unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas. Loss of tumor suppressor function Neurofibromas arise from nonmyelinating Schwann cells that only express the inactive version of the NF1 gene, which leads to a complete loss of expression of functional neurofibromin. While one defective allele may be inherited, loss of heterozygosity (LOH) must occur before a neurofibroma can form; this is called the 'two-hit hypothesis'. This LOH happens by the same mechanisms, such as oxidative DNA damage, that causes mutations in other cells. Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is called hyperplasia, which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet. In order for the neurofibroma to develop, cells that are heterozygous for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete chemoattractants such as the KIT ligand, and angiogenic factors such as the heparin-binding growth factor midkine. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic lesions created by the nonmyelinating Schwann cells. These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells. The mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment and result in neurofibroma formation. Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point. Diagnosis Dermal neurofibromas may be 2 to 20 mm in diameter, is soft, flaccid, and pinkish-white, and frequently this soft small tumor can be invaginated, as if through a ring in the skin by pressure with the finger, a maneuver called "button-holing". A blood test for protein melanoma inhibitory activity may be used to detect the presence of neurofibromas. A biopsy can be used for histopathology diagnosis. Treatments Dermal neurofibroma Dermal neurofibromas are not usually surgically removed unless they are painful or disfiguring, because there are generally so many of them and they are not dangerous. CO2 lasers have been used to remove dermal neurofibromas. In a paper titled Hypertrophic Scars After Therapy with CO2 Laser for Treatment of Multiple Cutaneous Neurofibromas Ostertag et al. said this about treatment by laser: "The