In early November, several colleagues from the UAB NF Program will attend the 2018 NF Conference in Paris organized by the Children’s Tumor Foundation. Although the meeting is usually held in the U.S., CTF has partnered this year with the European NF Conference to further promote and encourage international scientific collaboration. Established in the 1980s, the annual NF Conference represents the largest meeting of NF scientists and clinicians and serves as the global forum for several hundred participants from diverse scientific and clinical backgrounds to encourage collaboration and advance research for all forms of NF. Our UAB group will present at least one platform presentation, as well as several poster presentations, summarizing our drug discovery initiatives and progress in clinical trials. We look forward to participating in this important scientific meeting and will review highlights of the event in a subsequent blog post.

Psychiatric and Neurocognitive Issues

In this last installment of our review of the ACMG practice resource, I’d like to first discuss some psychiatric and neurocognitive issues associated with NF in adults. It is well recognized that cognitive problems occur in at least 50% of children with NF, including learning disabilities and attention-deficit disorder (ADD).  However, less attention is paid to cognitive problems in adults with NF, although many individuals have neurocognitive issues that persist beyond childhood. One of the most common psychiatric problems in adults with NF1 is depression, which is sometimes related to cosmetic disfigurement or chronic medical problems, but this probably is not the only explanation; it’s uncertain whether NF1 has a primary effect on brain function that increases the risk of depression. Because of the prevalence of depression in people with NF, it’s important to pay attention to signs of depression that might include: irritable mood; feelings of sadness or emptiness; overeating or loss of appetite; changes in sleep patterns; difficulty concentrating; persistent fatigue; feelings of guilt or helplessness; and suicidal thoughts. Neurocognitive problems such as learning disabilities and attention-deficit disorder (ADD), which are common in children with NF1, often persist into adulthood. More research is needed to determine how these problems affect adults with NF1, as most studies have focused on the pediatric population. Clinicians are advised to be aware of the potential for neurocognitive and psychiatric problems in adults with NF1.  

Headache, Polyneuropathy, and Glomus Tumors

Another common problem in adults with NF1 is headache, which is often a component of migraine.  These headaches, usually throbbing in character, seem to be more common in people with NF1 than in the general population.  They can last several hours and cause extreme sensitivity to light and noise. While over-the-counter medications can be effective in treating occasional migraines, prescription medications are sometimes required to manage frequent migraine headaches. This includes not only medications to treat an ongoing headache, but also medications that can help to prevent them.  Because the occurrence of headache in people with NF1 is underreported and underappreciated, clinicians should be vigilant in discussing headache frequency and treatment options with patients.

Another problem addressed in the ACMG practice resource is polyneuropathy, which is an impairment of multiple nerves that affects approximately 2% to 3% of people with NF1. This condition usually presents as numbness or tingling in the hands and feet. While it doesn’t usually cause pain, it can predispose an individual to injury due to the lack of feeling in the extremities. Also, some adults with NF1 may experience severe pain with pressure applied to the tips of fingers and toes due to the presence of glomus tumors that occur under the nail beds. Most people with this problem don’t associate the pain with NF and therefore don’t seek treatment. Fortunately, these tumors can be successfully removed surgically, eliminating the pain. Therefore, it is important for clinicians and patients to recognize this type of pain so that surgery can be performed if needed. Pain related to NF can occur anywhere in the body, often, but not always, due to a tumor.  As we have discussed in the past, sometimes pain can be a sign of malignant change, so it is important to report persistent pain to a physician for further evaluation.   

Pregnancy and Contraception

Women with NF often report a progression of cutaneous neurofibromas during pregnancy.  This also occurs in both males and females during puberty, resulting in speculation about a possible hormonal link to the growth of neurofibromas. Because oral contraceptives contain a combination of progesterone and estrogen, many women with NF are concerned about whether it’s safe to take oral contraceptives.  There is no clear evidence that oral contraceptives contribute to the growth of neurofibromas in women with NF, though the issue is difficult to study, especially given the various formulations in use.   A woman with NF needs to balance the potential risks and benefits of oral contraceptive use, and should discuss the question with her physician.  As to other risks of pregnancy, problems such as high blood pressure, pre-eclampsia and fluid balance problems may occur more often in women with NF, although these problems require further study.  These risks warrant close monitoring during pregnancy by an obstetrician who is familiar with NF.

Another common pregnancy-related concern is whether epidurals administered prior to delivery are safe for women with NF. Although there are few studies related to the safety of epidurals in women with NF, the general feeling is that the procedure is not dangerous. While some people may be concerned about the presence of spinal neurofibromas, the ACMG group did not feel that it is necessary to perform imaging for spinal neurofibromas prior to the administration of anesthesia unless there are specific concerns about the presence of tumors (as from prior imaging or clinical signs).

