Relocation of Adult and Pediatric NF Clinics

I’d like to provide an update of a development mentioned in a previous blog regarding the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District. The relocation, which has recently been completed, originated earlier this year with the reorganization of the NF Clinic into adult and pediatric clinics.  The adult clinic is located in the Kirklin Clinic at UAB, while the pediatric clinic is at the downtown Children’s Hospital of Alabama location.  Both of these facilities provide our patients with more convenient parking than our previous NF Clinic location in the Hugh Kaul Human Genetics building.  Also, the new locations will enable improved integration with the range of other medical specialties involved in the multidisciplinary care we provide while allowing our patients to remain in one physical location for blood draws, imaging, or consultations with other specialists. Although our previous clinic location allowed us to see adults and children in the same visit, we now see adults at the Kirklin Clinic location on Mondays and children at the Children’s Hospital facility on Thursdays; at the Kirklin location, patients must be 16 or older, while patients in the children’s clinic must be 18 or younger. Because we understand that these split clinic days could be an inconvenience for some patients, we can certainly arrange to see members of the same family on the same day if needed, by prior request on a case-by-case basis.  Overall, we believe that our patients and families will benefit from the convenience and integration of care that our adult and pediatric clinics provide.

Increased Breast Cancer Risk in Women with NF1

Next, I want to review information concerning the increased risk of breast cancer in women with NF1. In recent years, it has become clear that women with NF1 are at an increased risk for breast cancer, with the risk being two to three time higher in women with NF1 than in those in the general population.  Also, these cancers occur at a younger age and tend to be more aggressive in women with NF1 than those that occur in women in the general population. The nature and composition of the cancers, however, are not different. 

In many women who have been diagnosed with breast cancer, a genetic panel of tests is performed to detect mutations that might be associated with the cancer.  The NF1 gene is now being tested as part of this panel, as well as other genes including BRCA1 and BRCA2.  However, it’s important to note that the increased risk of breast cancer in women with NF1 is not associated with mutations in the BRCA1 or BRCA2 genes.

The reason for the increased risk of breast cancer in women with NF1 is not completely understood. We know that cancer is the result of the accumulation of genetic alterations that cause cells to behave abnormally. The NF1 gene has been shown to have mutated in many common cancers, which might indicate that the NF1 mutation puts an individual one step closer to developing other cancers.

Some women diagnosed with breast cancer have been referred to our clinic because of an unexpected NF1 mutation detected in the genetic testing panel.  There are a few possible explanations for this finding, including that the individual has NF1 and was never diagnosed because the clinical features went unnoticed. Another possibility is that the individual has a mosaic form of NF1 that is detected in the blood but may not be clinically evident. Lastly, genetic variants are sometimes found in testing that are different from the normal gene variations. These are known as variants of unknown significance, and it can be a challenge to know what to do with this information. Often, when these patients are evaluated, they are not found to have NF1.

Breast Cancer Screening Recommendations

The increased risk of breast cancer in women with NF1 raises questions about screening recommendations. The National Comprehensive Cancer Network (NCCN), an organization that issues screening guidelines for various cancers, recommends that women with NF1 should be screened for breast cancer at an earlier age than the general population, beginning at age 30. In addition, the NCCN states that some consideration should be given to the use of breast MRI from age 30 to age 50.  After this, the guidelines shift back to that of the general population. We are now recommending these screening standards to the patients we see in our clinic with the goal of achieving an early diagnosis for improved outcomes.

Some patients are concerned that neurofibromas in the breast may be confused with breast tumors during imaging. Although neurofibromas can develop in the skin of the breast, they are clinically distinguishable from tumors in breast tissue. However, it is important for radiologists to know the NF history when reading imaging results for these patients.

Highlights of 3rd Annual Alabama NF Walk

The 3rd annual Alabama NF Walk, held on October 16th in Veteran’s Park in Hoover, proved to be another highly successful event that raised both awareness of NF in our community and critical funds for NF-related research. Held in cities across the nation, the NF Walk is an important fundraising event for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults. Launched only three years ago in our local area, this year’s Alabama NF Walk raised more than $40,000 and registered more than 300 participants.  In addition to raising awareness of NF among people in our community, the event also provided an opportunity for NF patients and families to enroll in the NF Registry, established by CTF in 2012; the purpose of the NF Registry is to notify NF patients who may be eligible for clinical trials or other research studies and to determine the frequency of NF characteristics.  Several newly diagnosed patients and their families in attendance expressed their gratitude for the hope and support they received as a result of coming together as an NF community, which is an important and meaningful benefit of this special fundraising event.

