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.

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.

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.