In previous blogs, I’ve discussed to the fact that NF is a highly variable condition that can manifest differently among affected individuals. For example, two people within the same family can have very different symptoms of the condition. It’s an enigma as to why such a high degree of variability exists within NF. However, we do have a general understanding of three probable sources of variability that could provide a framework for determining, through further research, the extent to which complications of NF are predictable.

Sources of Variability Among People with NF

The first possible source of variability is the specific genetic mutation associated with NF in an individual. More than 3,000 mutations have been identified in the NF1 gene, and there a few examples in which a specific mutation can be correlated to certain NF symptoms. The UAB Medical Genomics Laboratory is engaged in ongoing efforts to determine correlations between physical manifestations of NF and specific mutations in the NF1 gene. While it is probable that certain mutations do predict specific NF symptoms, it’s also very likely that most mutations don’t predict the specific NF features or the course of the condition.

Another factor that likely plays a role in the variability of NF is an individual’s genetic background. Because individuals express genetic variants across the genome, it’s likely that there are other genes that can influence the manifestations of NF. Evidence for this phenomenon can be seen in mouse models. When the NF1 gene is introduced into genetically distinct strains of mice, the manifestations of NF can be very different. It seems likely that an individual’s distinct genetic background can help to determine the symptoms of NF that he or she experiences.  It is difficult to design human studies to look for this phenomenon, however, due to the need to determine phenotypes (symptoms) and perform genetic sequencing on hundreds of patients, though efforts are underway to try to address this issue.

We are reasonably certain there is also a random nature to some of the physical manifestations of NF. Each individual is born with two copies of the NF1 gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered, or mutated, due to either inheriting the altered gene from a parent, a new mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development. This represents the “first-hit” genetic mutation in NF1. In a neurofibroma or in most other tissues affected by NF1, the second copy of the NF1 gene is also altered due to a random genetic mutation that represents the “second-hit” mutation. This “second-hit” mutation seems to be a random event that leads to a specific complication, such as a neurofibroma. It is possible that there may be factors in a person’s genetic background that increase the likelihood of a “second-hit”mutation.

NF Chest Examination

Turning back to our discussion in the previous blog about what to expect during an NF exam, I’d like to briefly review what NF clinicians are focused on during a chest examination. Because people with NF have an increased risk of congenital heart defects, the chest exam includes listening for a specific type of heart murmur associated with pulmonic stenosis. This condition causes a narrowing of the pulmonary valve, interfering with blood flow from the heart to the lungs. However, the condition is not as common in NF as in other RAS pathway disorders.

While the lungs are not commonly affected in NF, some adults may experience emphysema-like changes thought to be related to NF. It is also possible for neurofibromas to develop in the chest, which can interfere with inflation of the lungs and with breathing.  Occasionally, we can feel a nodular neurofibroma at the base of the neck or near the collarbone. Some people develop plexiform neurofibromas deep inside the chest, although we usually don’t see plexiform neurofibromas in the lungs or heart muscle.  The only treatment for plexiform neurofibromas is surgical removal, which is reserved for cases in which important structures are affected.

Sometimes a bony deformation of the chest wall, called pectus excavatum, can occur in people with NF. The condition causes a depression in the breast bone and usually doesn’t result in problems or require treatment unless it interferes with lung inflation and breathing. In these cases, surgical treatment can be offered.  Another condition, called pectus carinatum, causes the chest wall to bulge out, probably due to disproportionate rib cage growth. In most cases, the condition doesn’t require treatment.

In some people with NF, spinal tumors can become large enough that they can push on the lungs, which may require surgical removal of the tumors if breathing is affected. Also, people with NF are at increased for developing abnormal tissue growth inside of blood vessels, including major arteries in the heart and lungs. This condition weakens the vessel wall and leads to narrowing and possible rupture, which is a serious emergency. Sudden onset of severe chest or abdominal pain is a symptom that this condition may be present, indicating the need for diagnostic testing, though many other things can lead to pain other than vascular rupture. 

NF Awareness Month

Finally, I’d like to remind everyone that May is NF Awareness Month.  The Children’s Tumor Foundation has developed a number of activities to inform the public about NF [http://www.ctf.org/NFawareness], and there will be events here in Birmingham as well.  Keep an eye on our Facebook page [https://www.facebook.com/uabnfprogram/], as well as the Neurofibromatosis Alabama page [https://www.facebook.com/Neurofibromatosis-Alabama-Childrens-Tumor-Foundation-203255213153983/] for further details.











