Of the more than 3,000 variants that have been identified in the NF1 gene, only a handful of specific variants can be correlated to certain NF1 symptoms. In this post, I’ll discuss the major known correlations between the physical manifestations of NF1 (phenotype) and specific mutations in the NF1 gene (genotype) as well as the clinical value of these correlations in helping to anticipate certain complications of NF1 for more effective management of the condition.

Established Genotype/Phenotype Correlations

NF1 is caused by a genetic variant in the NF1 gene, located on chromosome 17, that encodes for the protein neurofibromin. To make the neurofibromin protein, a cell must first copy information found in DNA into messenger RNA (mRNA) before using the mRNA to make the mature protein. DNA in the human genome consists of a sequence of more than 3 billion bases – called “A,” “T,” “C,” and “G,” which are the letters of the genetic code.  The genetic information is encoded in successive triplets of these bases to form “words,” called “codons,” each representing either a specific amino acid (building block of a protein) or a stop signal in the protein chain, similar to the period at the end of a sentence. A genetic variant consists of a deviation from the typical base sequence; this can be a change in a single letter in a codon, or a loss or gain of bases in the DNA sequence.  Most variants in the NF1 gene that lead to NF1 cause either a failure to produce neurofibromin at all or result in a neurofibromin protein that is non-functional. 

As more NF1 variants have been identified, an important question that has emerged is whether specific manifestations of NF1 can be predicted to occur in persons with certain genetic variants. The answer is that most of the time, variants in the NF1 gene do not predict specific NF features or the severity of the course of the condition; however, a few variants have been identified that can be correlated with specific NF1 features. Many of the clinically relevant genotype/phenotype correlations have been identified through research directed by UAB Professor of Genetics Ludwine Messiaen, Ph.D. in the UAB Medical Genomics Laboratory (undefined). 

Following is a brief description of known genotype/phenotype correlations:

• Whole gene deletion. In 3% - 5% of persons with NF1, the entire NF1 gene has been deleted, i.e., is no longer present in the DNA sequence. This usually produces a severe form of NF1 characterized by the appearance of skin neurofibromas earlier in life than usual as well as the development of larger number of tumors than usual. Individuals with whole gene deletions often have distinctive facial features, are taller than average, and may have loose skin on the palms and soles. Individuals with a whole NF1 gene deletion are also at an increased risk of developing malignant peripheral nerve sheath tumors (MPNSTs).  It is believed that some of these complex features are due to the fact that the deletions encompass not only the NF1 gene, but several additional nearby genes.

• Mutation of amino acid at codon position 1809. Individuals with this specific variant have a physical appearance that overlaps with another condition called Noonan syndrome, including distinctive facial features, short stature, developmental delays, malformations of the bones of the rib cage, and pulmonic artery stenosis (a narrowing of the artery from the heart to the lungs).

• Mutations at codon positions 844-848. Research led by Dr. Messiaen at the UAB Medical Genomics Laboratory has established that several variants at these locations in the NF1 gene result in a severe form of NF1 with features that include: a high incidence of benign tumors on peripheral nerves and/or pressure of the spinal cord; tumors of the optic nerve; and skeletal abnormalities. These individuals also have a higher risk of developing malignancies compared with the general NF1 population.

• Deletion of codon at position 992. This variant results in deleting the amino acid methionine. Individuals with this variant have café-au-lait spots and learning disabilities, but they do not develop neurofibromas.  Some have been reported to develop gliomas, although at a low frequency compared with others with NF1.

• Mutations at codon positions 1149, 1276, and 1423. All of these variants result in features of Noonan syndrome. In addition, individuals with mutations at position 1276 often develop spinal neurofibromas, and those with mutations at position 1423 are also more likely to develop pulmonic stenosis.

• Other correlations have been suggested, for example related to whether the variant occurs near the beginning or the end of the gene, though these have been less thoroughly validated.  Still others may remain to be elucidated, particularly for less common mutations that are seen in very few affected individuals.

