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【初稿】神经纤维瘤1型

Neurofibromatosis 1

NF1, Von Recklinghausen Disease, Von Recklinghausen's Neurofibromatosis

英文原文链接

JM Friedman, MD, PhD

Department of Medical Genetics
University of British Columbia
Vancouver, Canada

ac.cbu@namdeirf.naj

翻译者：杨涛/黄尚志

Initial Posting: 2017-09-01 11:51:55; Last Update: 2017-10-20 03:26:07.

摘要

临床特征.

神经纤维瘤1型(Neurofibromatosis 1, NF1) 以多发性的牛奶咖啡斑、腋窝和腹股沟雀斑、多发性皮肤神经纤维瘤、虹膜错构瘤为特征。有50%以上的患者存在学习障碍。其他虽不太常见但可能更为严重的表现包括：丛状神经纤维瘤、视神经和其他中枢神经系统胶质瘤，恶性周围神经鞘膜瘤，脊柱侧弯、胫骨发育不良，和血管病变。

诊断/检测. NF1的诊断通常依据其临床表现。NF1基因的杂合性变异可导致神经纤维瘤1型的发生。对NF1基因突变的分子遗传学检测并不常用于临床诊断。

临床处置.

对症治疗：参照专科医生对发生在眼部、中枢神经系统或外周神经系统、心血管系统、脊椎或长骨等器官并发症的治疗方案；手术切除散布的有碍美观和感官的皮肤或皮下神经纤维瘤。丛状神经纤维瘤的手术治疗往往效果不佳；应尽可能完全地切除恶性周围神经鞘膜瘤。视神经胶质瘤则因其常无症状且临床上稳定而通常无需治疗。营养不良性脊柱侧凸常需手术治疗，而非营养不良性脊柱侧凸则通常可采用保守治疗。

监管: 由熟悉本病的医师实施年度体检；儿童每年一次眼科检查，成人可间隔更长时间；对儿童进行常规发育评估；定期血压监测；对临床怀疑颅内肿瘤及其他内脏肿瘤的患者进行定期MRI检查。

遗传咨询.

NF1为常染色体显性遗传方式，患者有50%的几率将突变基因传给后代，半数患者为NF1基因新生突变所致。即使一个家庭内，患者临床表现也是多变的。如果一个家系的致病突变已知，则有可能对风险家庭孕妇实施产前基因诊断。

诊断

对有任何下列症状之一的患者应怀疑为神经纤维瘤病1型，并根据美国国立卫生研究院制定的NF1的诊断标准 [NIH 1988 ]确诊。临床表现符合以下两个或两个以上的特征则可确定为NF1患者：

有6个以上直径超过5毫米（在青春期前个体）或15毫米（在青春期后个体）的牛奶咖啡斑 (图 1)
2个或以上任何类型的神经纤维瘤 (图 2) 或1个丛状神经纤维瘤 (图 3)
腋窝或腹股沟区雀斑
视神经胶质瘤
两个或以上虹膜上结节（Lisch nodules）
一个特别的骨性病变如蝶窦发育不良、胫骨假关节
有一位一级亲属 (父母, 同胞,或后代 ) 为符合NF1诊断标准的患者。

图 3.

丛状神经纤维瘤

成人. NIH诊断标准对NF1成人患者高度特异、灵敏 [Ferner et al 2011, Ferner & Gutmann 2013]。

儿童

仅有大约半数无家族史NF1儿童患者在一岁龄时符合NIH诊断标准；但到8岁时几乎都符合NIH诊断标准 [DeBella et al 2000a] ,这是因为更多的症状随着年龄的增加逐渐显现。
父母一方为患者的NF1儿童患者通常在其一岁前能够得到诊断，这是因为除了阳性家族史外，患者只需显现另一个NF1特征表现则可得以诊断，这个特征通常为多发性牛奶咖啡斑，有95%以上的NF1患者在婴儿期就出现该症状 [DeBella et al 2000b, Nunley et al 2009]。
对有多发性牛奶咖啡斑但无其他NF1特征表现、无家族史的幼儿也应高度怀疑为NF1并进行临床随访。 [Nunley et al 2009]。
按照NF1-NIH标准，这些孩子中的大多数能在四岁前得以确诊。

