神经纤维瘤与神经纤维瘤病发病机制、诊断与治疗进展
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摘要
神经纤维瘤是一种临床常见的良性肿瘤，而神经纤维瘤病又是一种涉及多个系统复杂的疾病，两者在临床有很多重叠面，但两者的病因、病理、治疗及预后又有不同，认知两者，尤其是后者，提高对两疾病的早期诊断及治疗水平，对临床医生及患者都有重要意义。
神经纤维瘤是指起源于神经鞘细胞的一种良性的周围神经瘤样增生性病变。当神经纤维瘤多发或伴发全身其它系统疾患时，称为神经纤维瘤病(NF)。本文通过对大量文献的复习，从临床表现、病理特征、诊断和治疗方面对神经纤维瘤做了简要概述，对神经纤维瘤病做了详尽论述，包括对该病的历史回顾、临床特征、病理特征、分型、诊断标准、影像诊断、最新分子生物学研究进展、发病机制以及基因生化治疗方面的研究进展。
单纯的神经纤维瘤与神经纤维瘤病的神经纤维瘤无论是在发病的部位、形态还是病理表现都几乎一样，只是前者多为单发，以皮肤及皮下组织多见，而后者则以多发者常见，且病变范围广，程度严重，还伴有其它典型征象或其他系统疾病。单纯的局限性神经纤维瘤一般无明显症状，生长较为缓慢，仅在青春期或妊
郑州大学(2 004)硕士学位论文神经纤维瘤与神经纤维瘤病发病机制、诊断与治疗新进展
娠期可有部分加速生长，通常采用手术切除瘤体治疗，部分可完全治愈。而神经
纤维瘤病是目前临床治疗的难点及研究热点。
神经纤维瘤病，以前又称von Recknn沙ausen病，属常染色体显性遗传病。
1987年美国国立健康研究院(NIH)明确了该病有两种类型，即NFI(周围型神
经纤维瘤病)和Nn(中枢型神经纤维瘤病)，分别代表不同的突变基因和不同的
临床特征。而von ReCklinghausen病仅代表其中的NFI;NFZ主要代表颅内神经纤
维瘤病类型。
NFI的临床发病率为1/2 500一1/3000，整体发病在种族间、性别间无明显差别。
NFI基因位于17qll.2上，其编码的神经纤维素蛋白，可使获得活性的ras原癌基
因失活，从而负性调控周围神经鞘膜细胞的分裂增殖。神经纤维瘤病患者的NFI
基因发生了突变或其它改变而丧失了功能，没有了神经纤维素蛋白负性调控的神
经鞘膜细胞便过度增生持续生长，形成典型的神经纤维瘤症状。临床表现为周围
神经分布的地方多发的瘤样增生性结节，可出现于全身各个部位，以皮肤及皮下
多见。镜下结节主要由神经鞘膜细胞、纤维母细胞、肥大细胞等细胞组成，以神
经鞘膜细胞为最多;间质内有较多的粘液样基质。NFI另外两个颇具特征性的征
象是皮肤的咖啡色素斑和虹膜的Lis比结节(即虹膜色素错构瘤)。到了一定年龄，
几乎所有的NFI患者都会出现这三种病症。其他合并症少见并呈明显多样性。神
经纤维瘤病的诊断一般采用1 987年ND扭公布的诊断标准，现代影像学的飞速发展
为该病的临床诊断及治疗提供了很大的帮助。治疗方面仍以针对出现的各种并发
症进行对症处理为主，手术切除有明显症状或恶变的肿瘤，一些生化、基因药物
均在开发和初步的临床试验阶段。NFZ在临床远较NFI少见，发病率为1/50000。
临床主要表现为双侧听神经纤维瘤，咖啡色素斑和周围神经纤维瘤极少见，可并
发中枢神经其他肿瘤。NFZ基因位于22号染色体上，编码merlin蛋白，其功能尚
在研究中，但都提示其有负性生长调节作用。NFI和NFZ均属于常染色体显型遗
郑州大学(2004)硕士学位论文神经纤维瘤与神经纤维瘤病发病机制、诊断与治疗新进展
传性疾病，遗传病的最佳疗法是基因治疗。目前NFZ基因治疗已在体外研究中取
得一定进展，NFI基因治疗由于NFI基因突变率高、病变涉及系统多、动物模型
制作困难等因素影响尚无大的进展，但基因治疗将是我们今后努力的方向。
对于临床多见的神经纤维瘤患者，考虑到有神经纤维瘤病的可能(因为一些
基因突变型的神经纤维瘤病患者早期可能只表现为单发的神经纤维瘤)，所以作者
认为临床有必要对每一位神经纤维瘤患者详细询问病史、做家族史调查及全面的
体检，以排除神经纤维瘤病。对无明确神经纤维瘤病诊断指征的，可暂且按一般
神经纤维瘤来对待，但必须登记以便进行长期随访。对于神经纤维瘤病患者，随
着对其基因、分子生物学水平的深入研究，有望在充分了解发病机制后寻找出对
其有效的治疗方法。