The Clinical and Research Value of Genotype/Phenotype Correlations

While these well-established genetic variants have a correlation to specific clinical features of NF1, most mutations do not predict specific manifestations of the condition or disease severity. For people with a known genotype/phenotype correlation, this information can be clinically valuable because certain complications can be anticipated with the potential of managing the condition more effectively.  When these variants are identified, clinicians can be more vigilant for certain problems, such as an increased risk of malignancies. Also, a known genotype/phenotype correlation provides information about how the gene works and may lead to answers regarding why some genetic variants result in specific features of NF. The UAB Medical Genomics Laboratory, led by Dr. Messiaen, is utilizing a repository of around 3,000 NF mutations, the largest in the world, for determining additional genotpye/phenotype correlations. Some of these variants are being reproduced in animal models to observe manifestations of NF correlated with these changes; other studies involve developing a cell culture system that will help to determine the way specific genetic variants alter function within the cell. These studies will yield information about the ability of specific variants to cause NF1 and will also provide a framework to test new treatment approaches. 

As a new year begins, plans are underway for the 8^th Annual Rare Disease Genomics Symposium to be held on February 26^th and 27^th.  The two-day event will be virtual this year to limit the spread of COVID-19, and that, in turn, will make it more accessible to participants, even those who reside far from Birmingham. As in previous years, the Symposium is designed to share information about the role of genomics in the diagnosis and treatment of rare disease with members of the community and healthcare practitioners who are non-genetic specialists. While the event is not specific to neurofibromatosis, NF1 is a rare disorder that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders. To view the full Symposium agenda or to register, please visit: 8th Annual Rare Disease Genomics Symposium - School of Medicine - Genetics | UAB

When the NF1 gene was discovered in 1990, it was quickly learned that the gene product functions as a regulator of a protein called Ras.  Ras is a key component of a cell signaling pathway that controls cell growth and development.  This pathway involves multiple proteins that are involved in transmission of signals received at the cell surface to regulation of genes in the cell nucleus.  In more recent years it has been learned that variants in genes that encode these other proteins also lead to medical disorders, which now are collectively called “Rasopathies.”  These have distinctive, but in some cases overlapping, clinical features.  I will briefly review some of these features here.   

Syndromes Associated with Disruptions in the RAS/MAPK Pathway

Legius syndrome – This condition, which produces café-au-lait spots, skin fold freckles, and learning disabilities, is due to a mutation of the SPRED1 gene.   Leguis syndrome can be impossible to distinguish from NF1 in young children who have only café-au-lait spots and skin fold freckles; other features of NF1, especially neurofibromas, are not seen in Legius syndrome, but even in NF1 these may take years to develop.  Diagnosis of Legius syndrome is done by genetic testing of the SPRED1 gene, which is usually tested alongside the NF1 gene in evaluation of a child with multiple café-au-lait spots.  NF1 is much more common than Legius syndrome, so most children with multiple café-au-lait spots will turn out to have NF1, but for those few who do have Legius syndrome, there is less need to carry out surveillance for tumors.

Noonan syndrome –  Noonan syndrome is characterized by short stature, cardiac defects, characteristic facial appearance, and learning and developmental problems.   It has long been noted that some people with NF1 have facial features similar to those with Noonan Syndrome, and now it is clear that the reason for this is that the conditions share a disruption of Ras signaling.  Also, some people with Noonan syndrome have café-au-lait spots, and even neurofibromas, that may overlap with NF1.  Noonan syndrome is caused by a mutation in any one of many genes that encode various proteins involved in Ras signaling, including some forms of Ras itself.  This alteration of the normal RAS/MAPK signaling disrupts the regulation of cell growth and division, resulting in the characteristic features of Noonan syndrome.

Cardiofaciocutaneous (CFC) syndrome – This condition does not share many characteristics with NF1.  It can be caused by mutations in any one of several genes involved in the Ras pathway, and affects many parts of the body, including the heart, skin, and facial features. People with CFC also have developmental and intellectual disability, ranging from moderate to severe.