先证者可根据NF1-NIH诊断标准得以确诊，部分个体可进行分子遗传诊断：:

对于怀疑NF1但又不完全符合NIH的诊断标准的个体进行分子遗传检测。这在童年期后少有需要。
患有严重肿瘤（如视神经胶质瘤）的幼儿通过分子检测快速建立NF1诊断有助于临床治疗。
对于准备进行产前或植入前基因诊断的NF1成人患者分子检测是必要的。
在一些患有脊髓 NF1 [Burkitt Wright et al 2013] 或者携带NF1基因c.2970-2972 delAAT 致病突变的家庭[Upadhyaya et al 2007, Quintáns et al 2011] ，特别是儿童期患者，并不符合NIH诊断标准，分子检测可为这些家庭的风险亲属建立诊断。

NF1基因分子遗传学检测

NF1基因杂合性功能丧失（ loss-of-function）致病突变可导致NF1发生 (见表1)，而这些病理性变异呈高度异质性，包括无义（ nonsense）和错义（missense）的单核苷酸改变、插入缺失、剪切（splicing）改变（约占患者的30%）、全基因缺失（占4%-5%）、基因内拷贝数改变及其他结构重排[Wimmer et al 2006, Messiaen & Wimmer 2008, Valero et al 2011, Cooper & Upadhyaya 2012, Sabbagh et al 2013]。未发现热点突变。
多步骤变异检测方案可为95%以上符合NIH诊断标准的患者检出NF1致病突变 [Wimmer et al 2006, Messiaen & Wimmer 2008, Valero et al 2011, Sabbagh et al 2013]。该方案涉及 mRNA (cDNA) 和基因组(genomic) DNA分析、以及NF1全基因缺失的检测。由于NF1患者致病突变的多样性和稀有性、以及频繁出现的剪切突变，采用多步法比单纯基于基因组DNA的分析方法有更高的检测率 (表1)。
缺失/重复(duplication)检测. NF1 全基因缺失可发生在4%-5%的NF1患者 [Kluwe et al 2004]。当怀疑患者有“大片段缺失临床表型”时可仅针对全基因缺失进行检测 [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012]。缺失/重复分析也可以作为多步骤变异检测方案的一部分，或作为应对测序分析无果时的进一步检测手段。
一个可供选择的基因检测策略是利用多基因组合（panel）测序，panel包括NF1和其他多个目标基因（参见鉴别诊断Differential Diagnosis）。尽管如此, 除 SPRED1基因外，其他RAS通路相关蛋白基因突变导致的疾病，如Noonan综合征，或遗传性癌症可能并不与NF1表型交叉，通过panel测序NF1基因的致病突变检出率大大低于基于多步骤方案的NF1 cDNA 靶向测序。注：多基因panel测序所包括的基因和采用的方法在不同实验室和不时期有所不同。

表 1.

神经纤维瘤病 1型分子遗传学检测概述

基因 ¹	检测方法	先证者致病突变检出率
NF1	基于cDNA 测序 ^2, 3多步骤变异检测方法	>95% ⁴
	基因组DNA 测序 ²	~61% ⁵
	缺失/重复分析 ³	~5%
	细胞遗传学分析 ⁶	<1%

1.: 参见表A. 染色体座位及蛋白质的基因和数据库。参考该基因等位基因变异的分子遗传学信息。
2.: 测序检测到的变异可分为良性、可能良性、意义不确定、疑似致病或致病。致病性变异可包括基因内小缺失/插入、错义、无义和剪切位点改变；通常不能检出外显子或全基因缺失/重复。有关测序结果的解读, 点击此处.
3.: 通过基因组DNA测序编码区及旁侧内含子区不能发现外显子或全基因缺失/重复。用于缺失/重复检测的方法包括：针对目标基因/染色体区域的定量PCR、大片段PCR、多重连接依赖探针扩增 (MLPA)、位点特异FISH, 及染色体微阵列分析(CMA)，等。
4.: Messiaen & Wimmer [2008], Valero et al [2011], Sabbagh et al [2013]
5.: Fahsold et al [2000], Griffiths et al [2007], van Minkelen et al [2014]
6.: 大范围重排

临床特点

临床描述

不同神经纤维瘤病1型患者（NF1）的临床表现有很大差异 [Ferner et al 2007, Williams et al 2009, Ferner et al 2011, Ferner & Gutmann 2013].