Neurofibroma is a common benign tumor in clinic , neurofibromatosis is a complex disorder involved multiple systems instead. There are many overlaps between them in clinic, but their etiology, pathology, treatment and prognosis are different . It's very important for clinicians and patients to recognize these diseases (especially later) and to improve their level of early diagnosis and therapy at last.
Neurofibroma refers to a kind of benign hyperplasia disease which arises from epineurium of peripheral nerve system. It is usually be named as neurofibromatosis when there are multiple tumors in the body or accompanied with other systematic diseases. By reviewing a lot of references the author made a brief summary to neurofibroma in this article from clinic manifestation, pathologic features, diagnosis and therapy, and discussed neurofibromatosis in detail including the history, pathogenesis, clinic signs, pathologic characteristics, types, diagnostic criterion, imaging diagnosis, newest developments in molecular biochemistry, pathogenesis and genetic treatment.
The lesions or tumors of neurofibromatosis is almost the same as solitary neurofibroma whether in site of occurrence, morphology or pathology of the lesion, but the latter always presents as solitary and dermal lesion, the former often multi-occurs and involves extensively and seriously instead, usually accompanied with other typical signs or systematic lesions. Solitary neurofibroma is generally asymptomatic, grows slowly, only increases faster in special period. Operation is usually needed and some of the patients can be cured. The nodus and hotpoints of research are focus on neurofibromatosis now.
Neurofibromatosis is an autosomal dominant genetic disease, which also named as Von Recklinghausen disease before. Two types were suggested by NIH of USA in 1987, namely the peripheral type (NF1) and central type (NF2), presenting different mutating gene and clinical characteristics respectively. Von Recklinghausen disease just means NF1 and NF2 mainly indicates neurofibroma in encephalic instead.
