The pathoetiology of neurofibromatosis 1

Abstract

Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell-extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a "second hit" seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1(+/-) genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis.

Figure 1

Proposed model for the development of cutaneous neurofibromas. As opposed to the traditional understanding of neurofibromas being formed by the dissociation of peripheral nerve components, the proposed model views neurofibromas as resulting from divergent cellular differentiation of multipotent precursor cells. The requirements for the development of neurofibromas include the presence of a clonal population of NF1^−/− Schwann cells in a microenvironment harboring other cell types with an NF1^+/− genotype. The potential sources of NF1^−/− Schwann cells are small cutaneous nerve twigs, hair roots, and subcutaneous fat. The close proximity of hair and incipient neurofibromas may suggest that the multipotent NF1^+/− cells residing in this area are the major source of neurofibroma-derived progenitors (NFPs), which can give rise to the different cell types found in the neurofibromas. Animal studies have suggested that the neurofibroma mast cells may be derived from bone marrow. These cellular components alone are, apparently, not sufficient to allow the cutaneous neurofibromas to develop into visible tumors because the latter do not appear before puberty, when marked changes in the hormonal status of an individual take place.