皮肤特征

牛奶咖啡斑和雀斑. 几乎所有的患者有多个牛奶咖啡斑，大约90%患者发生擦烂性雀斑。

典型的NF1牛奶咖啡斑呈卵圆形，边界清楚，颜色均匀（比皮肤的着色稍深），约1-3厘米大，但在不同患者中可能更小或更大、颜色更浅或更深、或形状不规则。在典型的更大着色病变区内，色素沉着可能不规则，带有斑点或作色更深的小牛奶咖啡斑。牛奶咖啡斑与周围的皮肤齐平-如果病变皮肤凸起或有异常的软的纹理，有可能是潜在的丛状神经纤维瘤。在白皙的皮肤或深黑皮肤的患者中，病灶皮肤的颜色与周围皮肤相似，牛奶咖啡斑的色素沉着可能难以观察到。除手掌或脚掌外，牛奶咖啡斑几乎可以发生在NF1患者身体任何部位。

丛状雀斑常发生在暴露阳光的皮肤区域，也可见于NF1患者躯干、四肢近端和颈部。类似的雀斑也常在皮肤白皙的健康人中见到，但NF1患者的雀斑还出现在皮肤间摩擦的部位–在女性腋下、腹股沟和乳下，外观和其他人没区别，只是出现的位置是不寻常。

神经纤维瘤：多数良性皮肤神经纤维瘤通常出现在NF1成人患者。

离散性皮肤和皮下神经纤维瘤罕见于儿童后期之前。成人NF1患者全身神经纤维瘤总数可为几个、几百乃至上千。皮肤和皮下神经纤维瘤持续发生可伴随患者终生，但不同时期的发生率可能有很大变化，很多女性患者在妊娠期神经纤维瘤的数量和体量快速增加 [Roth et al 2008]。

大约半数NF1患者出现丛状神经纤维瘤，但大多数在体内并没有引起临床怀疑 [Tonsgard et al 1998, Mautner et al 2008, Plotkin et al 2012]。大多数的肿瘤多年生长缓慢，但部分良性病变也可非常快速地增长，尤其是在儿童早期 [Dombi et al 2007, Tucker et al 2009a; Nguyen et al 2012]。当出现症状时，丛状神经纤维瘤可引起畸形、累及功能甚至危及生命。

其他皮肤症状：青少年黄色肉芽肿和贫血痣的发生比在NF1患者所预期的更为常见，可能有助于诊断尚不符合诊断标准的儿童患者 [Marque et al 2013, Ferrari et al 2014]。青少年黄肉芽肿为小的褐色或橘红色的丘疹，可成簇发生。贫血痣是一个形状不规则的浅色斑，摩擦时也不会像其周围皮肤一样变红。

眼部表现

NF1眼部表现包括可能导致失明的视神经胶质瘤和虹膜上结节（无害的虹膜错构瘤）。NF1患者有症状的视神经通路胶质瘤通常出现在六岁之前，伴随视力丧失或眼球突出，但这些肿瘤也可能直到童年后期甚至成年期才出现症状。NF1患者有症状的视神经胶质瘤经常多年保持稳定或生长非常缓慢，某些肿瘤甚至自发消退 [Listernick et al 2007, Shamji & Benoit 2007, Nicolin et al 2009]。NF1较为少见的眼部表现包括视网膜血管增生性肿瘤 [Hood et al 2009, Shields et al 2014] 和新生血管性青光眼 [Elgi et al 2010, Chiu et al 2011, Al Freihi et al 2013]。

神经系统表现

有关周围神经与中枢神经系统肿瘤的探讨见皮肤特征和肿瘤.

