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.


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