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.