大部分NF1患者智力正常，但有50% - 75%发生学习障碍和学习困难。 [Gilboa et al 2011, Pride & North 2012, Lehtonen et al 2013, Templer et al 2013]。有明显智力残疾的人数占6%-7%，约为普通人群的两倍 [Gilboa et al 2011, Pride & North 2012, Lehtonen et al 2013]，发生自闭症谱系障碍的NF1患儿占30% [Garg et al 2013a, Garg et al 2013b, Walsh et al 2013]。其他持续到成年的各种学习和行为问题已有描述 [Uttner et al 2003, Pavol et al 2006, Descheemaeker et al 2013]。NF1患者频繁发生在视觉空间表现、社交能力和注意力方面的不足、以及在运动功能、执行功能、记忆和语言方面的问题 [Gilboa et al 2011, Pride & North 2012, Lehtonen et al 2013, Templer et al 2013]。

部分NF1患者发展成弥漫性多发性神经疾病，常与多个神经根肿瘤相联系 [Drouet et al 2004, Ferner et al 2004]。受累患者有发生恶性外周神经鞘膜瘤的高风险。

NF1患者癫痫发作率高于一般人群，可发生于任何年龄阶段 [Hsieh et al 2011, Ostendorf et al 2013]。癫痫发作通常有病灶，可能与脑肿瘤或梗死区的存在有关 [Ostendorf et al 2013]，与头部MRI影像中不明原因的明亮的物体无关 [Hsieh et al 2011]。控制NF1患者局灶性癫痫发作需要一个以上的抗癫痫药物治疗或手术切除大脑中病灶部位 [Ostendorf et al 2013]。

睡眠障碍常见于NF1患者[Leschziner et al 2013, Licis et al 2013]。头痛，包括偏头痛，发生的情况远高于预期 [DiMario & Langshur 2000, Pinho et al 2014]。丛状神经纤维瘤也常引发疼痛 [Kim et al 2009, Tucker et al 2009a] 这可能是恶性的周围神经鞘膜肿瘤转化的最早征兆，必须和普通疼痛相区别。

肌肉骨骼特征

NF1患者中广义的骨量减少比预期更为多见，骨质疏松的发生比一般人群出现得更早且更为常见 [Tucker et al 2009b, Petramala et al 2012, Heerv? et al 2012, Armstrong et al 2013, Heerv? et al 2013]。这些骨病变的发病机制尚不完全清楚，但NF1患者经常被发现有低于预期的血清25羟基维生素D、升高的血清甲状旁腺激素水平和增加的骨吸收证据 [Lammert et al 2006, Brunetti-Pierri et al 2008, Stevenson et al 2008, Tucker et al 2009b, Stevenson et al 2011, Heerv? et al 2012, Petramala et al 2012]。NF1患者成骨细胞和破骨细胞的功能似乎都异常[Seitz et al 2010, Kühnisch et al 2014]。

长骨发育不良，以胫骨和腓骨骨折最为常见，是一种不常发生的NF1 特征表现 [Elefteriou et al 2009]。病变是先天性的，几乎总是单测发生。通常在婴儿中表现为小腿前侧弯曲，这与幼儿开始学步时常见到的生理弯曲完全不同。对胫骨发育不良早期识别并辅以支撑可能防止骨折。最初的放射影像学改变是伴随弓形凸端皮质增厚发生的髓管的变细 [Stevenson et al 2007]。长骨发育不良的出现反映骨骼自身的异常，通常不与相邻神经纤维瘤相关。与之相反，其他两个特征如局灶性骨病变-蝶骨翼发育不良和脊椎发育不良，与相邻的丛状神经纤维瘤或（和）硬脊膜膨出相关 [Alwan et al 2005, Arrington et al 2013]。

蝶骨翼发育不良可在头颅成像中偶然发现，或表现为斜视或眼眶不对称。病情通常稳定但也可能进展，有时扰乱眼眶的完整性和产生脉动眼球内陷 [Friedrich et al 2010]。

