I’d like to begin with month’s blog with a special word of recognition for our NF Program Genetics Counselor, Ashley Cannon, MS, PhD, CGC, who has been named a 2016 recipient of the prestigious Francis S. Collins Scholars Program Award.  Ashley is the first individual in our program to have received this significant honor, which is designed to attract the highest level of talent to the field of NF1 by providing salary and research support to advance rigorous clinical translational research that will lead to improved treatment options for NF1.  The award is named in honor of Dr. Francis S. Collins, who led one of the teams that discovered the NF1 gene in 1990 and currently serves as the Director of the National Institutes of Health (NIH). It is Dr. Collins’ hope that the Scholars Award will encourage others to combine a career in patient care and research, as he did. Because Ashely is trained in and serves both as a genetic counselor and a neuroscientist, her work embodies the clinician-scientist role that Dr. Collins envisioned for the program.  As a Collins Scholar, Ashley’s work will focus on two primary areas.  In the patient care arena, she will utilize her training as a genetic counselor and a neuroscientist in working closely with patients to better understand the specific problems and challenges they face related to NF and develop methods to address these problems. In the area of research, she will be working on a clinical trial for dermal neurofibromas with the goal of developing new treatments. Our entire NF clinic team joins me in congratulating Ashley for this outstanding achievement, which is very exciting for our program. 

In another special recognition of a dedicated individual in our local NF community, Renie Moss, tireless patient advocate, was recently presented with the Volunteer of the Year Award by the Children’s Tumor Foundation (CTF) during the CTF Volunteer Leadership Council Meeting in Austin, TX.  Renie was recognized for her inspirational leadership and dedication to patient advocacy and increasing NF awareness nationwide as well as her unique spirit of caring and compassion for NF families. The NF community is very fortunate to have someone with Renie’s many talents dedicated to the cause of patient advocacy and education.

Re-Cap of NF Forum
Last month, 10 people from our NF program attended the annual NF Forum held in Austin, TX, which marks the largest group from our team to attend this meeting. The NF Forum is the largest worldwide meeting dedicated to NF, bringing together patients and families as well as more than 300 NF clinicians and scientists from around the world to discuss advances in patient care, treatment, and research.  The meeting provides an invaluable collaborative environment in which to exchange ideas and research findings with international clinicians and scientists working in the field of NF.  Several members of our team gave poster presentations summarizing research conducted as part of our NF research program. The meeting left all of us energized with new ideas and goals for our program.  One of the most interesting aspects of this year’s meeting was learning about new animal models that have been developed using pigs instead of mice.  The pig model replicates the features of NF1 more closely than the mouse model, providing significant research advantages.  We’re currently establishing a collaboration with one of the groups that developed the pig model and are hoping to incorporate these models into our research in the near future.

NF Genital Exam
In continuing our discussion of what to expect during an NF exam, I’d like to briefly review issues that could be detected during a genital exam. The most relevant potential problem we’re looking for is evidence of early or delayed puberty.  As clinicians, we’re looking for changes such as the appearance of pubic hair and an early growth spurt as indicators of precocious (early) puberty. Sometimes, precocious puberty occurs for no known reason, but usually it is associated with optic nerve tumors (optic glioma) that involve the nearby hypothalamus that controls hormonal production in the brain.  If signs of precocious puberty are found, we use MRI to check for the presence of an optic glioma and obtain hormonal studies.  We also arrange for referral to a pediatric endocrinologist.  Early puberty is difficult for children both emotionally and psychologically, and it causes them to be significantly taller than their peers at a very young age, but, because of premature closure of the growth plate, ultimate height attainment is shorter than normal. Precocious puberty can be successfully treated hormonally; if there is an optic glioma, sometimes that, too, requires treatment, though if there is no impairment of vision or evidence of progression, the optic pathway tumor may not require treatment.  Aside from precocious puberty, signs of puberty can also occur later than normal.  If delayed puberty is suspected based on a lack of physical indicators such as pubic hair and an adolescent growth spurt, we would also perform hormonal testing and refer to an endocrinologist.   

In some people with NF, plexiform neurofibromas can affect the genital region, sometimes causing an overgrowth of the genitalia in males and females. Surgical treatment can be performed in these cases to help manage the problem. In women, plexiform neurofibromas can also sometimes impinge on the uterus and cause issues during pregnancy that might require surgical treatment, though sometimes these are too large to be amenable to surgical resection.

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 [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.