Neurofibromatosis type 1

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder affecting approximately 1 in 3500 people. Significant advances in the understanding of the pathophysiology of NF1 have been made in the last decade. While no medical therapies for NF1 are currently available, trials are ongoing to discover and test medical treatments for the various manifestations of NF1, primarily plexiform neurofibromas, learning disabilities, and optic pathway gliomas. In addition, mutational analysis has become available on a clinical basis and is useful for diagnostic confirmation in individuals who do not fulfill diagnostic criteria or when a prenatal diagnosis is desired. There are several disorders that may share overlapping features with NF1; in 2007, a disorder with cutaneous findings similar to NF1 was described. This paper addresses the dermatologist's role in diagnosis and management of NF1 and describes the variety of cutaneous and extracutaneous findings in NF1 to which the dermatologist may be exposed.

Learning objectives: After completing this learning activity, participants should be able to discuss the indications and limitations of genetic testing in neurofibromatosis type 1, distinguish common and uncommon cutaneous findings, and recognize the dermatologist's role in diagnosis and management.

Figure 1. Schematic of interactions of key proteins and genes involved in the pathogenesis of NF1

The MAPK/ERK pathway is a complex series of signals and interactions involved in cell growth and proliferation. Under normal conditions, the NF1 gene product neurofibromin promotes the conversion of Ras into its inactive form, thus suppressing cell growth. In NF1, there is a loss of or diminished function of the NF1 gene and the process is left unhindered. SPRED1 inhibits Raf and is the implicated gene/protein in NF1-like syndrome. mTOR has a key role in an additional pathway leading to cell growth and proliferation. Sirolimus inhibits it by binding to an intracellular receptor, FKBP12 (not shown), the complex of which then binds directly to mTOR.

Figure 2

Figures 3

a & b. Pictures of segmental NF1 showing patients with a) pigmentary and b) tumor manifestations.

Figures 3

a & b. Pictures of segmental NF1 showing patients with a) pigmentary and b) tumor manifestations.

Figure 4

Cafe-au-lait macules on the thigh of a child.

Figure 5

Bilateral axillary freckling in a child.

Figures 6

a & b. Various morphologies of cutaneous neurofibromas.

Figures 6

a & b. Various morphologies of cutaneous neurofibromas.

Figure 7

Plexiform neurofibroma on the abdomen of a child.