Lastly, a couple in which one partner has NF1 needs to be aware of the 50% risk of transmission the NF1gene change to any offspring. This risk should be considered in family planning along with the fact that the wide variability of NF, even within families, means there is no way to predict the severity of NF in an individual. It is possible to do prenatal diagnosis of NF1, which first requires identifying the genetic mutation in the mother or father. The first method involves obtaining a fetal tissue sample through amniocentesis at 15-18 weeks of pregnancy to determine if the child has the genetic change. Another method involves chorionic villus sampling at 10-12 of pregnancy to identify the genetic change. A genetic counselor, who has specialized training in medical genetics and counseling, can provide information about specific tests available to couples regarding genetic risks and options to manage those risks.  

This month, our discussion continues about the newly released American College of Medical Genetics and Genomics (ACMG) clinical practice resource for adults with NF1.  The resource, written for general practitioners and other healthcare professionals, summarizes current knowledge of clinical care and proposes an approach to management for general practitioners and other healthcare professionals providing care to individuals with NF1.  I’d like to focus on a review of the ACMG recommendations in three areas: hypertension and vasculopathy; osteoporosis; and cutaneous neurofibromas.

Hypertension and Vasculopathy

The most common reason for hypertension, or high blood pressure, in individuals with NF1 is essential hypertension, which means that there is no known cause for why the high blood pressure is occurring.  This is similar to hypertension occurring in the general population.  Another cause of hypertension in individuals with NF1 is pheochromocytoma, a tumor of the adrenal gland discussed in last month’s blog that affects fewer than 5% of people with NF1. The tumor causes the irregular and excessive release of the hormones epinephrine and norepinephrine, causing symptoms of high blood pressure as well as rapid heart rate and palpitations, flushing, and excessive sweating. 

An important cause of hypertension in children and young adults with NF1 is renal artery stenosis, which is a narrowing of the artery that carries blood to the kidney. The kidneys control blood pressure by regulating the amount of water excreted from the body, and restriction in blood flow causes the kidneys to misinterpret this as low blood pressure in the body. In response, the kidneys release hormones that raise blood pressure and result in hypertension. It’s important to monitor blood pressure in people with NF1 beginning in childhood. If blood pressure is elevated, a vascular imaging study such as MRA (magnetic resonance arteriogram) is performed to diagnose the problem. If renal artery stenosis is found, it is treated with medication and sometimes surgery or stenting of the vessel to increase blood flow.

Vascular problems can occur in other areas of the body in people with NF1.  Moyamoya disease is a rare vascular disorder in which the internal carotid artery to the brain becomes blocked or narrowed, reducing blood flow to the brain.  In response to the blockage, which develops very slowly, tiny blood vessels open up in the brain in an attempt to restore blood flow. The word “moyamoya” means “puff of smoke” in Japanese (the condition was first described in Japan, among children who did not have NF1), which describes the appearance on an angiogram (where dye is injected into the artery and it is visualized by X-ray) of the cluster of blood vessels formed that compensate for the carotid artery blockage. Moyamoya disease significantly increases the risk of stroke and transient ischemic attack (TIA), a temporary reduction of blood flow to the brain.  Moyamoya occurs with increased frequency in individuals – usually children – with NF1, and is especially common among children exposed to radiation therapy to the brain for treatment of a brain tumor.

Other blood vessels can be narrowed in individuals with NF1, causing a weakening of the arterial wall and an increased risk of hemorrhage. However, screening for vascular problems in people with NF1 isn’t routinely performed unless there are instances of high blood pressure or TIA.  In these cases, a vascular imaging study would be performed to locate the vascular abnormality. 

Osteoporosis

Decreased bone mineral density and osteoporosis are more common in people with NF1 than the general population. Some studies have shown vitamin D deficiencies in people with NF1, which increases the risk of osteoporosis. A possible contributing factor to vitamin D deficiency may be that individuals with skin neurofibromas tend to cover up more often and not be exposed to enough sunlight as a result. Vitamin D deficiency is also common in the general population, and the practice resource recommends vitamin D supplementation to maintain regular levels. It’s important to note that supplementation should be done under the supervision of a physician to avoid toxicity that can occur with taking too much of the vitamin.  If osteoporosis is diagnosed, the treatments are the same as those for the general population, including the administration of medications to increase bone mineral density.

Cutaneous Neurofibromas

Cutaneous neurofibromas, benign tumors in or on the skin, are common in adults with NF1.  Numbers of tumors can be highly variable, with some individuals having very few and others having a wide distribution covering a large portion of the body. Cutaneous neurofibromas typically increase in number during puberty and continue to progress during adulthood. A substantial proportion of women develop them during pregnancy, and the neurofibromas typically don’t regress when the pregnancy is over. Studies indicate that quality of life for people with cutaneous neurofibromas can be significantly impaired, with major cosmetic concerns often arising in those with a large number and wide distribution of neurofibromas due to the potentially disfiguring aspect of the tumors. Also, the tumors may itch, cause pain, and can sometimes bleed. 