NF1患者的脊柱侧凸可分为营养不良或非营养不良型 [Elefteriou et al 2009]。后者类似于常见的青少年脊柱侧凸，与椎体畸形无关。营养不良性脊柱侧弯常发生在很小的年龄（典型为6-8岁），以脊柱短节段锐角为特征，进展很快。骨折或有缺陷的骨骼在病灶处的愈合往往不理想且治疗困难，最好是由有经验的专家来进行治疗。

NF1儿童与健康同龄儿童相比有减弱的肌力[Johnson et al 2012, Stevenson et al 2012, Hockett et al 2013]。

血管受累

高血压在NF1患者中常见并可发生于任何年龄 [Friedman et al 2002, Lama et al 2004]。在大多数病例中，高血压是“基础病因”，特征性的NF1血管病变可产生肾动脉狭窄、主动脉窄缩，或其他高血压相关血管损害。肾脏血管病变常见于患有高血压的NF1儿童患者[Fossali et al 2000, Han & Criado 2005]。

累及大动脉或心脑血管动脉的NF1血管病变有严重甚至致命的后果 [Cairns & North 2008, Rea et al 2009, Stansfield et al 2012, Koss et al 2013]。

NF1脑血管异常典型地表现在内颈动脉、大脑或大脑前动脉狭窄或闭塞。
在血管狭窄区域周围形成小毛细血管扩张，从脑血管造影看似出现一丛“烟雾”（脑基底异常血管网）。
经头颅放射治疗原发性脑瘤的NF1儿童患者比预期约增加三倍发生脑基底异常血管网的几率 [Ullrich et al 2007b]。
NF1患者解剖学上的脑动脉改变、血管扩张及颅内动脉瘤发生高于普通人群[Rosser et al 2005, Schievink et al 2005, Bekiesińska-Figatowska et al 2014]。

心脏问题

NF1患者肺动脉瓣膜狭窄的发生高于普通人群 [Lin et al 2000]。先天性心脏缺陷或肥厚性心肌病尤其多见于整个NF1基因缺失的患者 [Nguyen et al 2013b]。成人NF1患者可能发展为肺动脉高压，该病常与另一个的迟发性但可能相当严重的症状-肺实质病相联系 [Stewart et al 2007, Zamora et al 2007, Montani et al 2011]，也可能发生心内神经纤维瘤 [Nguyen et al 2013b]。

肿瘤

神经纤维瘤是良性雪旺细胞肿瘤，可累及几乎所有的神经 [Stemmer-Rachamimov & Nielsen 2012]。皮肤神经纤维瘤发生在几乎所有的NF1患者，并随着年龄的增长在数量和体积上非常缓慢地增加。约一半NF1患者有丛状神经纤维瘤，但在大多数情况下发生在体内，在临床检查中不被发现。体表可见的丛状神经纤维瘤的病程往往不能仅通过临床检查确定，MRI成像是丛状神经纤维瘤检查的首选方法 (见成像)。

丛状神经纤维瘤倾向于儿童期和青春期生长，成年后保持稳定 [Dombi et al 2007, Tucker et al 2009a, Nguyen et al 2012]。虽然大多数的丛状神经纤维瘤是无症状的，但可能会导致疼痛，长到巨大的尺寸，造成严重的毁容，导致邻近组织增生或侵蚀，或影响神经等结构的功能。

恶性周围神经鞘膜瘤是NF1相关的最常见的恶性肿瘤，发生在约10%的NF1患者中[Rasmussen et al 2001, Evans et al 2002, Walker et al 2006, Friedrich et al 2007, McCaughan et al 2007]。相比于一般人群，恶性周围神经鞘膜瘤倾向于发生在更为年轻NF1患者人群，多为青春期或成年早期 [Evans et al 2002, Friedrich et al 2007, Hagel et al 2007, McCaughan et al 2007]。整个NF1基因缺失[De Raedt et al 2003, Kluwe et al 2003, Kehrer-Sawatzki et al 2012]并伴有良性的皮下神经纤维瘤或良性内丛状神经纤维瘤的NF1患者，其患恶性外周神经鞘肿瘤的风险似乎大于不具备这些特点的NF1患者[Tucker et al 2005, Mautner et al 2008, Plotkin et al 2012, Nguyen et al 2014]。