Highlights of CDMRP Meetings

At the beginning of March, I spent a day in Washington, DC, meeting with congressional legislative aids to discuss the importance of continued NF research funding for the Congressionally Directed Medical Research Programs (CDMRP).  The CDMRP was established in 1992 to support novel approaches in biomedical research to benefit the American public and the military.  The program is funded by the Department of Defense (DoD) through the annual Defense Appropriations Act.  However, funds for the program are not included in the DoD’s annual budget and must instead be renewed each year during the congressional budget approval cycle based on response to requests by consumer advocates and those affected by the condition. Our primary purpose in meeting with congressional aids was to explain the relevance and impact of NF research and the need for a continued investment that will lead to breakthrough treatments and improvements in patient care.

In addition to neurofibromatosis research, a wide range of biomedical research projects are funded by the CDMRP, including breast and ovarian cancer, autism, multiple sclerosis, and spinal cord injury, to name only a few.  We emphasized during our meetings that NF research has implications for bone and wound healing, medical issues important to the military.  Also, we discussed the fact that NF genetics research is yielding information that is applicable to several other areas of medicine. For example, it has been established that the NF1 gene is one of the most commonly altered genes in cancer.  Some may wonder if these research projects could be funded through the National Institutes of Health (NIH), the nation’s largest government-funded medical research agency.  While the NIH does fund important basic and translational research relevant to NF, it’s difficult for the NIH to direct funding to a specific condition, as the CDMRP has the flexibility to do. In fact, a hallmark of the CDMRP is filling critical research gaps by funding high-impact projects that would be not be feasible for other agencies. For example, the NF Clinical Trials Consortium –  funded by a grant that integrates research at more than 17 sites coordinated by UAB – was developed 10 years ago in response to a funding need identified by the CDMRP for NF-related clinical trials.  In this way, the CDMRP complements the work of the NIH by filling a critical niche.  We found the congressional aids with whom we met to be supportive of continued NF funding for the CDMRP primarily because the program has a substantial return on investment. It also has the unique capability to leverage funds for high-impact research that might not otherwise receive needed support.

NF Neck Examination

Continuing our discussion about what to expect during an NF exam, I’d like to discuss issues that may be identified during a neck examination.  The most common feature we look for on the neck is neurofibromas, benign nerve sheath tumors that appear on or under the skin. In children, neurofibromas can be sometimes difficult to distinguish from lymph nodes, which can usually be palpated in the neck; however, an experienced NF clinician can usually make this distinction.

Plexiform neurofibromas, which involve large branches of multiple nerves, can cause significant problems in the neck. In some people, they grow aggressively and can compress the airway and other structures in the neck.  While it is possible for plexiform neurofibromas to encase the carotid artery and jugular vein, usually the blood flow is unimpaired.

Another problem associated with plexiform neurofibromas in the neck is possible compression of the spinal nerves as they exit the spinal cord, causing pain or weakness in one or both arms.  For this reason, an NF exam should include monitoring of patients for pain and neurologic function in the arms.  It’s also possible for plexiform neurofibromas to grow into the vertebral foramen, the gap between vertebral bones where nerve roots connect to the spinal cord.  Surgical removal is the only treatment option for plexiform neurofibromas, which can be difficult in the neck due to the risk of damage to vessels and nerves that could cause serious bleeding and other problems. Because of these significant risks, we reserve surgery for critical cases in which important structures in the neck are affected.  

Some people with NF develop narrowing of the major arteries, which commonly occurs in one or both kidneys. The reduced blood flow caused by the narrowing signals the kidneys to release hormones that result in high blood pressure, which is a significant health risk.  During each NF exam, blood pressure is closely monitored to ensure this problem isn’t developing.  Narrowing can also occur in one or both of the carotid arteries, the major arteries in the neck supplying blood flow to the brain. As this condition gradually develops, collateral blood vessels are formed to compensate for reduced blood flow to the brain. Although most people with carotid artery narrowing don’t experience significant symptoms, certain conditions, such as dehydration, significantly increase the risk of stroke in these individuals. We don’t routinely perform imaging tests to screen for this issue, although we’re alert to any symptoms a patient may be experiencing that could indicate this problem.  When this problem is recognized we usually recommend starting a mild blood thinner, typically baby aspirin.  In symptomatic cases, there are surgical approaches that can restore blood flow to the brain.

