Genetic Predisposition of Neurofibromas in Neurofibromatosis Type 1
Genetic Predisposition of Neurofibromas in Neurofibromatosis Type 1
The author addresses the issue of neurofibroma classification and implications for treatment. He emphasizes the importance of understanding that not all neurofibromas are the same and that the key differences between the types of neurofibromas involve which portions of the nerve sheath contribute to the distinctive behavior of the different types of lesions.
Endoneurial neurofibromas derive from cellular elements ordinarily restricted to the endoneurium. Perineurial neurofibromas arise within individual fascicles of a nerve and are largely confined thereby, precluding a breach of the epineurium. Epineurial neurofibromas are contained only by the epineurium, and ultimately that portion of the nerve sheath is breached by these lesions.
Whether the perineurium is present or breached becomes the key element for exploiting this approach to neurofibroma origins, behaviors, and treatment, surgical and medical. With respect to surgical treatment, perineurial neurofibromas will have clean planes of dissection about the involved nerve. In contrast, endoneurial and epineurial neurofibromas infiltrate adjacent tissues, leading to surgical challenges. With respect to pharmaceutical approaches, the integrity of the perineurium is likely to prove critical: a specific function of the perineurium is to serve as a barrier to various materials, microbiological or chemical. Thus, drugs that might be effective when the perineurium is absent or rent may be less effective (or not effective at all) if the perineurium is intact, as is expected in cases of perineurial neurofibromas.
I have previously proposed that the neurofibromas, specifically as we have come to know them in the context of the human disorder NF1, are not necessarily "tumors" in the usual sense. Rather, I think that they are best understood as dysplasias, aberrant patterns of growth originating in the embryo or at various times after birth. On the basis of this notion, I have elaborated on two approaches to understanding the origin, progression and treatment-surgical and nonsurgical-of neurofibromas. The first of these involves the suggestion that at least some neurofibromas are a manifestation of aberrant wound healing, with a critical role for the mast cell. The second approach involves the notion that not all neurofibromas are the same, that they are different in terms of histological characteristics, timing of onset, natural history, and other aspects, ultimately with particular focus on the perineurium.
In this paper I will focus on the details of the second approach, with some emphasis on the neurosurgical relevance. At this point, many experts on NF1 would emphasize that the NF1 gene is a "tumor suppressor gene" and proceed to explain neurofibroma "tumor" formation in terms of the NF1 gene product, neurofibromin, and its role in the p21-ras growth promotion pathways. Focusing on this tumor suppressor function results in the tendency to interpret genetic information in terms of what is currently the most obvious biochemical element of pathogenesis. However, given the very large size of NF1 and its quite incredible conservation during evolution, there must be more to the gene than simply tumor suppression. This conclusion is supported both by the protean nontumor manifestations of the disorder NF1 and the disorder's almost total absence from feral animal populations (although neurofibromas are common among vertebrates).
Although I will focus on how the genetic abnormalities and the formation of NF1 neurofibromas are interrelated- with a less intense discussion of neurofibrosarcomas- I also wish to emphasize that the NF1 phenotype entails much more than tumors of the central and peripheral nervous systems and, conversely, that NF1 neurofibromas cannot be explained solely in terms of NF1 mutations and abnormal function of neurofibromin. For example, as I pointed out over 20 years ago, mast cells play a key role in the origin and progression of neurofibromas.
Ultimately, NF1 is a genetic disorder that is particularly efficient at producing neurofibromas. It is one of the most common of all human genetic disorders, with a prevalence of about one in 3000 and a mutation rate of about one in 10,000. Given that there are over a million people with NF1 at any one time, it is not surprising that differences among the innumerable NF1 neurofibromas have become obvious.