除良性神经纤维瘤外，NF1儿童患者最常见的肿瘤是视神经胶质瘤和脑肿瘤 [Ferner et al 2007, Listernick et al 2007, Ullrich et al 2007a, Cassiman et al 2013]。NF1患者的视神经胶质瘤通常乃至终生无症状，症状往往要比不患NF1的孩子轻得多，而女性似乎比男性患者更多发生有症状视神经胶质瘤需要治疗 [Diggs-Andrews et al 2014]。NF1患者脑干和小脑胶质瘤也可能比非NF1患者的病症更轻 [Vinchon et al 2000, Rosser & Packer 2002, Ullrich et al 2007a]。继发中枢神经系统胶质瘤发生在至少20%的儿童期被诊断患有视神经胶质瘤并实施放疗的NF1 患者 [Kleinerman 2009, Madden et al 2014]。

白血病（特别是幼年型慢性粒细胞白血病和骨髓增生异常综合征）在NF1儿童患者罕见但仍然大大高于非NF1儿童。其他多种肿瘤也在NF1患者中观察到，包括胃肠道间质瘤[Andersson et al 2005, Takazawa et al 2005, Guillaud et al 2006, Miettinen et al 2006, Kramer et al 2007] 和视网膜血管增生性肿瘤 [Shields et al 2014]。NF1妇女50岁之前罹患 [Walker et al 2006, Sharif et al 2007, Madanikia et al 2012, Wang et al 23012] 和死于乳腺癌 [Evans et al 2011] 的风险大大增加。在其他许多常见的癌症，NF1患者也可能有增加的患病风险 [Seminog & Goldacre 2013]。

症状发生的年龄

很多NF1患者只发生皮肤症状和虹膜上结节，但更为严重的并发症伴随年龄增长而增加。不同的NF1症状发生在特定的不同阶段 [DeBella et al 2000b, Boulanger & Larbrisseau 2005, Williams et al 2009, Ferner et al 2011]。例如:

骨症状如前侧胫骨弯曲为先天性（ congenital）
牛奶咖啡斑往往在出生时即可见，数量在最初几年增加。
脸和脖子处的弥漫性丛状神经纤维瘤很少出现在一岁后，而身体其他部位的弥漫性丛状神经纤维瘤很少在青春期后发生。
深部结节丛状神经纤维瘤可出现在任何年龄，但通常是儿童期没有症状的则在成年后也没有症状。
视神经胶质瘤发生在六岁前。
脊柱侧弯快速进展（发育异常）类型几乎总是在六岁到十岁之间发展，而没有脊柱畸形轻度脊柱侧凸类型则通常发生在青春期。
恶性外周神经鞘膜瘤常发生于青年期或成年期。.

生长

NF1患者往往低于同龄人平均身高和高于平均头围 [Clementi et al 1999, Szudek et al 2000a, Szudek et al 2000b, Virdis et al 2003, Karvonen et al 2013, Soucy et al 2013]。尽管如此，很少有患者身高低于人群均值3SD或头围超过人群均值4SD。相比之下，整个NF1基因缺失的患者表现有所不同，在2-6岁间出现过度生长（特别是高度） [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012]。部分儿童的临床特征类似于Weaver综合征。患者青春期发育通常正常，但青春期早熟可能出现，特别是患有视神经交叉肿瘤的NF1患者 [Virdis et al 2000]。而另一方面，青春期延迟也常见于患者 [Virdis et al 2003]。

预期寿命

NF1患者寿命的中值比一般人群约短八年 [Evans et al 2011, Wilding et al 2012]。恶性肿瘤（尤其是恶性周围神经鞘膜瘤）和血管病变是导致NF1患者早期死亡的最重要的原因 [Z?ller et al 1995, Rasmussen et al 2001, Evans et al 2011, Masocco et al 2011]。

生活质量

儿童和成年NF1患者生活质量都低于其相应的对照组 [Birch & Friedman 2012, Vranceanu et al 2013]。本病在容颜、医疗、行为和社会方面的特点可能影响NF1患者的生活质量。

