Director's Blog
The Role of Precision Medicine in NF Diagnosis and Treatment
With the start of a new year, I’d like to discuss the topic of precision medicine, which is reshaping traditional approaches to disease treatment and prevention and opening new possibilities for the treatment of NF. Precision medicine is also sometimes referred to as personalized or individualized medicine. Many clinicians, however, prefer to use the term precision medicine because the terms personalized or individualized medicine imply that previous medical approaches have not been personalized. Medicine has always been personalized in treating people as individuals, but we now have powerful new approaches that vastly increase our ability to make a difference in a person’s health.
Precision Medicine Tools
Precision medicine uses a variety of tools that help to identify the underlying mechanisms of disease and provide specific information about the most effective treatment. Traditional medical approaches develop strategies for a group or cohort of patients with a common clinical presentation, whereas precision medicine evaluates the impact of lifestyle, environment, and genetics on a person’s health. Precision medicine takes advantage of many advances in medical science, and especially of developments in imaging and in genomics. In the past, the diagnosis of tumors was based on inference from a clinical exam because imaging tools to detect a tumor were not available. Today, when clinical symptoms are present, advanced imaging such as CT or MRI can provide vivid and clear pictures of a tumor.
Genomics evaluates an individual’s genetic information through DNA sequencing of the genome. Genome sequencing can reveal the underlying causes of disease by identifying specific genetic alterations, or mutations. Understanding the genetic drivers of disease and tumors enables the development of more precisely targeted treatments that can minimize side effects and maximize benefits. For example, tumors are driven by an accumulation of genetic changes that drive the cancer cells to divide rapidly and spread throughout the body. Traditional cancer treatments, such as chemotherapy, kill all the rapidly dividing cells in the body, resulting in side effects such as nausea, vomiting, and hair loss. Also, the tumors eventually develop resistance to treatment by acquiring further genetic mutations. Genomic medicine-based treatment approaches more precisely target the underlying mechanism driving the growth of a tumor. Because this targeted approach only affects the tumor cells and not healthy cells in the body, side effects should be minimized. The hope is to develop treatments that target multiple mechanisms simultaneously so that tumors are unable to develop resistance in response to treatment.
An additional treatment challenge that can be addressed by precision medicine relates to individual patient responses to a particular medication. For a medication to be utilized effectively by the body, it must be absorbed, distributed, interact with its target, and then be metabolized and excreted. Each of these steps is controlled by an individual’s genetic make-up and can lead to a medicine not being metabolized quickly enough to achieve an optimal therapeutic effect, or accumulating so quickly as to cause side effects. Genomic medicine provides information that allows the choice and dosage of a medication to be customized to an individual’s genetic profile so that therapeutic benefits can be maximized and side effects minimized.
Precision Medicine in NF Treatment
The discovery of the NF gene in 1990 revealed the underlying mechanism of NF that involves the activity of the Ras/MAPK cellular signaling pathway. This pathway, which is hyperactive in individuals with NF, helps to control cell growth and division. Precision medicine treatments have focused on blocking the activity of this pathway with inhibitors of the components of the pathway. Using inhibitors to one of the components of the pathway called MEK, this approach has achieved success in shrinking plexiform neurofibromas. We are learning that the environment between tumor cells and surrounding cells is also important, and new drugs are in development to target this component of tumor growth. Advances in imaging have also enabled tumors to be detected earlier and targeted more effectively.
Another precision medicine-based approach is focused on restoring function to a mutated gene or gene product, or editing out the mutation entirely. An advantage of this approach to treatment of NF1 is that restoring function to the mutated gene might result in fewer side effects than drug treatments that block Ras signaling. Research on this approach is underway at UAB, though the challenges lie in targeting therapeutics to the right cells as well as precisely correcting the mutation or its effects on the protein. We are hopeful that progress our scientists make in this area will eventually result in new treatments, that, together with other approaches such as the use of MEK inhibitors, will significantly improve quality of life for those who deal with NF.
