Clinical meaning
Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is an autosomal dominant neurocutaneous (phakomatosis) disorder caused by loss-of-function mutations in the NF1 gene on chromosome 17q11.2, which encodes neurofibromin, a GTPase-activating protein (GAP) that negatively regulates the RAS-MAPK signaling pathway. Neurofibromin normally accelerates the conversion of active RAS-GTP to inactive RAS-GDP, serving as a tumor suppressor. When neurofibromin is absent or dysfunctional, RAS remains constitutively active, driving uncontrolled cellular proliferation through the RAF-MEK-ERK signaling cascade. This affects cells of neural crest origin (Schwann cells, melanocytes, endoneurial fibroblasts), producing the hallmark tumors: neurofibromas (benign peripheral nerve sheath tumors composed of Schwann cells, fibroblasts, mast cells, and perineural cells within a myxoid matrix). Cutaneous neurofibromas are discrete, soft, pedunculated tumors confined to the skin that increase in number with age and during puberty and pregnancy (hormonal influence on tumor growth). Plexiform neurofibromas are congenital, diffuse tumors that grow along the length of a nerve, infiltrating surrounding tissues; they carry an 8-13% lifetime risk of malignant transformation to malignant peripheral nerve sheath tumor (MPNST), which is the leading cause of disease-related mortality in NF1....