Before continuing our discussion from last month regarding a review of the pediatric NF clinical care guidelines, I’d like to mention that our annual UAB NF Symposium Family Day was held on Saturday, August 24, in the Bradley Lecture Center of the Children’s Harbor Building. Co-sponsored by the UAB Department of Genetics and the Children’s Tumor Foundation (CTF), this half-day, free event provides NF families and patients an opportunity to hear a series of presentations on a range of NF-related topics from clinical experts. Also, the event offers a venue for families to establish a connection with others who are sharing the same journey, which can be especially meaningful for those who are newly diagnosed. The event was a great success, with more than 100 people registered.

Malignancies Related to NF1

In addition to optic gliomas, discussed in last month’s blog, the pediatric NF clinical care guidelines provide a review of the most commonly occurring malignancies in children with NF1; these include malignant peripheral nerve sheath tumors (MPNSTs), pheochromocytomas, and leukemia. MPNSTs represent one of the few life-threatening complications of the condition. These tumors are uncommon in children and occur mostly in teens and young adults, with the lifetime risk between 8% and 13% for those with NF1. Malignant peripheral nerve sheath tumors usually arise from pre-existing plexiform or nodular neurofibromas. Because MPNSTs can be difficult to treat, the focus is on early diagnosis. The clinical care guidelines indicate a possible diagnosis based on any one of the following: persistent unexplained pain, particularly if it progresses in intensity or wakes one from sleep; rapid growth of a tumor; and a change in a tumor from soft to hard.

If a malignancy is suspected based on clinical presentation, an MRI is usually performed. While MRI will not diagnose a malignancy, it can indicate unusually solid areas of a tumor where cells have deteriorated that are characteristic of a malignancy. Based on these results, a positron emission tomography (PET) scan with radiographic computed tomography (PET-CT) or magnetic resonance imaging (PET-MRI) may be performed to determine the tumor’s uptake of radioactive tracer material. Malignant tumors take up more of the radioactive material on the scan, indicating a possible malignancy, though a biopsy needs to be performed for pathological confirmation. Treatment of MPNSTs usually involves surgery, sometimes with accompanying radiation therapy.  Chemotherapy may be used, though if the tumor has spread this is often unsuccessful.

The guidelines also mention other, less commonly occurring pediatric malignancies in NF1, including astrocytomas, a type of malignant brain tumor; rhabdomyosarcoma, a malignant tumor that originates in the soft tissues of the body; pheochromocytoma, a tumor of the adrenal gland; and juvenile myelomonocytic leukemia, a rare type of blood cancer that occurs in young children.

Although pheochromocytoma affects fewer than 5% of people with NF1 and usually occurs in young adults, it’s an important tumor to recognize. A pheochromocytoma causes the irregular and excessive release of the hormones epinephrine and norepinephrine, resulting in symptoms of high blood pressure, rapid heart rate and palpitations, episodes of flushing, and excessive sweating. When these symptoms are present, a blood test is performed to assess the amounts of metabolic byproducts of epinephrine and norepinephrine present in the blood. A positive result requires a confirmatory 24-hour urine collection for measurement of the same substances. If laboratory results indicate a possible tumor, abdominal imaging is performed and other studies, including use of a radioactive tracer. Treatment is surgical and requires careful planning by an experienced surgical team.

>The clinical guidelines also note that breast cancer occurs more frequently in women with NF1 than in the general population, which should be kept in mind as females with NF1 progress into young adulthood. This risk, along with surveillance guidelines, has been discussed in a previous blog about the adult management guidelines.

Neurologic Issues

Migraine headaches are more common in people with NF1 than in the general population. In addition to the primary symptom of headache, migraines may also present with stomachache and nausea in children. The guidelines indicate that clinical judgement should be used in determining whether MRI is needed to determine other causes for headache. Indications for MRI could include: symptoms of increased intracranial pressure; a new neurologic deficit; or a new onset of seizures. Migraine in children with NF1 can usually be managed in the same way as similar headaches in the general population and may include lifestyle modification, the use of non-prescription medication and, in some cases, treatment with prescription medications.

