

The second condition that can be associated with NF1 is nevus anemicus, which appears as a flat, sharply marginated area of reduced skin pigmentation. These areas are benign, but because they may be more frequent in people with NF1, their presence may be useful as a diagnostic tool.

The Role of Genetic Testing

The guidelines emphasize that genetic testing can be useful in the following circumstances: to confirm a diagnosis in a young child; to distinguish NF1 from Legius Syndrome; and to diagnose individuals who present with unusual features. The guidelines emphasize that genetic testing will not generally predict future complications of NF, as only a few genotype-phenotype correlations have been established for some specific mutations. Approximately 95% of individuals who fulfill the diagnostic criteria for NF1 will test positive, although some people who have mosaicism may not test positive. Mosaicism is caused by a genetic mutation of the NF1 gene that arises after conception and during early embryonic development. As a result, some cells in the body have the NF1 mutation while other cells do not. This can lead to having signs of NF1 confined to a restricted area of the body, though in some instances it just causes milder generalized NF.

Neurofibromas

The guidelines discuss various types of neurofibromas and some of the associated symptoms. These include isolated neurofibromas on or under the skin, as well as plexiform neurofibromas. Itching can occur in some people with NF1, although this is more common in adults and typically happens when neurofibromas are forming. In addition, the guidelines emphasize that non-plexiform cutaneous neurofibromas are not believed to pose a risk for malignant transformation. Plexiform neurofibromas, which occur in 50% of NF1 cases, are believed to be congenital, i.e., present from birth. They tend to grow most rapidly in children, though growth can occur any time. One should always be alert to symptoms such as pain, rapid growth, or nerve compression, as these could be signs of malignant changes and indicate the need for evaluation.

NF Awareness Month

May was NF Awareness Month. Here is a link to a few pictures taken around the UAB campus showing related activities.

By: Bruce Korf Published Date: May 06

Because the occurrence of tumors is one of the hallmarks of all forms of NF, imaging studies, such as CT or MRI scans, serve a central role in the clinical diagnosis and management of the disease. This month, I’d like to focus our discussion on the primary clinical approaches regarding the use of imaging in the diagnosis and management of NF. Within the NF clinical community, there are essentially two different perspectives on the use of imaging. The first approach advocates proactive screening to identify the presence of tumors. While many of these tumors may be small at the time, the idea is that early identification of the tumors may allow for more effective treatment. The second approach recommends the use of imaging only when specific clinical indications are present. I have tended to adhere to the latter approach of performing imaging to address specific clinical problems or concerns.

Clinical Approach to Imaging

Although lesions can be identified at an early point in some people, the problem is that most are untreatable at that point in time. Moreover, in some cases, identifying these tumors at an early stage may open the possibility of instituting potentially harmful treatments, including surgery. Finding these tumors can also cause anxiety and worry in many patients and families. For these reasons, we in the UAB NF Clinic advocate a clinical approach to imaging based on the presence of specific signs, symptoms, or problems.

A common goal of imaging in NF is to identify tumors in the nervous system, especially, in children, the presence of an optic glioma, which is a tumor of the optic pathway that occurs in 15% of children with NF1. While this condition can cause problems such as loss of vision or hormonal imbalances, it is known that the majority of optic gliomas are non-progressive and do not require treatment. An important question for clinicians is how to identify those patients with optic gliomas who need treatment. We have tended to use the clinical measures to identify children at risk for optic glioma, including routine yearly eye exams with a pediatric ophthalmologist. If a concern arises based on the ophthalmologic exam, a brain MRI scan would be performed. We would plan to re-evaluate this approach in the future when treatments have advanced to the point that early scanning for the identification of optic glioma tumors is beneficial. For example, if scanning children at a certain age could identify optic gliomas for a specific treatment protocol, preventive scanning could be justified. However, at this time, the information gained from preventive scanning for optic gliomas does not offset the risks, such as the fact that sedation is required for imaging in children and there is no definite clinical benefit to identifying these tumors in the absence of clinical symptoms.

The use of whole body MRI is beginning to emerge as a screening tool for the identification of tumors in people with NF. This approach can identify tumors, but the detail of imaging is usually less than would be obtained from a focused study. As with brain imaging, the question is what would we do with the information if we found a tumor that currently can’t be treated? As treatment options mature, we may reach a point where identifying tumors early on is beneficial to institute therapy. For the moment, however, routine imaging produces a fair amount of information that is not actionable as well as the risk of anxiety in patients and their families. For these reasons, we continue to take a clinical approach to imaging that involves performing imaging studies when clinically indicated, though not as a broad screening test.

A few months ago, I reviewed a publication of clinical guidelines for adults with NF1. Recently, a parallel set of guidelines for children with NF1 was published. I will review these guidelines as well, beginning with next month’s blog.

By: Bruce Korf Published Date: Mar 20

Questions From Individuals Outside the NF Clinic

In this month’s post, I’d like to explain a new method I’ve established for responding to the many emails I receive from individuals from all over the world with medical questions about their children whom I have not seen clinically.  Most of these email questions are from parents who are concerned that skin pigmentation on their children might be café-au-lait spots that can be indicative of NF. These emails are often accompanied by photos of the skin spots, which very often are not of high enough quality to clearly see the spots. In the past, I have tried to answer these emails in a general way as best as possible, although an email exchange allows for only limited information to be shared. 