The incidence of NF1 in clinic is 1/2500- l/3000.There are no differences between nations and sex. Gene of NF1 sites in 17qll.2 and encodes neurofibomin which can make ras inactive resulting in preventing the proliferation of epineurium which will grow overly and persistently if there is no negative regulating of neurofibromin, when the patient lost the gene's function due to mutation or other changes, and typical symptoms will appear eventually which shows as multi-nodules in the area of peripheral nerves. Every part of human body could be involved and more common in skin or subcutaneous. Under microscope the nodule is found basically composed of Schwann cells, fibroblasts, mast cells et al, and Schwann cells account for the most. There are many mucosubstances in the matrix. Another two featured signs of NF1 are caf -au-lait and iris Lisch nodules. All most all of the patients of NF1 will present these three signs at certain ages. Other complications are seldom but show diversity. The diagnostic criterion suggested by NIH in
1987 is applied in clinic practice at present. The rapid developing medical imaging provides helps greatly to diagnosis and treatment of these two diseases. Therapy still focuses on the treatments to those complications, and surgery have to be considered if the tumors are obvious or have changes of malignant. Some biologic-based therapies and genome medicines are still at their stage of test. NF2 is seldom compared with NF1 in clinic, the incidence of it is about 1/50000, which mainly demonstrates as dual acoustic neuroma and may accompany with other central nerve tumors. Peripheral neurofibroma and cafe-au-lait are seldom at the same time. NF2 gene localizes in 22q and encodes merlin which function is still in research. Many studies show that it has function of negative regulating. NF1 and NF2 all belong to genetic disease and gene therapy must be the best method to treat them. Gene therapy to NF2 has had some development in the research
神经纤维瘤是指起源于神经鞘细胞的一种良性的周围神经瘤样增生性病变。当神经纤维瘤多发或伴发全身其它系统疾患时，称为神经纤维瘤病(NF)。本文通过对大量文献的复习，从临床表现、病理特征、诊断和治疗方面对神经纤维瘤做了简要概述，对神经纤维瘤病做了详尽论述，包括对该病的历史回顾、临床特征、病理特征、分型、诊断标准、影像诊断、最新分子生物学研究进展、发病机制以及基因生化治疗方面的研究进展。
单纯的神经纤维瘤与神经纤维瘤病的神经纤维瘤无论是在发病的部位、形态还是病理表现都几乎一样，只是前者多为单发，以皮肤及皮下组织多见，而后者则以多发者常见，且病变范围广，程度严重，还伴有其它典型征象或其他系统疾病。单纯的局限性神经纤维瘤一般无明显症状，生长较为缓慢，仅在青春期或妊
郑州大学(2 004)硕士学位论文神经纤维瘤与神经纤维瘤病发病机制、诊断与治疗新进展
娠期可有部分加速生长，通常采用手术切除瘤体治疗，部分可完全治愈。而神经
纤维瘤病是目前临床治疗的难点及研究热点。
神经纤维瘤病，以前又称von Recknn沙ausen病，属常染色体显性遗传病。
1987年美国国立健康研究院(NIH)明确了该病有两种类型，即NFI(周围型神
经纤维瘤病)和Nn(中枢型神经纤维瘤病)，分别代表不同的突变基因和不同的
临床特征。而von ReCklinghausen病仅代表其中的NFI;NFZ主要代表颅内神经纤
维瘤病类型。
NFI的临床发病率为1/2 500一1/3000，整体发病在种族间、性别间无明显差别。
NFI基因位于17qll.2上，其编码的神经纤维素蛋白，可使获得活性的ras原癌基
因失活，从而负性调控周围神经鞘膜细胞的分裂增殖。神经纤维瘤病患者的NFI
基因发生了突变或其它改变而丧失了功能，没有了神经纤维素蛋白负性调控的神
经鞘膜细胞便过度增生持续生长，形成典型的神经纤维瘤症状。临床表现为周围
神经分布的地方多发的瘤样增生性结节，可出现于全身各个部位，以皮肤及皮下
多见。镜下结节主要由神经鞘膜细胞、纤维母细胞、肥大细胞等细胞组成，以神