Costello syndrome – This disorder affects many parts of the body, including the heart and skin, and is also characterized by developmental and intellectual disabilities and distinctive facial appearance.  Costello syndrome is associated with mutations in the gene that encodes one of the many Ras proteins, called HRAS.  

Mechanism-based Therapies as Potential Treatments for RASopathy Disorders

An important question that has emerged in recent years is whether mechanism-based therapies developed for NF1, such as MEK-inhibitor treatments, may be effective in treating other RASopathy disorders. Mechanism-based therapies that inhibit the over-activated RAS pathway and other RAS-connected pathways may open new avenues of therapeutic intervention for the many complications of the RAS-related disorders. When considering the potential effectiveness of inhibitor-based therapies, there are a few factors that present challenges in using these therapies to treat RASopathies other than NF1. It is unclear whether the cognitive or developmental manifestations can be improved with treatment, for example.   Another consideration is that it’s relatively straightforward to evaluate treatment success in people with NF because tumor growth is measurable.  Identifying such measurable outcomes for other Rasopathies may be more difficult.  A notable exception is the occurrence of cardiomyopathy in several of the Rasopathies.  Cardiomyopathy is a failure of the function of heart muscle and can be debilitating and even life-threatening in some with Rasopathies.  This important manifestation is a subject for study of medications that inhibit Ras signaling.

Lastly, our NF Clinic is continuing to see patients for routine visits using telemedicine as part of an effort to slow the spread of COVID-19 and protect our patients. Telemedicine has been helpful in addressing specific patient concerns, arranging diagnostic testing, and discussing the results of imaging and other tests. Though we’re looking forward to seeing patients for in-person clinic visits again in the near future, we also believe many of our patients will continue to benefit from the enhanced access and convenience that telemedicine can provide, and we’ll be  glad to provide this option going forward.  

One of the most impactful events that our program sponsors each year is the UAB NF Symposium Family Day, a free half-day event that gives NF families and patients an opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. Co-sponsored by the UAB NF Program and the Children’s Tumor Foundation (CTF), the Symposium also offers a venue for NF families to connect with others who are sharing the same journey, which can be especially helpful for those who are newly diagnosed. Unfortunately, this year’s NF Symposium Family Day was cancelled due to concerns about COIVD-19, although we’re currently considering the possibility of rescheduling the Symposium as a virtual event for a date in 2021. Through our program’s frequent use of Zoom and other online meeting platforms during the pandemic, we realize that a virtual event can be easier for many people to attend than an in-person event. However, a disadvantage of a virtual event is that it eliminates the possibility of face-to-face interaction and networking that has become a meaningful part of this event in past years.  I’ll provide updates here as our plans develop regarding the possibility of a rescheduled, virtual event next year.

Brain MRI Findings in NF1

In this post, I’d like to discuss a few characteristic brain MRI findings that can occur in people with NF1, including T2 hyperintensities. These are also sometimes referred to as “unidentified bright objects” (UBOs) or “NF spots.” These are benign lesions that appear brighter on specific MRI sequences, predominantly in the basal ganglia, thalamus, brainstem, and cerebellum. These lesions do not enhance with contrast on MRI and are considered an incidental finding that do not require additional follow-up. However, if the lesions enhance with contrast on MRI or exert pressure in the brain, this could indicate the presence of a low-grade glioma, which requires more active follow-up. 

Most children with NF1 have these changes, but these eventually regress and may disappear without causing neurologic problems. Some literature suggests that people with a larger number of these changes, or their presence in specific brain regions, have an increased risk of learning disabilities.  I haven’t found that MRI changes are that useful in clinical practice to predict learning problems, however. The presence of these signal changes has not been used as part of the diagnostic criteria for NF because similar changes sometimes can also occur in individuals who do not have NF. Therefore, brain MRI is not a critical component of the diagnostic evaluation of NF1, unless there are signs or symptoms suggestive of a problem in the brain.