Cognitive Function and Learning Difficulties

I’d like to focus our discussion this month on developmental issues and cognitive function in individuals with NF.  Neurofibromatosis type 1 is associated with an increased risk of learning disabilities as well as a constellation of other symptoms that can impede school performance, including attention-deficit/hyperactivity disorder (ADHD), delayed language development, immature behavior, and low muscle tone. Sometimes cognitive problems are severe and evident early in life; however, sometimes these problems don’t appear until children have reached school age.  It is estimated that 50% of children with NF1 have some type of learning problem, although this statistic may be an underestimate of the prevalence of learning issues in children with NF1. I find that the more one looks for learning problems in children with NF, the more these problems are identified.

We therefore keep a watchful eye out for learning difficulties among children with NF1. Although we don’t always perform formal developmental assessments, we do focus on developmental issues and evaluate whether a child’s development is in the normal range of what is expected for his or her age.  Also, we educate families about the prevalence of learning disabilities in children with NF1 and arrange an evaluation with a neuropsychologist for a formal developmental assessment if needed.  Some parents have found that developmental assessments administered by schools can be difficult to obtain. Families considering formal evaluations for their child with NF should seek out an experienced professional, usually a neuropsychologist with experience in administering developmental assessments, who is familiar with resources in the community and can also advocate effectively for their child.

It’s important to note that learning problems are also common among the general population. Because there is not a specific profile of learning issues unique to NF, there is not a specific management plan that is unique for those with NF1. Learning problems are managed using the same methods as for individuals who don’t have NF. Effective management of learning difficulties involves providing a supportive educational environment with a focus on early intervention to address specific issues such as delayed language development. The same management approach applies to children with ADHD, although these children may also benefit from the use of stimulant medication to help control symptoms.

Regarding other developmental issues in children with NF1, the low muscle tone that occurs in some children tends to improve over time. It may, however, evolve into less overall coordination in adolescence and adulthood.  The lax muscle tone may cause some children with NF, even those of normal weight, to have a protuberant belly. This is a common occurrence, however, and not a cause for concern.

Questions sometimes arise as to whether parents should tell a teacher that their child has NF. The concern is that providing this information may cause a teacher to assume that the child has a learning disability. If learning issues are occurring, however, early intervention and support can lead to better outcomes for the child. Without this critical support, children are at risk for performing below their academic capabilities, which may lead to more limited opportunities in adulthood. Another consideration is that when parents don’t inform the teacher that their child has NF they are not in control of the information acquired and assumptions the teacher may form about their child. Most parents find that sharing information and recruiting the teacher as an ally is a helpful step in ensuring their child’s academic success. The Children’s Tumor Foundation offers a brochure designed specifically for educators that can be helpful in sharing information about NF (www.ctf.org or 1-800-323-7938).

While there are no medications that are effective in improving learning disabilities, there was hope that statin drugs may improve learning based on studies a few years ago using mouse models. However, three subsequent clinical trials showed no beneficial effect of statin drugs on learning.  Possible reasons that statins showed improved learning in mice but not humans include the fact that mice are inherently different than humans and the measures for learning are also different. Also, the dosage administered to mice in the studies may have been higher than is safe for humans. Based on the findings of the clinical trials and the risks associated with statins, the use of these medications for learning disabilities is not a recommended approach to treatment.
Re-Cap of Successful NF Symposium and Plans for 3rd Annual NF Walk

Last month saw another successful annual NF Symposium, held for the first time at the Children’s Harbor Building at Children’s of Alabama on Saturday, August 27th.  Co-sponsored by UAB and Children’s Tumor Foundation (CTF), this half-day, free event, also known as NF Family Day, provided an invaluable opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics presented by clinical experts.  A special program of activities was provided for the children in attendance, and our NF families also had an opportunity to learn about the range of services available at Children’s Harbor, a non-profit organization that supports seriously ill children and their families through education and counseling services. I opened the Symposium with an introduction to the features of NF as well as an overview of our research initiatives in the NF Program.  UAB Professor of Pediatrics and Director of Neuro-Oncology Alyssa Reddy, MD, provided an update of NF-related clinical trials currently in progress, and UAB Assistant Professor of Pediatrics Critical Care Michele Kong, MD, gave an interesting and informative talk on developmental issues in children (not just those with NF). Also, our NF Program Genetic Counselor Ashley Cannon, MS, PhD, CGC, presented the natural history of dermal neurofibromas, followed by Birmingham patient advocate Renie Moss’ review of advocacy, fundraising, and upcoming events. In addition to providing an opportunity for NF patients and families to gain important information about NF, it’s also rewarding to know that this annual event facilitates connections among patients and families that allow them to share their unique challenges, experiences, and concerns.