经鞘膜细胞为最多;间质内有较多的粘液样基质。NFI另外两个颇具特征性的征
象是皮肤的咖啡色素斑和虹膜的Lis比结节(即虹膜色素错构瘤)。到了一定年龄，
几乎所有的NFI患者都会出现这三种病症。其他合并症少见并呈明显多样性。神
经纤维瘤病的诊断一般采用1 987年ND扭公布的诊断标准，现代影像学的飞速发展
为该病的临床诊断及治疗提供了很大的帮助。治疗方面仍以针对出现的各种并发
症进行对症处理为主，手术切除有明显症状或恶变的肿瘤，一些生化、基因药物
均在开发和初步的临床试验阶段。NFZ在临床远较NFI少见，发病率为1/50000。
临床主要表现为双侧听神经纤维瘤，咖啡色素斑和周围神经纤维瘤极少见，可并
发中枢神经其他肿瘤。NFZ基因位于22号染色体上，编码merlin蛋白，其功能尚
在研究中，但都提示其有负性生长调节作用。NFI和NFZ均属于常染色体显型遗
郑州大学(2004)硕士学位论文神经纤维瘤与神经纤维瘤病发病机制、诊断与治疗新进展
传性疾病，遗传病的最佳疗法是基因治疗。目前NFZ基因治疗已在体外研究中取
得一定进展，NFI基因治疗由于NFI基因突变率高、病变涉及系统多、动物模型
制作困难等因素影响尚无大的进展，但基因治疗将是我们今后努力的方向。
对于临床多见的神经纤维瘤患者，考虑到有神经纤维瘤病的可能(因为一些
基因突变型的神经纤维瘤病患者早期可能只表现为单发的神经纤维瘤)，所以作者
认为临床有必要对每一位神经纤维瘤患者详细询问病史、做家族史调查及全面的
体检，以排除神经纤维瘤病。对无明确神经纤维瘤病诊断指征的，可暂且按一般
神经纤维瘤来对待，但必须登记以便进行长期随访。对于神经纤维瘤病患者，随
着对其基因、分子生物学水平的深入研究，有望在充分了解发病机制后寻找出对
其有效的治疗方法。
Neurofibroma is a common benign tumor in clinic , neurofibromatosis is a complex disorder involved multiple systems instead. There are many overlaps between them in clinic, but their etiology, pathology, treatment and prognosis are different . It's very important for clinicians and patients to recognize these diseases (especially later) and to improve their level of early diagnosis and therapy at last.
Neurofibroma refers to a kind of benign hyperplasia disease which arises from epineurium of peripheral nerve system. It is usually be named as neurofibromatosis when there are multiple tumors in the body or accompanied with other systematic diseases. By reviewing a lot of references the author made a brief summary to neurofibroma in this article from clinic manifestation, pathologic features, diagnosis and therapy, and discussed neurofibromatosis in detail including the history, pathogenesis, clinic signs, pathologic characteristics, types, diagnostic criterion, imaging diagnosis, newest developments in molecular biochemistry, pathogenesis and genetic treatment.
The lesions or tumors of neurofibromatosis is almost the same as solitary neurofibroma whether in site of occurrence, morphology or pathology of the lesion, but the latter always presents as solitary and dermal lesion, the former often multi-occurs and involves extensively and seriously instead, usually accompanied with other typical signs or systematic lesions. Solitary neurofibroma is generally asymptomatic, grows slowly, only increases faster in special period. Operation is usually needed and some of the patients can be cured. The nodus and hotpoints of research are focus on neurofibromatosis now.
Neurofibromatosis is an autosomal dominant genetic disease, which also named as Von Recklinghausen disease before. Two types were suggested by NIH of USA in 1987, namely the peripheral type (NF1) and central type (NF2), presenting different mutating gene and clinical characteristics respectively. Von Recklinghausen disease just means NF1 and NF2 mainly indicates neurofibroma in encephalic instead.