In some children with NF1, the corpus callosum – a large c-shaped bundle of nerve fibers that connects the two hemispheres of the brain – is thicker than normal. This condition may be associated with learning problems, but not with other neurological problems. Another incidental MRI finding sometimes seen in people with NF1 is the presence of Chiari malformation, a structural defect in which part of the cerebellum and brainstem extends below the foramen magnum and into the upper spinal canal. In most people, this condition is mild and doesn’t cause any problems. However, in some individuals it can cause headaches or neurologic problems and requires surgical correction.

A final NF complication that may be diagnosed by brain MRI is the occurrence of occlusion of a major artery to the brain.  This occurs in a small proportion of affected individuals, and in most cases is asymptomatic.  The reason there may be no symptoms seems to be that alternative pathways of blood flow develop, as the occlusion seems to occur slowly, probably over a period of years.  In some instances, however, this collateral circulation may not be able to keep up with demand and can lead to symptoms due to transient reduction of blood flow, or even a stroke.  Detection of this altered blood circulation can be done with MRI, particularly a method called MR angiography, which visualizes blood vessels.  It’s not something we do routinely in all individuals with NF1, but may be done if there are signs or symptoms suggestive of a problem with blood flow.  Sometimes you may hear the term “moyamoya,” which is the name given when multiple small collateral blood vessels are visualized.  Moyamoya can occur to anyone in the population, usually for unknown reasons, but is more common in those with NF1.  If an occluded artery to the brain is identified, it is common to prescribe baby aspirin as a mild blood thinner in the hope of reducing the risk of stroke.  In some cases, a surgical procedure can be performed to attach a blood vessel in the brain to another blood vessel to bypass the blockage.  This disorder of cerebral blood flow is one example of a risk of occlusion of arteries that can occur in some individuals with NF1, affecting for example the renal arteries (arteries to the kidneys) or others.  I’ll go into more detail about this in a future post.

Of the more than 3,000 variants that have been identified in the NF1 gene, only a handful of specific variants can be correlated to certain NF1 symptoms. In this post, I’ll discuss the major known correlations between the physical manifestations of NF1 (phenotype) and specific mutations in the NF1 gene (genotype) as well as the clinical value of these correlations in helping to anticipate certain complications of NF1 for more effective management of the condition.

Established Genotype/Phenotype Correlations

NF1 is caused by a genetic variant in the NF1 gene, located on chromosome 17, that encodes for the protein neurofibromin. To make the neurofibromin protein, a cell must first copy information found in DNA into messenger RNA (mRNA) before using the mRNA to make the mature protein. DNA in the human genome consists of a sequence of more than 3 billion bases – called “A,” “T,” “C,” and “G,” which are the letters of the genetic code.  The genetic information is encoded in successive triplets of these bases to form “words,” called “codons,” each representing either a specific amino acid (building block of a protein) or a stop signal in the protein chain, similar to the period at the end of a sentence. A genetic variant consists of a deviation from the typical base sequence; this can be a change in a single letter in a codon, or a loss or gain of bases in the DNA sequence.  Most variants in the NF1 gene that lead to NF1 cause either a failure to produce neurofibromin at all or result in a neurofibromin protein that is non-functional. 

As more NF1 variants have been identified, an important question that has emerged is whether specific manifestations of NF1 can be predicted to occur in persons with certain genetic variants. The answer is that most of the time, variants in the NF1 gene do not predict specific NF features or the severity of the course of the condition; however, a few variants have been identified that can be correlated with specific NF1 features. Many of the clinically relevant genotype/phenotype correlations have been identified through research directed by UAB Professor of Genetics Ludwine Messiaen, Ph.D. in the UAB Medical Genomics Laboratory (undefined). 