Neurofibromatosis Type 1 is an autosomal dominant disorder; approximately one third of cases represent new germinal mutations and a much smaller proportion represent mosaicism due to postzygotic mutations. The occurrence rate among offspring of patients with NF1 is no less than 50%, meaning that penetrance is complete, with no "skipped generations." The expressivity is markedly variable, meaning that from one person to another, even within a family, the manifestations are quite different. Conversely, some mutations seem to have more or less distinctive phenotypes. For example, patients whose mutation is accounted for by deletion of the entire gene (usually the maternal allele) have more problems with learning disabilities, perhaps a distinctive facies and habitus and earlier onset of neurofibromas, involving both the skin and paraspinal regions. Another group of NF1 patients- those having a deletion of the nucleotide base triplet AAT in exon 17 of NF1-actually have no neurofibromas involving the skin and very few elsewhere.
The NF1 gene is very large and is located proximally on the long arm of human chromosome 17 at position 17q11.2. It is highly conserved, being present, for example, in the fruit fly (Drosophila). The NF1 gene is also very complex, with an open reading frame of 8454 nucleotides in about 335 kilobases of genomic DNA and 61 exons. Splice variants are known, and posttranslational modification is a factor as well. This last fact means that expression of NF1 is complex. The gene product, neurofibromin, is a relatively large peptide, with a molecular weight of greater than 220 kD. One region of neurofibromin functions as a GAP. The neurofibromin GAP function is one of many within the cell that are involved in the coordination of cellular and tissue physiology. The GAPrelated domain of NF1 selectively stimulates the intrinsic GTPase of p21-ras, which in turn curbs cell proliferation under the control of p21-ras. Loss-of-function mutations in NF1 result in reduced control of cell proliferation. In short, by this description, NF1 is a tumor suppressor gene, although obviously this explanation does not account for all of the functions of either NF1 or neurofibromin or for all aspects of disorders resulting from NF1 mutation. For example, the deletion mutation noted above that leads to NF1 without skin neurofibromas is in exon 17, which is not part of the NF1 GAP-related domain.
Exactly how loss of function of neurofibromin accounts for all of the features of NF1 and neurofibromas in particular is unknown. More specifically, it is not known how one mutation can manifest as multiple types of neurofibromas, each of which has a distinctive natural history and consequence. When loss of the second-normal-allele is sought in cells of NF1-associated tumors, only some neurofibromas and virtually all NF1-associated malignancies (neurofibrosarcomas) show such a deficiency (loss of heterozygosity).
Abstract and Introduction
Abstract
The author addresses the issue of neurofibroma classification and implications for treatment. He emphasizes the importance of understanding that not all neurofibromas are the same and that the key differences between the types of neurofibromas involve which portions of the nerve sheath contribute to the distinctive behavior of the different types of lesions.
Endoneurial neurofibromas derive from cellular elements ordinarily restricted to the endoneurium. Perineurial neurofibromas arise within individual fascicles of a nerve and are largely confined thereby, precluding a breach of the epineurium. Epineurial neurofibromas are contained only by the epineurium, and ultimately that portion of the nerve sheath is breached by these lesions.
Whether the perineurium is present or breached becomes the key element for exploiting this approach to neurofibroma origins, behaviors, and treatment, surgical and medical. With respect to surgical treatment, perineurial neurofibromas will have clean planes of dissection about the involved nerve. In contrast, endoneurial and epineurial neurofibromas infiltrate adjacent tissues, leading to surgical challenges. With respect to pharmaceutical approaches, the integrity of the perineurium is likely to prove critical: a specific function of the perineurium is to serve as a barrier to various materials, microbiological or chemical. Thus, drugs that might be effective when the perineurium is absent or rent may be less effective (or not effective at all) if the perineurium is intact, as is expected in cases of perineurial neurofibromas.
Introduction
I have previously proposed that the neurofibromas, specifically as we have come to know them in the context of the human disorder NF1, are not necessarily "tumors" in the usual sense. Rather, I think that they are best understood as dysplasias, aberrant patterns of growth originating in the embryo or at various times after birth. On the basis of this notion, I have elaborated on two approaches to understanding the origin, progression and treatment-surgical and nonsurgical-of neurofibromas. The first of these involves the suggestion that at least some neurofibromas are a manifestation of aberrant wound healing, with a critical role for the mast cell. The second approach involves the notion that not all neurofibromas are the same, that they are different in terms of histological characteristics, timing of onset, natural history, and other aspects, ultimately with particular focus on the perineurium.