The incidence of NF1 in clinic is 1/2500- l/3000.There are no differences between nations and sex. Gene of NF1 sites in 17qll.2 and encodes neurofibomin which can make ras inactive resulting in preventing the proliferation of epineurium which will grow overly and persistently if there is no negative regulating of neurofibromin, when the patient lost the gene's function due to mutation or other changes, and typical symptoms will appear eventually which shows as multi-nodules in the area of peripheral nerves. Every part of human body could be involved and more common in skin or subcutaneous. Under microscope the nodule is found basically composed of Schwann cells, fibroblasts, mast cells et al, and Schwann cells account for the most. There are many mucosubstances in the matrix. Another two featured signs of NF1 are caf -au-lait and iris Lisch nodules. All most all of the patients of NF1 will present these three signs at certain ages. Other complications are seldom but show diversity. The diagnostic criterion suggested by NIH in
1987 is applied in clinic practice at present. The rapid developing medical imaging provides helps greatly to diagnosis and treatment of these two diseases. Therapy still focuses on the treatments to those complications, and surgery have to be considered if the tumors are obvious or have changes of malignant. Some biologic-based therapies and genome medicines are still at their stage of test. NF2 is seldom compared with NF1 in clinic, the incidence of it is about 1/50000, which mainly demonstrates as dual acoustic neuroma and may accompany with other central nerve tumors. Peripheral neurofibroma and cafe-au-lait are seldom at the same time. NF2 gene localizes in 22q and encodes merlin which function is still in research. Many studies show that it has function of negative regulating. NF1 and NF2 all belong to genetic disease and gene therapy must be the best method to treat them. Gene therapy to NF2 has had some development in the research
引文
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34. Wallace MR, Marchuk DA, Andersen LB, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249:181-186.
35. Marchuk DA, Saulino AM, Tavakkol R, et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 1991; 11:931-940.
36. Fountain JW, Wallace MR, Bruce MA, et al. Physical mapping of a translocation breakpoint in neurofibromatosis. Science 1989;
37. Basu TN, Gutmann DH, Fletcher JA, Glover TW, Collins FS, Downward J. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 1992; 356:713-715.
38. Xu H, Gutmann DH. Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules. Brain Res 1997; 759:149-152.
39. Scheffzek K, Ahmadian MR, Wiesmuller L, et al. Structural analysis of the GAP-related domain from neurofibromin and its implications. Embo J 1998; 17:4313-4327.
40. von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1: pathology,
clinical features and molecular genetics. Brain Pathol 1995; 5:153-162.
41. Fahsold R, Hoffmeyer S, Mischung C, et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet 2000; 66:790-818.
42. Ballester R, Marchuk D, Boguski M, et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 1990; 63:851-859.
43. Sherman LS, Atit R, Rosenbaum T, Cox AD, Rather N. Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts. J Biol Chem 2000; 275:30740-30745.
44. Lau N, Feldkamp MM, Roncari L, et al. Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol 2000; 59:759-767.
45. Kopelovich L, Rich RF. Enhanced radiotolerance to ionizing radiation is correlated with increased cancer proneness of cultured fibroblasts from precursor states in neurofibromatosis patients. Cancer Genet Cytogenet 1986; 22:203-210.
46. Ingram DA, Yang FC, Travers JB, et al. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med 2000; 191:181-188.
47. Perosio PM, Brooks JJ. Expression of growth factors and growth factor receptors in soft tissue tumors. Implications for the autocrine hypothesis. Lab Invest 1989; 60:245-253.
48. DeClue JE, Heffelfinger S, Benvenuto G, et al. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest 2000; 105:1233-1241.
49. Arbiser JL, Flynn E, Barnhill RL. Analysis of vascularity of human neurofibromas. J Am Acad Dermatol 1998; 38:950-954.
50. Muir D. Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression. Clin Exp Metastasis 1995; 13:303-314.
51. Kadono T, Kikuchi K, Nakagawa H, Tamaki K. Expressions of various growth factors and their receptors in tissues from neurofibroma. Dermatology 2000; 201:10-14.
52. Birindelli S, Perrone F, Oggionni M, et al. Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Lab Invest 2001; 81:833-844.
53. Liapis H, Marley EF, Lin Y, Dehner LP. p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant peripheral nerve sheath tumors in children. Pediatr Dev Pathol 1999; 2:377-384.
54. Nielsen GP, Stemmer-Rachamimov AO, Ino Y, Moller MB, Rosenberg AE, Louis DN. Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. Am J Pathol 1999; 155:1879-1884.
55. Kourea HP, Cordon-Cardo C, Dudas M, Leung D, Woodruff JM. Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas. Am J Pathol 1999; 155:1885-1891.