Following is a brief description of known genotype/phenotype correlations:

• Whole gene deletion. In 3% - 5% of persons with NF1, the entire NF1 gene has been deleted, i.e., is no longer present in the DNA sequence. This usually produces a severe form of NF1 characterized by the appearance of skin neurofibromas earlier in life than usual as well as the development of larger number of tumors than usual. Individuals with whole gene deletions often have distinctive facial features, are taller than average, and may have loose skin on the palms and soles. Individuals with a whole NF1 gene deletion are also at an increased risk of developing malignant peripheral nerve sheath tumors (MPNSTs).  It is believed that some of these complex features are due to the fact that the deletions encompass not only the NF1 gene, but several additional nearby genes.

• Mutation of amino acid at codon position 1809. Individuals with this specific variant have a physical appearance that overlaps with another condition called Noonan syndrome, including distinctive facial features, short stature, developmental delays, malformations of the bones of the rib cage, and pulmonic artery stenosis (a narrowing of the artery from the heart to the lungs).

• Mutations at codon positions 844-848. Research led by Dr. Messiaen at the UAB Medical Genomics Laboratory has established that several variants at these locations in the NF1 gene result in a severe form of NF1 with features that include: a high incidence of benign tumors on peripheral nerves and/or pressure of the spinal cord; tumors of the optic nerve; and skeletal abnormalities. These individuals also have a higher risk of developing malignancies compared with the general NF1 population.

• Deletion of codon at position 992. This variant results in deleting the amino acid methionine. Individuals with this variant have café-au-lait spots and learning disabilities, but they do not develop neurofibromas.  Some have been reported to develop gliomas, although at a low frequency compared with others with NF1.

• Mutations at codon positions 1149, 1276, and 1423. All of these variants result in features of Noonan syndrome. In addition, individuals with mutations at position 1276 often develop spinal neurofibromas, and those with mutations at position 1423 are also more likely to develop pulmonic stenosis.

• Other correlations have been suggested, for example related to whether the variant occurs near the beginning or the end of the gene, though these have been less thoroughly validated.  Still others may remain to be elucidated, particularly for less common mutations that are seen in very few affected individuals.

The Clinical and Research Value of Genotype/Phenotype Correlations

While these well-established genetic variants have a correlation to specific clinical features of NF1, most mutations do not predict specific manifestations of the condition or disease severity. For people with a known genotype/phenotype correlation, this information can be clinically valuable because certain complications can be anticipated with the potential of managing the condition more effectively.  When these variants are identified, clinicians can be more vigilant for certain problems, such as an increased risk of malignancies. Also, a known genotype/phenotype correlation provides information about how the gene works and may lead to answers regarding why some genetic variants result in specific features of NF. The UAB Medical Genomics Laboratory, led by Dr. Messiaen, is utilizing a repository of around 3,000 NF mutations, the largest in the world, for determining additional genotpye/phenotype correlations. Some of these variants are being reproduced in animal models to observe manifestations of NF correlated with these changes; other studies involve developing a cell culture system that will help to determine the way specific genetic variants alter function within the cell. These studies will yield information about the ability of specific variants to cause NF1 and will also provide a framework to test new treatment approaches. 

I’d like to discuss here the evolving therapeutic landscape in NF1. For the past several years, the NF scientific community, including the UAB NF Research Program, has put major emphasis on conducting clinical trials for plexiform neurofibromas. Affecting upwards of 50% of people with NF1, plexiform neurofibromas are tumors that often involve multiple branches of either large or small nerves. They can be located on the surface of the body where they are easily visible or may be deep inside the body and recognized only if seen by imaging or if they cause symptoms.  Because these tumors can present serious complications and surgical removal can be complex, investigators have worked to identify drugs that can reduce the size of plexiform neurofibromas.

MEK Inhibitor-Based Treatments and FDA Approval of Selumetinib (Koselugo)

Several clinical trials have investigated the effectiveness of drugs called MEK inhibitors as potential treatments for plexiform neurofibromas. MEK is an abbreviation for one of the proteins that becomes hyperactivated in a neurofibroma when the NF1 protein is non-functional.  A medication called Selumetinib is one of the MEK inhibitor drugs that was found to be effective in shrinking some plexiform neurofibromas in clinical trials; published data, including a paper published in March in the New England Journal of Medicine have shown that 70% of study participants with NF1 and a plexiform neurofibroma who took this drug have experienced a 20% or greater reduction in tumor volume over the course of the study.

