I am writing this as I am on my way to the 2019 NF Conference in San Francisco organized by the Children’s Tumor Foundation. 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 have a strong presence at the conference again this year; I will present a talk on genome-guided therapeutics, and several of our scientists will have poster presentations summarizing our drug discovery initiatives and progress in clinical trials. We look forward to participating in this important scientific forum and sharing highlights of the event in a subsequent blog post.

Neurodevelopmental Problems

Turning back to our review of the pediatric NF clinical care resource, the next issue to consider is the occurrence of neurodevelopmental problems associated with NF1. Children with NF1 often have low muscle tone, which can be associated with a delay in gross motor development and poor coordination. Low muscle tone means that muscles feel more lax than normal, although muscle strength is typically within normal limits. The bellies of some children with this condition may protrude and give the appearance of a potbelly, which is due to abdominal and spinal muscles that are laxer than normal. Although low muscle tone usually gradually improves through childhood, some have relatively poor coordination compared to their peers that is persistent. Studies of muscles in individuals with NF1 have shown some abnormalities of the function of muscle cells, suggesting that the NF1 gene can directly affect the muscle.

Speech and language problems also occur with greater frequency in children with NF1 than in the general population, and these problems may be helped with speech therapy. Also, a condition called velopharyngeal insufficiency, which leads to a nasal-sounding voice, is an occasional finding in children with NF1. Evaluation by a speech therapist and otolaryngologist would be appropriate if this is present.

It is estimated that at least 50% of children with NF1 have some type of learning problem, which is a higher occurrence than in the general population. Learning problems in children with NF1 are highly variable, and common problems can include difficulties with executive function and verbal or nonverbal learning disabilities. It’s also not uncommon for children with NF1 to be diagnosed with attention deficit disorder (ADD), sometimes with hyperactivity (ADHD). The same treatment approaches for management of ADHD as are used in the general population are used for children with NF1, which may include the use of stimulant medication to help manage symptoms. Parents and educators should be vigilant in recognizing possible signs of learning problems in children with NF1 so that a neuropsychological assessment can be performed to identify specific needs and interventions, including a 504 plan or an individualized education plan. Appropriate interventions and supports for children with learning problems can make a significant difference in long-term academic success.

In addition to learning problems, some studies suggest that features of autism spectrum disorder (ASD) occur with greater frequency in individuals with NF1. The most common ASD-related features in children with NF1 include difficulty with social pragmatics and communication skills, which can increase the risk of social anxiety. Therapies that focus on improving social skills and communication can be helpful in addressing these problems. A small proportion of individuals with NF1 have severe intellectual disability. Many of these have a distinctive NF1 gene variant in which the entire gene, along with several surrounding genes, are deleted from the chromosome. This distinctive mutation generally results in more severe manifestations of NF1 than most other types of mutations.

Skeletal Abnormalities

We often find that children with NF1 have relatively large head sizes compared to their body size. The large head size usually is benign, although there are rare instances of obstruction of spinal fluid flow in the brain, called aqueductal stenosis, that causes increased fluid pressure and large head size. While rare, it’s important to recognize the symptoms, which include severe headaches that might be associated with vomiting and other neurological signs.

Children with NF1 frequently have relatively short stature. In most cases, the cause is unknown, though some can be demonstrated to be growth hormone deficient. Treatment with growth hormone can be helpful and might be considered for these children. Although there has been some concern that use of growth hormone might stimulate tumor growth in children with NF1, there is no clear evidence to support this. We have used growth hormone for some of our patients with no apparent adverse effects, though we monitor these children closely for potential tumor growth.

Other problems such as osteopenia, or deficient bone calcification, can occur in children with NF1. This issue presents a minor increased risk of fractures. The cause of osteopenia in children with NF1 is not well understood. Some children with NF1 have low levels of vitamin D, which might be a contributing factor. It is therefore recommended to monitor vitamin D levels and consider supplementation if the level is low. Also, long bone dysplasia, which is an abnormality of the structure of the bone, can occur. This problem usually affects the tibia, which is the shin bone in the lower leg, and usually causes a bowing of the leg that presents in infancy. If the condition is confirmed with X-ray, the child is referred to an orthopedist for treatment with a leg brace to prevent future fracture. Dysplasia of the sphenoid, one of the bones in the skull that forms the orbit (eye socket), is another skeletal abnormality that can occur in children with NF1. The deformity is present at birth and can be associated with plexiform neurofibroma. The eye may be recessed if there is sphenoid dysplasia without neurofibroma, or it may bulge outward if there is a neurofibroma. An X-ray or CT scan can confirm the presence of orbital dysplasia, and an MRI can detect a plexiform neurofibroma. Orbital dysplasia and plexiform neurofibroma can be difficult to treat, and requires a team that includes craniofacial surgeons and ophthalmologists to consider whether and when surgery is indicated. Plexiform neurofibromas may respond to non-surgical treatments, such as MEK inhibitors, that are currently in clinical trial.

Scoliosis, a lateral curve of the spine, is a common skeletal problem in children with NF1 that usually appears in early to mid-childhood. The condition usually involves angulation in the thoracic spine. Management includes periodic spine X-rays and physical examination to determine whether surgery is needed. A plexiform neurofibroma can sometime be present near the scoliosis and would also require monitoring.

Chest-wall deformities, either pectus excavatum or pectus carinatum, can sometimes occur in children with NF1; the former causes a sunken appearance of the chest, while the latter causes the chest to protrude outward. The condition should be monitored, as it can sometimes require surgery. Other skeletal abnormalities include nonossifying fibromas, which are areas of incomplete bone mineralization. The condition can occasionally result in fractures, although preventive screening for the problem is not recommended. Lastly, some individuals with NF1 can have incomplete closure of the lambdoidal suture, which results in a soft spot on the back of the head, most often on the left side. The condition is benign, and no treatment or follow-up is required.

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.