The guidelines also mention that seizures are more common in people with NF1 than in the general population. This may be due, in part, to structural or vascular changes in the brains of people with NF1, and rarely indicate the presence of a tumor. The guidelines recommend brain MRI at the initial onset of seizure in those with NF1 and management by a physician who is experienced in the treatment of seizures.

It has been several months since Dr. Lane Rutledge, who was our colleague in the UAB NF Clinic, passed away unexpectedly, and her absence has been felt by those of us in the NF Clinic as well as by her patients. While patients with urgent issues are seen in the clinic right away, others may sometimes wait longer for an appointment than we would like. We’re currently working to expand NF Clinic capacity by integrating pediatric and adult neuro-oncology into the clinic to assist in following NF patients who have brain tumors, optic gliomas, and complex plexiform neurofibromas.  Fortunately, as more treatments have become available, particularly for plexiform neurofibromas, our NF Clinic is in a position to enroll many patients in clinical trials for certain treatments. Patients are sometimes surprised at the therapeutic options we now have at our disposal, and we’re pleased to be able to offer these new and promising clinical trials.

Pediatric Clinical Care Guidelines for Optic Pathway Gliomas

Continuing our review of the newly published pediatric NF clinical care resource, the next issue to cover is the optic pathway glioma, which is a tumor that occurs in 15% of children with NF1 and usually presents before six years of age.  Optic gliomas can involve one or both optic nerves or the optic chiasm, the area where optic nerves meet in front of the brain.  Although optic glioma is the most common central nervous system-associated tumor in children with NF1, most optic gliomas are non-progressive and do not require treatment. The guidelines emphasize the consensus recommendation of annual eye exams with a pediatric ophthalmologist for children with NF1 beginning at the time of diagnosis, and these exams should be performed more frequently or repeated if there is a concern.

Because a small percentage of optic pathway gliomas can lead to vision loss or precocious puberty, there has been significant discussion among NF clinicians about whether early detection is beneficial. The practice guidelines at this point recognize that there is controversy about neuroimaging as a baseline screening test for optic gliomas. Baseline neuroimaging is viewed as optional unless symptoms are present. The practice guidelines provide a useful table regarding indications for neuroimaging in children with NF1, including the following:

  • Focal sensory or motor symptoms confined to one area of the body;
  • New onset of seizures in the brain, although these are not common in NF;
  • Headaches; these are common in NF but if especially severe may be an indication for neuroimaging;
  • Signs of increased intracranial pressure, such as severe headache, lethargy, and vomiting.
  • Stroke-like symptoms, including vision problems, numbness, and tingling. These symptoms could indicate a vascular event, such as a transient ischemic attack.
  • Declining visual acuity. Because children typically don’t report this problem, it would be suspected based on increased clumsiness, tripping, or difficulty with hand/eye coordination.
  • Precocious puberty, which includes breast development and the onset of menses in girls and the development of pubic, underarm, or facial hair in boys as well as accelerated growth in girls and boys. This condition could indicate the presence of an optic pathway glioma with contiguous involvement of the hypothalamus.
  • Head and neck plexiform neurofibromas increasing in size or the development of new pain;
  • Decline in cognitive function over time;
  • Significant difference in arm or leg length.

The guidelines also discuss characteristic MRI findings that can occur in children with NF1, including T2 hyperintensities. Also known as “unidentified bright objects,” these benign lesions are visible on MRI predominantly in the basal ganglia, brainstem, and cerebellum. They typically appear in young children between the ages of two and 10 years of age and eventually regress and disappear. If the lesions enhance with contrast on MRI, this could indicate the presence of a low-grade glioma, though these also can be very slowly progressive or may not progress at all. The practice guidelines recommend clinical monitoring for symptoms such as headache, hydrocephalus, or cranial nerve dysfunction in the setting of glioma found by MRI.