Based on these results, the FDA has recently approved Selumetinib for use in children with NF1 aged 2-18 who have inoperable plexiform neurofibromas. This is the first drug specifically approved for use with NF1 and represents a significant and exciting breakthrough in the advancement of effective therapies that improve the lives of people living with NF. Co-developed by AstraZeneca and Merck & Co., the drug will be marketed under the brand name Koselugo.  Information about the medication for both patients and physicians can be found on the Koselugo web site, and a MEK inhibitor patient information sheet can be found on the Children’s Tumor Foundation (CTF) web site

Clinical Management and Treatment of Plexiform Neurofibromas with Selumetinib and Other MEK Inhibitors

Many individuals with plexiform neurofibromas have been followed in our clinic over the years. Surgical removal of the plexiform neurofibromas in patients who do not have symptoms is usually not recommended due the risk of complications, mainly as a result of nerve and blood vessel involvement in these tumors. Surgery is reserved for cases in which important structures are affected, such as the need to relieve pressure from the tumor on the airway or spine.  Usually the tumors cannot be completely removed, and many eventually grow back after surgery.

For individuals with symptoms due to plexiform neurofibromas, the availability of MEK inhibitors, such as the newly FDA-approved Selumetinib, has opened new opportunities for treatment and underscores an important question: When is it appropriate to treat plexiform neurofibromas? The answer is that we would not treat a plexiform neurofibroma just because it is there unless one or more of the following criteria is met: the tumor is progressive; the patient is experiencing significant symptoms; or the tumor is disfiguring.

>Although MEK inhibitors may be an effective treatment option for some patients, it’s important to understand that these oral medications have potential side effects that include problems with skin, heart function, and vision, among other issues.  Because of this, patients taking MEK inhibitor drugs receive regular echocardiograms and ophthalmologic examinations, as well as blood tests, to monitor for side effects. Skin rash may include an acne-like rash or a scaling rash. Medications are available to control these side effects and often are helpful. Also, fatigue and nausea can occur in some patients. Regarding Selumetinib, information about long-range tolerance of the medication, or at what point patients can safely withdraw without risk of tumor regrowth, is still being determined.

At this time, treatment for plexiform neurofibromas is in cases where there are significant indications. However, the increasing availability of MEK inhibitors such as Selumetinib and other drugs has made treatment of these tumors an evolving issue. As we learn more about these drugs, it is possible that we might move toward treating tumors at an earlier time in their evolution; whether these drugs will prevent progression when treatment is begun early is an important but so far unanswered question.  The increasing availability of MEK inhibitors is offering exciting new avenues for effective treatment of plexiform neurofibromas, which is an encouraging and hopeful development for the NF scientific and patient communities.

Role of Telemedicine in the UAB NF Clinic

To slow the spread of COVID-19 and protect our patients, our NF Clinic is currently seeing patients for routine visits using telemedicine. We’ve found that telemedicine works well to address specific patient concerns, arrange diagnostic testing, and discuss the results of imaging and other diagnostic tests. We can do a limited physical exam by telemedicine, but in some cases it is necessary to perform a face-to-face examination.  We hope that our clinic will open soon for regular visits, but in the meantime, telemedicine has been a helpful approach for dealing with some issues.  In the future we expect that we will continue to use telemedicine for some purposes, for example to return results of testing for patients who live a long distance from our site.  We had been interested in integrating telemedicine into our clinic for a while, and the pandemic has facilitated and accelerated this process. Our hope is that our patients will benefit over the long term from the convenience and accessibility that telemedicine can provide.

