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One to a couple of CALMs are common in the general population, therefore, six or more CALMs are required to fulfill one diagnostic criteria of NF1 (Table 1a).Histologically, CALMs show hyperpigmentation of the basal layer keratinocytes of the epidermis with normal to slightly increased number of melanocytes.

An array comparative genomic hybridization (a CGH) study of plexiform neurofibromas from NF1 patients showed a recurrent somatic 9p21.3 deletion involving the antisense noncoding RNA in the INK4 locus (ANRIL) and an association between a germline SNP rs2151280, resulting in reduced ANRIL transcript levels and the number of plexiform neurofibromas, suggesting that ANRIL expression mediated plexiform neurofibromas susceptibility.Therefore, the gene has been classified as a tumor suppressor.Consistent with a role of a tumor suppressor gene, loss of heterozygosity (LOH), or ‘second-hit’ somatic mutations in the inherited wild-type allele are present in many tumor types in NF1 patients, including neurofibromas, malignant peripheral nerve sheath tumors, pheochromocytomas, and myeloid tumors.Histologically, the tumor shows tight wavy or interlacing bundles of spindle cells with cellularity and mitoses determining tumor grade.As MPNSTs may resemble desmoplastic melanoma, exclusion of an associated melanocytic precursor lesion (intra-epidermal or intrafollicular melanoma in situ or melanocytic nevus) is required for the diagnosis of MPNST.

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The clinical features of NF1 are numerous and affect multiple organ systems.The most common clinical findings involve the skin, as exemplified by the diagnostic criteria of NF1 (Table 1a).Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma.This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.Though common in the general population as solitary lesions, their number in NF1 patients can vary from a few to thousands. Histologically, they are composed of loosely arranged wavy spindled Schwann-like cells, nerve fibers, perineurial cells and fibroblasts, and infiltrated by mast cells in the dermis or subcutis.

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Neurofibromas are benign but have a significant impact on quality-of-life, mainly due to their appearance.These include cafe-au-lait-macules, axillary and inguinal freckling, neurofibromas, and plexiform neurofibromas, present in 90Café-au-lait macules (CALMs) are tan to brown sharply demarcated, uniformly pigmented macules or patches typically on the trunk and extremities.In NF1, CALMs are the earliest manifestation, typically appearing at 0–3 years of age.Correspondence: Dr M Kiuru, MD, Ph D, Departments of Dermatology and Pathology, University of California Davis, 3301 C Street, Suite 1450, Sacramento, CA 95816, USA.E-mail: [email protected] 10 September 2016; Revised 10 November 2016; Accepted 29 November 2016Advance online publication 9 January 2017MAPK pathway is critical in melanoma.

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