Highlights from the 2019 NF Conference and ASHG Meeting, Re-Cap of NF Walk, UAB NF Clinic News, and Final Installment of a Review of the Pediatric NF Clinical Care Resource
In late September, several colleagues from the UAB NF Program participated in the 2019 NF Conference in San Francisco organized by the Children’s Tumor Foundation. The meeting is the largest international gathering of NF scientists and clinicians and is an important forum for several hundred participants from diverse scientific and clinical backgrounds to share knowledge and encourage collaboration with a focus on improving outcomes for all forms of NF. Several investigators from the UAB NF research program gave poster presentations summarizing our dug discovery initiatives and progress in clinical trials, including Robert Kesterson, Ph.D., Deeann Wallis, Ph.D, and David Bedwell, Ph.D. I participated in a panel discussion about differences in the way clinical care for NF is provided internationally, including speakers who discussed the approaches to care in Asia, Europe, South America and the U.S. The discussion focused on examining the effectiveness and strengths of various approaches to care in these different regions of the world.
Also, several colleagues from our program attended the American Society of Human Genetics (ASHG) meeting in Houston in October. This annual meeting is the largest conference of human genetics in the world and provides a forum for presentation and discussion of the most current science in all areas of human genetics. UAB investigator Deeann Wallis, Ph.D., from our NF research program presented a poster regarding her work in correcting NF mutations in model systems using a technique called exon skipping, which causes cells to skip over mutations in the genetic code while potentially still producing a functional protein.
Our program was again pleased to support the 7th Annual Alabama Children’s Tumor Foundation NF Walk that was held at the Tuscaloosa Buddy Powell Pavilion on November 2nd. The walk is held in cities across the nation as a fundraising event for the Children’s Tumor Foundation (CTF). This year’s walk raised more than $22k and gathered individuals and families from Alabama as well as surrounding states.
In NF clinic news, we are working to incorporate neuro-oncology into the clinic for both pediatric and adult patients to further enhance our multidisciplinary approach to care. Neuro-oncologists are familiar with many of the new treatment options available for NF, and our patients will significantly benefit from this additional expertise within our clinic.
Vascular Issues
Completing our review of the pediatric NF clinical care resource, several cardiac and vascular problems associated with NF1 are discussed. Regarding cardiac abnormalities, approximately 2% of children with NF1 have a congenital heart defect. The most common is pulmonic stenosis, which is a narrowing of the artery from the heart to the lungs that can result in a heart murmur as well as problems with exercise tolerance. Other cardiac abnormalities can include atrial septal defect, a hole in the wall between the heart’s upper chambers, and hypertrophic cardiomyopathy, which is a condition in which the heart muscle becomes thickened and has difficulty pumping blood. It seems that a complete deletion of the NF1 gene increases the risk of these cardiac abnormalities, and individuals with the NF1 gene deletion should be screened for cardiac problems. Also, newborns with NF1 should be examined for signs of a congenital heart defect.
Beyond the heart, blood vessels can also be affected in individuals with NF1. A condition called renal artery stenosis, a narrowing of the artery that carries blood to the kidney, is an important cause of hypertension in children and young adults with NF1. 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 renal artery stenosis is found, it is treated with medication or stenting of the vessel to increase blood flow.
Arteries to the brain can also be affected in people with NF1. Moyamoya syndrome 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 of the cluster of blood vessels formed that compensate for the carotid artery blockage. Moyamoya occurs with increased frequency in children with NF1 and is especially common among children exposed to radiation therapy to the brain for treatment of a brain tumor. For this reason, we try to avoid use of radiation therapy for treatment of brain tumors in children with NF1 whenever possible.
It is possible for blood vessel occlusions to develop anywhere in the body in those with NF1. Sometimes the blood vessel walls can become weakened and hemorrhage, although this is rare in individuals with NF1 and, if it occurs, it is typically in adults. The guidelines are open-ended about screening for these problems, although imaging is indicated if symptoms are present.