As the world grapples with the challenge of the novel coronavirus, I have received many inquiries related to the risks associated with viral infection in individuals with NF. Three of the most common questions are: 1) Are individuals with NF at greater risk for being infected with the virus; 2) does the virus lead to more severe illness in those with NF; and 3) if an NF patient is being treated with medication or on a clinical trial, does this pose a special risk?  In thinking about these questions, we need, of course, to remember that NF is really a term that covers three distinct conditions – NF1, NF2, and schwannomatosis, that might raise different issues regarding the viral infection.  Second, this is obviously new and uncharted territory – anything we say about risks of coronavirus infection is based on the limited recent knowledge of this new disorder and general experience regarding individuals with NF who develop other viral illnesses.  There is a lot left to be learned about coronavirus, and about infectious disease risks in NF in general.

Susceptibility to Coronavirus Infection

The reassuring news is that I’m not aware of any evidence that persons with any form of NF are at greater risk of viral infection compared to those who do not have NF.  I haven’t seen evidence of any generalized immune problems in persons with NF, and I haven’t noticed that those with NF are more susceptible to typical viruses such as common colds and flu, for example. However, if an individual with NF has medical problems that requires seeing a physician more often, this could increase human contact and could therefore increase the risk of exposure to the virus. My recommendation at this time is that people with NF should follow the same guidelines issued by the CDC (www.coronavirus.gov) and NIH (www.nih.gov/coronavirus), which include avoiding exposure to groups of more than 10 people and self-isolating at home as much as possible.    

Risk of Complications of Coronavirus Infection

Regarding the question of outcomes of people with NF who contract the virus, there are no data as of yet related to this issue. To my knowledge, it has also not been studied whether common colds or flu are more severe in individuals with NF, although the ability to fight infection in people with NF does not seem to be impaired.

It is possible that individuals with NF who have specific medical problems might be at greater risk of complications of coronavirus infection.  For example, those who have severe scoliosis (curvature of the spine) or large plexiform neurofibromas in the chest cavity, might already have impaired lung function.  In these individuals, one might expect that the lung manifestations of coronavirus infection could be exacerbated.  In addition, there is a subset of people with NF1, usually older adults, who develop chronic lung disease that can impair lung function. We don’t know how common these lung manifestations are; I’ve personally seen this just a few times in the many years I’ve been following patients with NF1, but it’s possible that milder versions are more common and have escaped notice.   This condition usually presents as respiratory distress upon exertion, and subsequent testing of lung function reveals impairment, along with visible changes on imaging of the lungs.  Again, one might imagine that a person with NF1 who has impaired lung function to begin with might be at increased risk of coronavirus complications.   There are no data on this point, however.  Additional studies are needed to determine the frequency of this lung manifestation and how COVID-19 impacts NF patients with this condition.

Risk to Patients on Treatment or in a Clinical Trial

There are some individuals with NF who are currently being treated for a complication of NF or are enrolled in a clinical trial of an investigational medication.  Given that there are many different types of medications being used, I suggest that these individuals should discuss any risks with the physician who is managing their treatment or participation in the trial.   Some types of medications, especially those used to treat malignancies, might impair the immune system and therefore could confer increased risk of infection, whereas others do not affect the immune system.  There is also the risk associated with frequent visits to the clinic, and therefore exposure to the virus.   As much as possible, we’re trying to work with patients by using telemedicine to minimize exposure; also, for those on clinical trials, we are trying to work with local physicians to reduce the need to travel to a specialized clinic.

Conclusion

This is a difficult time for everyone, and having NF adds an additional dimension for concern.  For now, the best advice is to follow guidance issued for everyone to minimize exposure to the virus; I would also recommend that persons with NF be in touch with their NF specialist if particular questions arise related to their condition.  Last week, Dr. Scott Plotkin (Massachusetts General Hospital) and I participated in a global video chat on coronavirus infection and NF organized by the Children’s Tumor Foundation.  A recording of this presentation can be found at https://www.ctf.org/news/coronavirus-covid-19-update. 

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 7^th Annual Alabama Children’s Tumor Foundation NF Walk that was held at the Tuscaloosa Buddy Powell Pavilion on November 2^nd.  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.