56. Kourea HP, Orlow I, Scheithauer BW, Cordon-Cardo C, Woodruff JM. Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. Am J Pathol 1999; 155:1855-1860.
57. Cichowski K, Shih TS, Schmitt E, et al. Mouse models of tumor development in neurofibromatosis type 1. Science 1999; 286:2172-2176.
58. Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing EJ, Parada LF. Mouse tumor model for neurofibromatosis type 1. Science 1999; 286:2176-2179.
59. Ars E, Serra E, Garcia J, et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet 2000; 9:237-247.
60. Gutmann DH. Recent insights into neurofibromatosis type 1: clear genetic progress. Arch Neurol 1998; 55:778-780.
61. Yla-Outinen H, Aaltonen V, Bjorkstrand AS, et al. Upregulation of tumor suppressor protein neurofibromin in normal human wound healing and in vitro evidence for platelet derived growth factor (PDGF) and transforming growth factor-betal (TGF-betal) elicited increase in neurofibromin mRNA steady-state levels in dermal fibroblasts. J Invest Dermatol 1998; 110:232-237.
62. Karvonen SL, Kallioinen M, Yla-Outinen H, Poyhonen M, Oikarinen A, Peltonen J. Occult neurofibroma and increased S100 protein in the skin of patients with neurofibromatosis type 1: new insight to the etiopathomechanism of neurofibromas. Arch Dermatol 2000; 136:1207-1209.
63. Riccardi VM. Of mass and men: neurofibromas and histogenesis. Arch Dermatol 2000; 136:1257-1258.
64. Stemmer-Rachamimov AO, Gonzalez-Agosti C, Xu L, et al. Expression of NF2-encoded merlin and related ERM family proteins in the human central nervous system. J Neuropathol Exp Neurol 1997; 56:735-742.
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66. Gronholm M, Sainio M, Zhao F, Heiska L, Vaheri A, Carpen O. Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin. J Cell Sci 1999; 112 (Pt 6):895-904.
67. Pearson MA, Reczek D, Bretscher A, Karplus PA. Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 2000; 101:259-270.
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69. Koga H, Araki N, Takeshima H, et al. Impairment of cell adhesion by expression of the mutant neurofibromatosis type 2 (NF2) genes which lack exons in the ERM-homology domain. Oncogene 1998; 17:801-810.
70. Shaw RJ, McClatchey AI, Jacks T. Regulation of the neurofibromatosis type 2 tumor suppressor protein, merlin, by adhesion and growth arrest stimuli. J Biol Chem 1998; 273:7757-7764.
71. Rouleau GA, Merel P, Lutchman M,etal. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature, 1993;363:515-521.
72. Ruehm SG, Hany TF, Pfammatter T, Schneider E, Ladd M, Debatin JF. Pelvic
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73. Wilkinson ID, Griffiths PD, Wales JK. Proton magnetic resonance spectroscopy of brain lesions in children with neurofibromatosis type 1. Magn Reson Imaging 2001; 19:1081-1089.
74. Weber AL, Montandon C, Robson CD. Neurogenic tumors of the neck. Radiol Clin North Am 2000; 38:1077-1090.
75. Gupta A, Cohen BH, Ruggieri P, Packer RJ, Phillips PC. Phase Ⅰ study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 2003; 60:130-132.
76. al-Took S, Murray C, Tulandi T. Effects of pirfenidone and dermoid cyst fluid on adhesion formation. Fertil Steril 1998; 69:341-343.
77. McLaughlin ME, Jacks T. Progesterone receptor expression in neurofibromas. Cancer Res 2003; 63:752-755.
78. Bashour AM, Meng JJ, Ip W, MacCollin M, Ratner N. The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells. Mol Cell Biol 2002; 22:1150-1157.
79. Ikeda K, Saeki Y, Gonzalez-Agosti C, Ramesh V, Chiocca EA. Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer. J Neurosurg 1999; 91:85-92.