In previous blogs, I’ve referred to the leading-edge work conducted in the UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D.  Viewed in the medical and scientific communities as the gold standard for NF genetic testing, the laboratory has identified mutations in more than 8,000 unrelated NF1 patients and has identified more than 3,000 NF1 mutations.  A recent UAB School of Medicine web site article highlights the groundbreaking work of Dr. Messiaen and her colleagues in determining correlations between specific NF1 mutations and symptoms of the disorder (http://www.uab.edu/medicine/news/latest/item/956-uab-researchers-work-to-unravel-the-complex-genetic-disease-neurofibromatosis-type-1).  Using the database of more than 3,000 different NF1 mutations and a catalogue of phenotypes (symptoms) in NF1 patients, Dr. Messiaen led a team of 74 researchers and clinicians from 58 centers (from 24 U.S. states and 8 non-U.S. countries) in identifying only the third genotype/phenotype correlation ever found for NF1.  The details of this and other recent investigations conducted by Dr. Messiaen’s team were published last year in the journals Human Mutation (http://www.ncbi.nlm.nih.gov/pubmed/26178382) and The American                                                           Journal of Human Genetics (http://www.ncbi.nlm.nih.gov/pubmed/26189818).                                                               

This finding is significant in giving patients and clinicians a better understanding of the expected course of the disease, including the symptoms that are likely to be most prominent, with a specific type of NF1 mutation. As we’ve discussed previously, there is broad clinical variability in the expression of NF among individual patients, and the course of the disease is often difficult to predict.  This uncertainty can be anxiety-provoking and unsettling for families of children facing a diagnosis of NF1.  Dr. Messiaen’s continued efforts in developing, utilizing and expanding the laboratory’s extensive mutation database to identify additional genotype/phenotype correlations will help to explain the causes of variability of expressions of NF and provide a greater degree of clarity and predictability for patients and clinicians about the expected course of the disease. 

Our NF research program is continuing to accelerate the development of new animal models of NF mutations. Recently, we have been in discussions with various groups about developing models of individual mutations.  Our goal remains to create models that allow us to test or develop new drugs that will restore function to the mutated gene or gene product. We will soon have completed our first mouse model preclinical trial of one new approach to therapy, and expect to launch others in the upcoming months.

I’d like to continue our discussion, featured in the previous few blogs, briefly reviewing specific NF features and symptoms clinicians may identify during a patient examination.  When conducting an exam of the head, the most obvious NF-related feature is often the presence of neurofibromas, soft benign tumors that develop on or under the skin. These are not usually seen in young children but typically appear during adolescence and continue to develop throughout life. Because skin neurofibromas are harmless, the primary concern may be cosmetic in individuals who have a significant distribution of neurofibromas on the face and neck. In these cases, treatment involves removal of neurofibromas using either surgery or laser treatment.

Another tumor that can occur on the face is a plexiform neurofibroma, a type of tumor that involves multiple branches of small or large nerves.  Some children with NF1 develop a plexiform neurofibroma behind an eye, which may show up as a swelling of the upper eyelid in the early years of life.  These can grow rapidly in childhood and cause significant disfigurement and interference with vision.  Approximately 2% to 3% of people with NF1 develop orbital plexiform neurofibromas.  Treatment involves surgical removal when possible, although surgery is complex and challenging due to the location of these tumors and the involvement of cranial nerves. Because recurrence after surgical removal is common, close follow-up with an experienced NF clinician as well as an ophthalmologist and plastic surgeon is important.

In some cases, distinctive facial features may be present in people with NF.  An example of a feature that may be noted by a clinician is palpebral fissures – the longitudinal opening between the eyelids – which slant downward from the midline to the lateral area. While many people with NF share this feature, it doesn’t appear in everyone with NF.  There also may be slight drooping of the upper eyelids.  Other NF features on the head include scalp neurofibromas, which can become painful and sometimes bleed, usually in adults.  Also, some people with NF retain a soft spot on the head, usually behind the left ear, that doesn’t completely close during the normal process of skull bone fusion that begins in early childhood. While this feature is uncommon, it may be noted by an experienced clinician during an  examination.  It is a benign feature that usually does not require treatment.