Gastrointestinal Problems
Constipation in those with NF1 seems to be more common than in the general population and is commonly treated with dietary modification and the use of stool softeners. Also, abdominal pain, with or without vomiting, and accompanied by headache, can be an indication of abdominal migraine and is treated with medications for migraine.
Neurofibromas can develop in the walls of the intestine, causing bleeding and obstruction, although this is rare. Also, gastrointestinal stromal tumors (GIST) can cause bleeding and pain in patients with NF1. It’s important to be alert to GI bleeding and pain so that the appropriate diagnostic screening can be performed.
Lastly, the guidelines emphasize the importance of children with NF1 having a medical home with an NF physician who can follow them and make referrals to other specialists when needed. Because there are more NF clinics for children than adults in the U.S., transition of care can be difficult for pediatric patients once they reach the age of 18. The UAB NF Clinic is a combined pediatric and adult clinic, which provides continuity of care for pediatric patients as they grow up.
Upcoming NF Conference and a Review of the Pediatric NF Clinical Care Resource for Neurodevelopmental Problems and Skeletal Abnormalities
I am writing this as I am on my way to the 2019 NF Conference in San Francisco organized by the Children’s Tumor Foundation. 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 have a strong presence at the conference again this year; I will present a talk on genome-guided therapeutics, and several of our scientists will have poster presentations summarizing our drug discovery initiatives and progress in clinical trials. We look forward to participating in this important scientific forum and sharing highlights of the event in a subsequent blog post.
Neurodevelopmental Problems
Turning back to our review of the pediatric NF clinical care resource, the next issue to consider is the occurrence of neurodevelopmental problems associated with NF1. Children with NF1 often have low muscle tone, which can be associated with a delay in gross motor development and poor coordination. Low muscle tone means that muscles feel more lax than normal, although muscle strength is typically within normal limits. The bellies of some children with this condition may protrude and give the appearance of a potbelly, which is due to abdominal and spinal muscles that are laxer than normal. Although low muscle tone usually gradually improves through childhood, some have relatively poor coordination compared to their peers that is persistent. Studies of muscles in individuals with NF1 have shown some abnormalities of the function of muscle cells, suggesting that the NF1 gene can directly affect the muscle.
Speech and language problems also occur with greater frequency in children with NF1 than in the general population, and these problems may be helped with speech therapy. Also, a condition called velopharyngeal insufficiency, which leads to a nasal-sounding voice, is an occasional finding in children with NF1. Evaluation by a speech therapist and otolaryngologist would be appropriate if this is present.
It is estimated that at least 50% of children with NF1 have some type of learning problem, which is a higher occurrence than in the general population. Learning problems in children with NF1 are highly variable, and common problems can include difficulties with executive function and verbal or nonverbal learning disabilities. It’s also not uncommon for children with NF1 to be diagnosed with attention deficit disorder (ADD), sometimes with hyperactivity (ADHD). The same treatment approaches for management of ADHD as are used in the general population are used for children with NF1, which may include the use of stimulant medication to help manage symptoms. Parents and educators should be vigilant in recognizing possible signs of learning problems in children with NF1 so that a neuropsychological assessment can be performed to identify specific needs and interventions, including a 504 plan or an individualized education plan. Appropriate interventions and supports for children with learning problems can make a significant difference in long-term academic success.
In addition to learning problems, some studies suggest that features of autism spectrum disorder (ASD) occur with greater frequency in individuals with NF1. The most common ASD-related features in children with NF1 include difficulty with social pragmatics and communication skills, which can increase the risk of social anxiety. Therapies that focus on improving social skills and communication can be helpful in addressing these problems. A small proportion of individuals with NF1 have severe intellectual disability. Many of these have a distinctive NF1 gene variant in which the entire gene, along with several surrounding genes, are deleted from the chromosome. This distinctive mutation generally results in more severe manifestations of NF1 than most other types of mutations.
