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.