In the next few blog posts, I’d like to review the newly released pediatric NF guidelines that were published in the journal Pediatrics (Vol.143, Issue 5) as a joint venture between the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG). These guidelines serve as an update to previous AAP guidelines regarding health supervision for pediatric patients with NF1, with additional input from the ACMG.

These are consensus guidelines developed by a group of clinical experts, of which I was a part, who provided their opinions based on clinical experience as well as a review of evidence from the literature. While evidence-based guidelines are developed through a formal review of published, peer-reviewed clinical research, consensus-based guidelines summarize current knowledge of clinical care and propose an approach to diagnosis and management.

Diagnosis and Differential Diagnosis

The first component of the new guidelines is diagnosis and differential diagnosis of NF1 in pediatric patients. It’s important to point out that this was not an effort to revise the diagnostic criteria, which were established in 1987 by the NIH consensus of experts, although there is currently an effort underway under the aegis of the Children’s Tumor Foundation to review these criteria.

The first feature usually seen in children with NF1 is multiple café-au-lait spots. These usually have relatively sharp borders that are clear and distinct from surrounding skin and are sometimes referred to as “typical” café-au-lait spots. It is possible for some children with NF1 to have some café- au-lait spots that are “atypical” in appearance, which means they may be highly variable in shape, size, degree of pigmentation, and distinctness of the margins. However, if all of the spots are atypical in appearance, this is less likely to be associated with NF1.

The guidelines also mention a differential diagnosis of other conditions with café-au-lait spots that can appear similar to NF1, including Legius syndrome, which is a benign condition that does not cause the development of tumors and is much rarer than NF1.  Legius syndrome should be considered in any child (or adult for that matter) who has café-au-lait spots and skin fold freckles but no other signs of NF1.  The guidelines also mention that some fair-skinned people can have up to six café-au-lait spots, although these individuals don’t seem to have any underlying medical condition.

Two additional conditions are discussed in the guidelines that can sometimes be associated with NF1. The first is juvenile xanthogranuloma, which occurs more in children with NF1 than in the general population. These small, yellowish bumps are seen in a some children with NF1 in the early years of life, after which time they gradually regress.  They can be anywhere on the body, but seem especially common around the hairline.   Because these bumps are benign, there is no need to monitor them. Although there was a previous suggestion in the clinical literature about an association with leukemia, there is not good evidence to support this in children with NF1. I tend to be reassuring with parents whose children develop juvenile xanthogranulomas that these are benign.

The second condition that can be associated with NF1 is nevus anemicus, which appears as a flat, sharply marginated area of reduced skin pigmentation. These areas are benign, but because they may be more frequent in people with NF1, their presence may be useful as a diagnostic tool.

The Role of Genetic Testing

The guidelines emphasize that genetic testing can be useful in the following circumstances: to confirm a diagnosis in a young child; to distinguish NF1 from Legius Syndrome; and to diagnose individuals who present with unusual features. The guidelines emphasize that genetic testing will not generally predict future complications of NF, as only a few genotype-phenotype correlations have been established for some specific mutations. Approximately 95% of individuals who fulfill the diagnostic criteria for NF1 will test positive, although some people who have mosaicism may not test positive. Mosaicism is 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 NF1 mutation while other cells do not. This can lead to having signs of NF1 confined to a restricted area of the body, though in some instances it just causes milder generalized NF.

Neurofibromas

The guidelines discuss various types of neurofibromas and some of the associated symptoms. These include isolated neurofibromas on or under the skin, as well as plexiform neurofibromas. Itching can occur in some people with NF1, although this is more common in adults and typically happens when neurofibromas are forming. In addition, the guidelines emphasize that non-plexiform cutaneous neurofibromas are not believed to pose a risk for malignant transformation. Plexiform neurofibromas, which occur in 50% of NF1 cases, are believed to be congenital, i.e., present from birth. They tend to grow most rapidly in children, though growth can occur any time. One should always be alert to symptoms such as pain, rapid growth, or nerve compression, as these could be signs of malignant changes and indicate the need for evaluation.

NF Awareness Month

May was NF Awareness Month. Here is a link to a few pictures taken around the UAB campus showing related activities.