Planning the Upcoming NF Symposium

As part of our NF Clinic’s ongoing efforts to maintain a patient-centered focus, the NF Community Advisory Board was developed last year with the objective of providing input and direction regarding patient information, education, support, and coordination of care.  Comprised of NF patients and family members, the Board meets four times a year. During the Board’s second meeting of the year held last month, plans were discussed for the upcoming NF Symposium scheduled for August 27th. Also known as NF Family Day, this half-day, free event co-sponsored by UAB and the Children’s Tumor Foundation (CTF), provides valuable information to NF patients and families through a series of presentations given by clinical experts on a range of NF-related topics. The Board was very helpful in offering suggestions for this year’s Symposium, which will be held for the first time in the Children’s Harbor Family Center at Children’s of Alabama. Children’s Harbor is a non-profit organization that supports seriously ill children and their families through educational and counseling services.  Although the previous NF Symposia have been held at the Kaul Building in the UAB Medical District, the Children’s Harbor Building offers better facilities and parking for this type of event. Also, our NF Clinic has formed a collaboration with Children’s Harbor so that our NF patients and families can take advantage of the educational and counseling services they provide.

Enhanced Patient Exam Procedure in the NF Clinic

We’re pleased to announce the addition of Tammy Skelton, MSN, CRNP, NP-C, a certified nurse practitioner, to our team of specialists in the UAB NF Clinic.  Tammy is enhancing patient care by performing preliminary patient examinations after our certified genetic counselor, Ashley Cannon, MS, PhD, CGC, collects or reviews a patient’s history. After I review the history and notes from Tammy’s preliminary examination, I perform a more focused exam and talk to the patient/family. We then confer as a team regarding next steps. The feedback from our Community Advisory Board on this new procedure has been very positive. Our goal is to reduce the backlog of patients waiting to be seen in the clinic by streamlining the examination process. By having Tammy perform preliminary exams, we’re able to see more patients in clinic and spend more focused time with them. We’re hoping our NF patients and families will be pleased and that the new procedure will make us more accessible.

On another note, a team from our NF Program will be attending the Neurofibromatosis Conference in mid-June in Austin, Texas. We’re presenting several abstracts and participating in a series of workshops and presentations. Stay tuned for a re-cap of this important meeting in next month’s blog.

Review of the NF Abdominal Exam

To continue our discussion of what occurs during the typical NF examination, this month we will consider the abdominal portion of the exam. Because the abdomen is covered by a large expanse of skin, neurofibromas are usually very visible in this area; sometimes they are obvious, and other times they can be seen using a pen light to illuminate the skin from the side.  We’re also looking for masses, although it’s not very common to feel a mass through the skin. While the liver and spleen can be palpated, these organs aren’t usually involved in NF.

The two main abdominal-related concerns in people with NF are episodes of nausea and sometimes vomiting, which tend to occur mostly in children, as well as the lower GI problem of constipation.  Children with NF have a tendency to develop migraine headaches, and I find that stomachaches, nausea, and occasional vomiting are common presentations of migraines in children. Sometimes treating children for migraines can be effective in resolving gastrointestinal symptoms. Constipation also seems to be more common in people with NF, probably because the condition affects the nerves in the intestine.

It’s rare that a tumor is the cause of a GI problem. Although plexiform neurofibromas can occur in the abdomen, they are usually too deep to palpate and are mostly asymptomatic. Tumors can also occur in the wall of the intestine, but these are usually also asymptomatic, though sometimes they can cause obstruction or bleeding.  Gastrointestinal stromal cell tumors are more common in people with NF1 than in the general population. They present with abdominal pain and bleeding in the GI tract. It’s important that an individual with abdominal pain and blood in the stool be evaluated for this potential problem.  Lastly, some people with NF may develop a specific type of tumor on the adrenal gland called pheochromocytoma.  The most common presentation is high blood pressure, which is caused by increased secretion of the hormones epinephrine and norepinephrine.  Some people may also experience episodes of skin flushing and a racing heart.  If symptoms are present, a blood test is performed to determine the presence of elevated hormone levels. If this is confirmed, a 24-hour urine collection is performed to further detect the presence of increased hormones followed by a scan to identify the tumors. If they are found during a scan, careful surgical removal is required as the treatment.

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 [], and there will be events here in Birmingham as well.  Keep an eye on our Facebook page [], as well as the Neurofibromatosis Alabama page [] 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.