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32. Barker D, Wright E, Nguyen K, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science 1987; 236:1100-1102.
33. Cawthon RM, Weiss R, Xu GF, et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 1990; 62:193-201.
34. Wallace MR, Marchuk DA, Andersen LB, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249:181-186.
35. Marchuk DA, Saulino AM, Tavakkol R, et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 1991; 11:931-940.
36. Fountain JW, Wallace MR, Bruce MA, et al. Physical mapping of a translocation breakpoint in neurofibromatosis. Science 1989;
37. Basu TN, Gutmann DH, Fletcher JA, Glover TW, Collins FS, Downward J. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 1992; 356:713-715.
38. Xu H, Gutmann DH. Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules. Brain Res 1997; 759:149-152.
39. Scheffzek K, Ahmadian MR, Wiesmuller L, et al. Structural analysis of the GAP-related domain from neurofibromin and its implications. Embo J 1998; 17:4313-4327.
40. von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1: pathology,
clinical features and molecular genetics. Brain Pathol 1995; 5:153-162.
41. Fahsold R, Hoffmeyer S, Mischung C, et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet 2000; 66:790-818.
42. Ballester R, Marchuk D, Boguski M, et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 1990; 63:851-859.
43. Sherman LS, Atit R, Rosenbaum T, Cox AD, Rather N. Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts. J Biol Chem 2000; 275:30740-30745.
44. Lau N, Feldkamp MM, Roncari L, et al. Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol 2000; 59:759-767.
45. Kopelovich L, Rich RF. Enhanced radiotolerance to ionizing radiation is correlated with increased cancer proneness of cultured fibroblasts from precursor states in neurofibromatosis patients. Cancer Genet Cytogenet 1986; 22:203-210.
46. Ingram DA, Yang FC, Travers JB, et al. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med 2000; 191:181-188.
47. Perosio PM, Brooks JJ. Expression of growth factors and growth factor receptors in soft tissue tumors. Implications for the autocrine hypothesis. Lab Invest 1989; 60:245-253.
48. DeClue JE, Heffelfinger S, Benvenuto G, et al. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest 2000; 105:1233-1241.
49. Arbiser JL, Flynn E, Barnhill RL. Analysis of vascularity of human neurofibromas. J Am Acad Dermatol 1998; 38:950-954.
50. Muir D. Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression. Clin Exp Metastasis 1995; 13:303-314.
51. Kadono T, Kikuchi K, Nakagawa H, Tamaki K. Expressions of various growth factors and their receptors in tissues from neurofibroma. Dermatology 2000; 201:10-14.
52. Birindelli S, Perrone F, Oggionni M, et al. Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Lab Invest 2001; 81:833-844.
53. Liapis H, Marley EF, Lin Y, Dehner LP. p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant peripheral nerve sheath tumors in children. Pediatr Dev Pathol 1999; 2:377-384.
54. Nielsen GP, Stemmer-Rachamimov AO, Ino Y, Moller MB, Rosenberg AE, Louis DN. Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. Am J Pathol 1999; 155:1879-1884.
55. Kourea HP, Cordon-Cardo C, Dudas M, Leung D, Woodruff JM. Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas. Am J Pathol 1999; 155:1885-1891.
56. Kourea HP, Orlow I, Scheithauer BW, Cordon-Cardo C, Woodruff JM. Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. Am J Pathol 1999; 155:1855-1860.
57. Cichowski K, Shih TS, Schmitt E, et al. Mouse models of tumor development in neurofibromatosis type 1. Science 1999; 286:2172-2176.
58. Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing EJ, Parada LF. Mouse tumor model for neurofibromatosis type 1. Science 1999; 286:2176-2179.