Skeletal Abnormalities
We often find that children with NF1 have relatively large head sizes compared to their body size. The large head size usually is benign, although there are rare instances of obstruction of spinal fluid flow in the brain, called aqueductal stenosis, that causes increased fluid pressure and large head size. While rare, it’s important to recognize the symptoms, which include severe headaches that might be associated with vomiting and other neurological signs.
Children with NF1 frequently have relatively short stature. In most cases, the cause is unknown, though some can be demonstrated to be growth hormone deficient. Treatment with growth hormone can be helpful and might be considered for these children. Although there has been some concern that use of growth hormone might stimulate tumor growth in children with NF1, there is no clear evidence to support this. We have used growth hormone for some of our patients with no apparent adverse effects, though we monitor these children closely for potential tumor growth.
Other problems such as osteopenia, or deficient bone calcification, can occur in children with NF1. This issue presents a minor increased risk of fractures. The cause of osteopenia in children with NF1 is not well understood. Some children with NF1 have low levels of vitamin D, which might be a contributing factor. It is therefore recommended to monitor vitamin D levels and consider supplementation if the level is low. Also, long bone dysplasia, which is an abnormality of the structure of the bone, can occur. This problem usually affects the tibia, which is the shin bone in the lower leg, and usually causes a bowing of the leg that presents in infancy. If the condition is confirmed with X-ray, the child is referred to an orthopedist for treatment with a leg brace to prevent future fracture. Dysplasia of the sphenoid, one of the bones in the skull that forms the orbit (eye socket), is another skeletal abnormality that can occur in children with NF1. The deformity is present at birth and can be associated with plexiform neurofibroma. The eye may be recessed if there is sphenoid dysplasia without neurofibroma, or it may bulge outward if there is a neurofibroma. An X-ray or CT scan can confirm the presence of orbital dysplasia, and an MRI can detect a plexiform neurofibroma. Orbital dysplasia and plexiform neurofibroma can be difficult to treat, and requires a team that includes craniofacial surgeons and ophthalmologists to consider whether and when surgery is indicated. Plexiform neurofibromas may respond to non-surgical treatments, such as MEK inhibitors, that are currently in clinical trial.
Scoliosis, a lateral curve of the spine, is a common skeletal problem in children with NF1 that usually appears in early to mid-childhood. The condition usually involves angulation in the thoracic spine. Management includes periodic spine X-rays and physical examination to determine whether surgery is needed. A plexiform neurofibroma can sometime be present near the scoliosis and would also require monitoring.
Chest-wall deformities, either pectus excavatum or pectus carinatum, can sometimes occur in children with NF1; the former causes a sunken appearance of the chest, while the latter causes the chest to protrude outward. The condition should be monitored, as it can sometimes require surgery. Other skeletal abnormalities include nonossifying fibromas, which are areas of incomplete bone mineralization. The condition can occasionally result in fractures, although preventive screening for the problem is not recommended. Lastly, some individuals with NF1 can have incomplete closure of the lambdoidal suture, which results in a soft spot on the back of the head, most often on the left side. The condition is benign, and no treatment or follow-up is required.
UAB NF Symposium Family Day and a Review of Pediatric NF Clinical Care Guidelines for Malignancies and Neurologic Issues Related to NF1
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.
NF Clinic Update and a Review of Pediatric NF Clinical Care Guidelines for Optic Pathway Gliomas and Indications for Neuroimaging in Children with NF1
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.
A Discussion of Newly Published Pediatric NF Clinical Care Guidelines
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.
Approaches to Imaging in the Diagnosis and Management of NF
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.
Explanation of a New Method for Answering NF-Related Email Questions
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.
NF Clinic Adjustments and a Discussion of the Differences Between Schwannomas and Neurofibromas
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.
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.