I certainly understand that parents often experience anxiety related to these questions and that many people live in areas where a clinician with experience in NF is not available. Also, there often are long wait times to get into a specialty clinic.  While I empathize with these parents’ concerns and need for guidance, it isn’t possible for me to provide medical advice to someone whom I have not seen clinically. When I perform a clinical evaluation of a child with café-au-lait spots, I include a comprehensive physical exam as well as a medical and family history.  As such, my clinical impressions are based on much more information than can be provided in an email exchange.

As a way to provide concerned parents with general information that might be helpful, I’ve written a brief statement about NF and café-au-lait spots that I will now forward to individuals who send me email questions about skin pigmentation and other NF-related concerns. Although I’m unable to reply to these questions with specific information, I’m hoping that the statement I’ve prepared will provide helpful information and initial guidance. If I receive frequently asked questions that aren’t addressed in the statement, I can always include additional information in the statement as well as provide these updates in a future NF blog. 

Questions from Physicians and NF Clinic Patients

Because we have an established and well-known NF Clinic, I often also receive email questions from physicians regarding their patients, which I do my best to answer. In this situation, I’m not providing medical advice, and the contacting physician is taking responsibility for providing care to the patient. In these situations, we also often review imaging or other test results submitted by physicians seeking guidance for their patients.

For patients with whom we already have an established clinical relationship, we’re glad to answer questions. Because email is not the preferred communication method due to privacy and security concerns, we encourage our patients to either call the NF Clinic or use the UAB Patient Portal, which we check regularly. The patient portal is a secure and efficient way for patients to ask questions or request and appointment, and we encourage all of our patients to register for the portal as a way to enhance and facilitate communication with the NF Clinic.  Any who need help in registering can call the clinic for assistance.

By: Bruce Korf Published Date: Feb 14

As I discussed in last month’s blog, the UAB NF Clinic staff is making the necessary adjustments to accommodate all patients after Dr. Lane Rutledge’s unexpected passing at the beginning of the year.  Our nurse practitioner, Ms. Tammi Skelton, who works with me in the NF Clinic and had also worked with Dr. Rutledge in clinic, is assisting Dr. Rutledge’s former patients with immediate needs in scheduling appointments with me as needed. Also, we have plans to open an extra clinic session once a week with the help of pediatric neuro-oncologist Katie Metrock, M.D. With all of us working together, we can continue providing the same high level of care to all of Dr. Rutledge’s former patients in the NF Clinic. We are also working with the adult neuro-oncology service to integrate experts in this area into the care of adults with NF.

Differences in Schwannomas and Neurofibromas

Because we frequently receive questions about the difference between neurofibromas and schwannomas, I’d like to explain the distinctions between these types of tumors.  Both neurofibromas and schwannomas are tumors of the peripheral nerve sheath, and the primary tumor cell in both is the Schwann cell.  There is, however, a difference in how the cells that comprise schwannomas and neurofibromas behave.  In schwannomas, the Schwann cells grow as a mass that pushes the nerve aside and may compress the nerve.  Also, the majority of cells in the schwannoma are Schwann cells.  In contrast, neurofibromas include a variety of cell types, including Schwann cells, but also others, such as specific types of blood cells, connective tissue cells, and other cells from the nerve sheath.  Neurofibromas usually consist of a loose mixture of these various cell types surrounding the nerve, but not displacing it.  They can compress the nerve, particularly if there is a nearby rigid structure, such as a bone.  These distinctions are mainly visible to the pathologist, who would examine a sample of a tumor through the microscope. 

Neurofibromas can sometimes be distinguished from schwannomas by their imaging characteristics, but this distinction is more difficult and sometimes not possible to do definitively.  Because of this, some people have been told that they have either neurofibromas or schwannomas based on imaging, but in fact the tumor has been mis-identified.  The distinction is important, however, in terms of both underlying diagnosis and treatment.  Neurofibromas are characteristic of NF1, whereas schwannomas are typically seen in NF2 and schwannomatosis.  There is some scientific debate as to whether neurofibromas are ever seen in NF2 or schwannomas in NF1.  Whatever the answer, it is a good rule of thumb that neurofibromas go with NF1 and schwannomas with NF2.  Usually, if a person with NF1 is told he or she has a schwannoma, or a person with NF2 is told he or she has a neurofibroma, it will turn out that the terminology of the two tumors was used incorrectly.  We have also heard from some people that they were told that they have both NF1 and NF2.  Although theoretically possible based on having two independent genetic mutations, this would be extraordinarily rare; an error in diagnosis is much more common.

It should be remembered, however, that it is possible for a person with NF1 to develop a vestibular schwannoma that is also a hallmark feature of NF2, on one or both hearing nerves.  Vestibular schwannomas are relatively common in the general population, and individuals with NF1 can coincidentally develop vestibular schwannomas without having NF2.  Vestibular schwannomas in the general population usually occur later in life than they do in NF2, so the sporadic vestibular tumors in rare individuals with NF1 usually happen later in life as well.

The distinction between NF1, NF2, and schwannomatosis is important to establish for clinical follow-up.  The surveillance and treatment guidelines are quite different for the three conditions.  That is why, when we see a new patient, we try to review a comprehensive picture, including medical history, review of any pathology and genetic testing, physical exam, and family history.  This facilitates correct diagnosis and provides guidance for further management.

By: Bruce Korf Published Date: Jan 25

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.

By: Bruce Korf Published Date: Dec 04

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.

By: Bruce Korf Published Date: Nov 02 Highlights of Australia Visit

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.

By: Bruce Korf Published Date: Sep 10

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.