59. Ars E, Serra E, Garcia J, et al. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet 2000; 9:237-247.
60. Gutmann DH. Recent insights into neurofibromatosis type 1: clear genetic progress. Arch Neurol 1998; 55:778-780.
61. Yla-Outinen H, Aaltonen V, Bjorkstrand AS, et al. Upregulation of tumor suppressor protein neurofibromin in normal human wound healing and in vitro evidence for platelet derived growth factor (PDGF) and transforming growth factor-betal (TGF-betal) elicited increase in neurofibromin mRNA steady-state levels in dermal fibroblasts. J Invest Dermatol 1998; 110:232-237.
62. Karvonen SL, Kallioinen M, Yla-Outinen H, Poyhonen M, Oikarinen A, Peltonen J. Occult neurofibroma and increased S100 protein in the skin of patients with neurofibromatosis type 1: new insight to the etiopathomechanism of neurofibromas. Arch Dermatol 2000; 136:1207-1209.
63. Riccardi VM. Of mass and men: neurofibromas and histogenesis. Arch Dermatol 2000; 136:1257-1258.
64. Stemmer-Rachamimov AO, Gonzalez-Agosti C, Xu L, et al. Expression of NF2-encoded merlin and related ERM family proteins in the human central nervous system. J Neuropathol Exp Neurol 1997; 56:735-742.
65. Gonzalez-Agosti C, Wiederhold T, Herndon ME, Gusella J, Ramesh V. Interdomain interaction of merlin isoforms and its influence on intermolecular binding to NHE-RF. J Biol Chem 1999; 274:34438-34442.
66. Gronholm M, Sainio M, Zhao F, Heiska L, Vaheri A, Carpen O. Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin. J Cell Sci 1999; 112 (Pt 6):895-904.
67. Pearson MA, Reczek D, Bretscher A, Karplus PA. Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 2000; 101:259-270.
68. Sherman L, Xu HM, Geist RT, et al. Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 1997; 15:2505-2509.
69. Koga H, Araki N, Takeshima H, et al. Impairment of cell adhesion by expression of the mutant neurofibromatosis type 2 (NF2) genes which lack exons in the ERM-homology domain. Oncogene 1998; 17:801-810.
70. Shaw RJ, McClatchey AI, Jacks T. Regulation of the neurofibromatosis type 2 tumor suppressor protein, merlin, by adhesion and growth arrest stimuli. J Biol Chem 1998; 273:7757-7764.
71. Rouleau GA, Merel P, Lutchman M,etal. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature, 1993;363:515-521.
72. Ruehm SG, Hany TF, Pfammatter T, Schneider E, Ladd M, Debatin JF. Pelvic
and lower extremity arterial imaging: diagnostic performance of three-dimensional contrast-enhanced MR angiography. AJR Am J Roentgenol 2000; 174:1127-1135.
73. Wilkinson ID, Griffiths PD, Wales JK. Proton magnetic resonance spectroscopy of brain lesions in children with neurofibromatosis type 1. Magn Reson Imaging 2001; 19:1081-1089.
74. Weber AL, Montandon C, Robson CD. Neurogenic tumors of the neck. Radiol Clin North Am 2000; 38:1077-1090.
75. Gupta A, Cohen BH, Ruggieri P, Packer RJ, Phillips PC. Phase Ⅰ study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 2003; 60:130-132.
76. al-Took S, Murray C, Tulandi T. Effects of pirfenidone and dermoid cyst fluid on adhesion formation. Fertil Steril 1998; 69:341-343.
77. McLaughlin ME, Jacks T. Progesterone receptor expression in neurofibromas. Cancer Res 2003; 63:752-755.
78. Bashour AM, Meng JJ, Ip W, MacCollin M, Ratner N. The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells. Mol Cell Biol 2002; 22:1150-1157.
79. Ikeda K, Saeki Y, Gonzalez-Agosti C, Ramesh V, Chiocca EA. Inhibition of NF2-negative and NF2-positive primary human meningioma cell proliferation by overexpression of merlin due to vector-mediated gene transfer. J Neurosurg 1999; 91:85-92.