In this paper I will focus on the details of the second approach, with some emphasis on the neurosurgical relevance. At this point, many experts on NF1 would emphasize that the NF1 gene is a "tumor suppressor gene" and proceed to explain neurofibroma "tumor" formation in terms of the NF1 gene product, neurofibromin, and its role in the p21-ras growth promotion pathways. Focusing on this tumor suppressor function results in the tendency to interpret genetic information in terms of what is currently the most obvious biochemical element of pathogenesis. However, given the very large size of NF1 and its quite incredible conservation during evolution, there must be more to the gene than simply tumor suppression. This conclusion is supported both by the protean nontumor manifestations of the disorder NF1 and the disorder's almost total absence from feral animal populations (although neurofibromas are common among vertebrates).
Although I will focus on how the genetic abnormalities and the formation of NF1 neurofibromas are interrelated- with a less intense discussion of neurofibrosarcomas- I also wish to emphasize that the NF1 phenotype entails much more than tumors of the central and peripheral nervous systems and, conversely, that NF1 neurofibromas cannot be explained solely in terms of NF1 mutations and abnormal function of neurofibromin. For example, as I pointed out over 20 years ago, mast cells play a key role in the origin and progression of neurofibromas.
Ultimately, NF1 is a genetic disorder that is particularly efficient at producing neurofibromas. It is one of the most common of all human genetic disorders, with a prevalence of about one in 3000 and a mutation rate of about one in 10,000. Given that there are over a million people with NF1 at any one time, it is not surprising that differences among the innumerable NF1 neurofibromas have become obvious.
Neurofibromatosis Type 1 is an autosomal dominant disorder; approximately one third of cases represent new germinal mutations and a much smaller proportion represent mosaicism due to postzygotic mutations. The occurrence rate among offspring of patients with NF1 is no less than 50%, meaning that penetrance is complete, with no "skipped generations." The expressivity is markedly variable, meaning that from one person to another, even within a family, the manifestations are quite different. Conversely, some mutations seem to have more or less distinctive phenotypes. For example, patients whose mutation is accounted for by deletion of the entire gene (usually the maternal allele) have more problems with learning disabilities, perhaps a distinctive facies and habitus and earlier onset of neurofibromas, involving both the skin and paraspinal regions. Another group of NF1 patients- those having a deletion of the nucleotide base triplet AAT in exon 17 of NF1-actually have no neurofibromas involving the skin and very few elsewhere.
The NF1 gene is very large and is located proximally on the long arm of human chromosome 17 at position 17q11.2. It is highly conserved, being present, for example, in the fruit fly (Drosophila). The NF1 gene is also very complex, with an open reading frame of 8454 nucleotides in about 335 kilobases of genomic DNA and 61 exons. Splice variants are known, and posttranslational modification is a factor as well. This last fact means that expression of NF1 is complex. The gene product, neurofibromin, is a relatively large peptide, with a molecular weight of greater than 220 kD. One region of neurofibromin functions as a GAP. The neurofibromin GAP function is one of many within the cell that are involved in the coordination of cellular and tissue physiology. The GAPrelated domain of NF1 selectively stimulates the intrinsic GTPase of p21-ras, which in turn curbs cell proliferation under the control of p21-ras. Loss-of-function mutations in NF1 result in reduced control of cell proliferation. In short, by this description, NF1 is a tumor suppressor gene, although obviously this explanation does not account for all of the functions of either NF1 or neurofibromin or for all aspects of disorders resulting from NF1 mutation. For example, the deletion mutation noted above that leads to NF1 without skin neurofibromas is in exon 17, which is not part of the NF1 GAP-related domain.
Exactly how loss of function of neurofibromin accounts for all of the features of NF1 and neurofibromas in particular is unknown. More specifically, it is not known how one mutation can manifest as multiple types of neurofibromas, each of which has a distinctive natural history and consequence. When loss of the second-normal-allele is sought in cells of NF1-associated tumors, only some neurofibromas and virtually all NF1-associated malignancies (neurofibrosarcomas) show such a deficiency (loss of heterozygosity).
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