There is no known prevention of cutaneous neurofibromas, and the recommended treatment is surgical removal by a physician who has experience removing cutaneous neurofibromas.  Treatment with a specialized laser called the COlaser has also shown success in removing cutaneous neurofibromas. Another treatment called electrodessication uses heat generated from electricity to remove the tumors. Anesthesia is often required if a large number of tumors are being removed at one time.  The risks of these treatments include scarring and regrowth of the neurofibromas.  Studies have shown that individuals treated with these approaches tend to be satisfied over a period of months following the procedure, but we do not have long term follow-up studies to know how long lasting the benefit might be.  

Here at UAB we are continuing our clinical trial targeting cutaneous neurofibromas using the investigational drug selumetinib, which has been shown to often be effective in reducing the growth of plexiform neurofibromas.  The trial is actively recruiting study participants at two study locations, UAB and the National Cancer Institute in Bethesda, Maryland. More information regarding the trial can be found at: www.clinicaltrials.gov(study number NCT02839720). 

We’re continuing our discussion from last month’s blog of the newly released American College of Medical Genetics and Genomics (ACMG) clinical practice resource for adults with NF1. This document summarizes current knowledge of clinical care and proposes an approach to management for general practitioners and other healthcare professionals providing care to adults with NF1. Previously, I reviewed some of the recommendations related to malignant peripheral nerve sheath tumors (MPNST). Next, I’d like to focus on recommendations related to other types of tumors. 

Breast Cancer

In recent years, it has become clear that women with NF1 are at an increased risk for breast cancer, with the risk two to three times higher in women with NF1 than in those in the general population. The increased risk is greatest in women below age 40, with the earliest cases occurring around age 30. The increased risk of breast cancer in women with NF1 is not necessarily an expected outcome, as breast tissue is different from that usually affected by the NF phenotype, such as the tissue comprising neurofibromas.  

The risk of breast cancer in women with NF1 is not as high as the risk of breast cancer in women with mutations in the BRCA1or BRCA2genes; women with mutations in BRCA1or BRCA2have a much higher risk of both breast and ovarian cancer.  The reason for the increased risk of breast cancer in women with NF1 is not understood. Notably, mutations in the NF1gene have been found in the breast cancer tissue of women who do not have NF1. It is known that cancer is the result of the accumulation of genetic alterations that cause cells to behave abnormally. The fact that the NF1gene has been shown to be mutated in some common cancers, including breast cancer, might indicate that the NF1 mutation puts an individual one step closer to developing other cancers.  

A genetic panel of tests is often performed in women who have been diagnosed with breast cancer or have a family history of breast cancer, 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 BRAC1and BRCA2. We sometimes receive referrals to our clinic from women who have undergone genetic testing for a breast cancer diagnosis and have been found to have a mutation for NF1.There are three possible reasons for this finding: first, the individual has NF1 and the clinical features have gone unrecognized; second, the individual has a mosaic form of NF1 that is detected in the blood but may not be present in all cells of the body; third, genetic variants are sometimes found in testing that are not pathogenic, and are referred to as “variants of unknown significance,” and do not necessarily equate with having a condition such as NF.

Due to the increased risk of breast cancer in women with NF1, the National Comprehensive Cancer Network (NCCN), an organization that issues screening guidelines for various cancers, has recently recommended that women with NF1 be screened for breast cancer at an earlier age than the general population, with mammograms starting at age 30. Also, the NCCN recommends consideration of use of contrast enhanced breast MRI between the ages of 30 and 50. After this, the guidelines shift back to that of the general population.  Because it isn’t uncommon for women with NF1 to have neurofibromas around the beast, most commonly around the areola, some patients are concerned that neurofibromas in the breast may be mistaken for breast tumors during imaging. While this issue may sometimes make it more difficult to interpret masses in the breast, neurofibromas 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.

Pheochromocytoma

A tumor of the adrenal gland called pheochromocytoma affects fewer than 5% of people with NF1, although it’s an important tumor to recognize. The adrenal glands produce the hormones epinephrine and norepinephrine that trigger the body’s fight-or-flight response to a perceived threat, causing an increase in heart rate and blood pressure. A pheochromocytoma causes the irregular and excessive release of these hormones, resulting in symptoms of high blood pressure, rapid heart rate and palpitations, episodes of flushing, and excessive sweating. 

When a patient presents with these symptoms, a blood test is done to measure plasma free metanephrines, which assesses the amounts of metabolic byproducts of epinephrine and norepinephrine present in the blood. A positive blood test result requires a confirmatory 24-hour urine collection for measurement of the same substances. If laboratory tests indicate the possibility of a tumor, abdominal imaging is performed to locate a possible tumor and may include CT scan and a form of PET scanning technology that can detect radioactive compounds taken up by a tumor.

Gastrointestinal Stromal Cell Tumors

Gastrointestinal stromal cell tumors (GISTs) are tumors of the GI tract that most commonly occur in the stomach or small intestine. Although rare, there is an increased risk of development of GIST in people with NF1. The primary symptoms of GISTs include abdominal pain and GI bleeding. These tumors are diagnosed using endoscopy, a procedure used to examine the digestive tract.