2.1. Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a dominantly inherited disease caused by mutations in the NF1 gene. The incidence of the disease is estimated to be about 1/3500 with no ethnic or gender-related variability (Fuller et al. 1989, Huson et al. 1989, Poyhonen et al. 2000). CALMs, neurofibromas, axillary/inguinal freckling and Lisch nodules, pigmented spots of the iris, are the most common clinical manifestations associated with the disease. Other important manifestations are vasculopathy involving multiple vessels with lesions varying from stenotic to aneurysmatic, a variety of osseous lesions, including short stature, scoliosis and pseudoarthrosis, optic gliomas and an increased risk for certain malignancies such as MPNSTs and leukemias. NF1 patients also display learning disabilities (Friedman & Riccardi 1999). The diagnostic criteria for NF1 are shown in Table 1 (Gutmann et al. 1997). The NF1 gene is considered as a tumor suppressor because either LOH or homozygous inactivation of the gene has been demonstrated in a number of tissues or cells, including neurofibromas (Sawada et al. 1996, Serra et al. 1997, Kluwe et al. 1999), MPNST (Glover et al. 1991, Legius et al. 1993), myelogenous leukaemias (Side et al. 1997) or melanomas (Andersen et al. 1993b).

The most common skin manifestations seen in NF1 are CALMs, neurofibromas and axillary/inguinal freckling (Friedman & Riccardi 1999). Dermal neurofibromas are benign tumors rising from small nerves. They are usually elevated upwards from skin and are slightly reddish in color. Neurofibromas are largely composed of Schwann cells, fibroblasts, perineural cells and extensive collagenous extracellular matrix (Harkin 1986, Peltonen et al. 1988). CALMs are pigmented patches of the epidermis 10mm or more in diameter. The histological features of CALMs show basilar hyperpigmentation with occasional melanocytic hyperplasia. CALMs are characterized by the presence of melanin macroglobules within melanocytes and keratinocytes. (Jimbow et al. 1973, Martuza et al. 1985) Freckling of skin occurs mainly in non-sun-exposed areas, such as the axillary or inguinal region (Friedman & Riccardi 1999).

Genetic and epigenetic factors have been proposed to play a role in the skin manifestations associated with the disease. LOH has been demonstrated in benign neurofibromas (Sawada et al. 1996, Serra et al. 1997). Physical factors, such as trauma or elevated skin temperature, have also been proposed to play a part in the formation of neurofibromas, CALMs and freckling (Friedman & Riccardi 1999, Karvonen et al. 2000, Kaufmann et al. 2001). Furthermore, monozygous twins with NF1 have been shown to carry different phenotypes of the disease, suggesting the role of epigenetic factors in the development of clinical manifestations (Akesson et al. 1983).