I also want to mention that plans are underway for another important NF event, the 3rd Annual Alabama NF Walk, which is scheduled for Sunday, October 16th, at 1 p.m. in Veteran’s Park in Hoover.  The purpose of the event is to raise funds for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults. Last year’s event raised more than $73,000 and registered more than 400 participants, which was a significant accomplishment for an event that was launched in our local area only two years ago.  We’re pleased that the NF Walk has continued to generate increased interest each year and has become a significant means of raising critical funds to support NF research focused on the development of breakthrough treatments. To learn more about the Alabama NF Walk or to register, visit www.nfwalk.org.

Brief Review of Mosaic NF1

In previous blogs, I’ve referred to the fact that some people have features of NF that are confined to a certain region or segment of the body. A possible explanation for the occurrence of isolated NF features in some individuals is mosaicism, caused by a genetic mutation of the NF1 gene that arises after conception and during early embryonic development. As a result, some cells in the body have the mutation while other cells do not.  The area of the body affected may be a cluster of cells in one region, such as an arm or leg, resulting in café-au-lait spots or a cluster of neurofibromas in one region of the body. Because genetic testing for NF1 using blood doesn’t always detect the mutation in people with mosaicism, the best method of diagnosing this form of NF is to perform genetic testing using a biopsy of affected tissues, either neurofibromas or café-au-lait spots.  

A question that often arises related to mosaicism is whether there may be features of NF present in the body that are not visible on the surface. In the majority of people with mosaicism, the outward manifestation is the only NF feature that is present, but we do remain vigilant for other manifestations that may occur internally. Unless specific symptoms are present, there is usually no need for imaging to detect tumors.

Another important question related to mosaic NF1 is whether it can be passed to a child at conception. An individual with mosaic N1 cannot have a child with the mosaic form of NF1. However, it is possible for someone with mosaicism to have a child with generalized NF1, in which every cell in the body has the NF1 mutation.  If we know an individual has a mosaic form of NF, we can offer prenatal counseling and genetic testing to assist in pre-conception planning.

Neurologic Exam

Continuing our discussion from last month’s blog about what to expect during an NF exam, I’d like to briefly review the components of the neurologic exam. First, mental status is evaluated by determining if the patient is awake and alert and able to understand and speak. For a child, this part of the exam involves an evaluation of developmental status, including a determination of whether the child can talk and follow basic commands in accordance with his or her age level. In addition, we evaluate the function of the 12 cranial nerves, which originate from the brain and brain stem and affect the head and neck.  Each nerve has a specific sensory or motor function. For example, the 3rd, 4th, and 6th cranial nerves are responsible for eye movements and could be affected either by neurofibromas or problems in the brainstem related to NF.  We also perform a visual assessment to evaluate functioning of the 2nd cranial nerve, the optic nerve, which carries visual information from the retina to the brain. People with NF may develop tumors on the optic nerve, called optic gliomas, that can cause loss of vision and can also affect hormone secretion in the pituitary gland that may lead to early onset of puberty. It’s important for children with NF to have a comprehensive eye exam yearly to check for symptoms of optic glioma.

Also as part of the neurologic exam, we evaluate the strength of the facial and jaw muscles, the tongue, and the neck and shoulders; muscle weakness in these areas may indicate a problem in the brain stem or a tumor on the nerve itself.  Next, we evaluate the peripheral nervous system, which involves an assessment of overall muscle strength as well as reflexes and coordination.  We look closely for asymmetry of motor strength, which could indicate the presence of a neurofibroma on the nerve as it exists the spine. Abnormal reflexes provide a possible indication that a tumor may be compressing the nerve or the spinal cord.  The last component of the exam is the sensory evaluation. Some individuals with NF have symptoms of neuropathy, or peripheral nerve damage, which may include numbness, tingling, or burning sensations usually in the feet and hands.