影像学

MRI用于显示丛状神经纤维瘤的大小、严重程度 [Mautner et al 2008, Cai et al 2009, Matsumine et al 2009, Van Meerbeeck et al 2009, Plotkin et al 2012, Hirbe & Gutmann 2014] ，并监测随时间的生长状态 [Dombi et al 2007, Tucker et al 2009a, Nguyen et al 2012]。MRI也可用于检测NF1患者脑部的肿瘤和结构异常、以及脑血管疾病的征兆 [Cairns & North 2008, Rea et al 2009, Lin et al 2011]。磁共振血管造影对于评估NF1血管病变很有价值 [D’Arco et al 2014]。传统的影像学研究能证实NF1患者发生骨骼异常 [Patel & Stacy 2012], 但在进行骨病变的手术治疗前的CT成像或三维CT重建是必要的。PET和CT/PET可帮助区分良恶性外周神经鞘瘤 [Ferner et al 2008, Matsumine et al 2009, Warbey et al 2009, Tsai et al 2012, Meany et al 2013, Salamon et al 2013, Hirbe & Gutmann 2014], 但最终的鉴别只能通过肿瘤的组织学检查。

MRI研究表明，平均而言，NF1患者拥有更大的大脑，但NF1患者灰质的体积并不对应于其智商高低 [Greenwood et al 2005, Margariti et al 2007, Karlsgodt et al 2012]，弥散张量成像显示白质、尤其是额叶的显微结构异常[Ferraz-Filho et al 2012b, Karlsgodt et al 2012]。胼胝体增大出现在部分NF1儿童并与其学习障碍相关 [Pride et al 2010]。MRI检测发现NF1儿童患者出现更多的视神经迂曲，但视神经迂曲并不与NF1患者中视神经胶质瘤的发生相关 [Ji et al 2013]。

超过50%的NF1儿童患者头部MRI可见所谓“不明光亮物”（UBO），但其临床意义是不确定的 [DeBella et al 2000a, Lopes Ferraz Filho et al 2008, Sabol et al 2011]。这些在T2加权成像中显示的高密度病灶可发生在视神经束、基底节、脑干、小脑，或皮质，通常无证据显示质量效应。典型的UBO并未在T1加权MRI成像或CT扫描中观察到。在弥散加权MRI中，UBOs预示髓鞘结构异常，病理性地对应于海绵状髓鞘病变 [Ferraz-Filho et al 2012a, Ferraz-Filho et al 2012b, Billiet et al 2014] [DiPaolo et al 1995]。UBO可随着年龄的增长而消失，在NF1成人患者较儿童患者中更少出现 [Gill et al 2006, Payne et al 2014] 。

UBO的存在似乎并不与NF1儿童癫痫的发生相关 [Hsieh et al 2011]。部分研究表明UBO的出现数量、体积、位置、或随着时间而消失与 NF1儿童学习障碍相关，但在不同的研究中得出的结论并不一致 [Hyman et al 2007, Chabernaud et al 2009, Feldmann et al 2010, Payne et al 2014]。

基因型-表型相关性

NF1有高度的临床变异性，在无血缘关系的个体间、同一家庭的不同个体、甚至同一个人的不同的生长阶段的临床表现皆有差异。仅有两个研究明确观察到NF1特定的突变等位基因与相应的临床表型相对应。

NF1全基因缺失与大量、早发的皮肤神经纤维瘤、频发、严重的认知障碍、身体过度生长、手脚宽大、和畸形面部特征等相关联 [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012]。
NF1基因外显子17 [ 神经纤维瘤协会命名；NCBI命名的第22外显子] 内三核苷酸框内缺失 (c.2970-2972 delAAT) 与典型的NF1色素特征、无皮肤或表皮的丛状神经纤维瘤相关联 [Upadhyaya et al 2007]。

NF1伴有肺动脉狭窄患者（包括 NF1 /努南综合征或沃森综合征表型）较其他类型NF1患者似乎更多为非截短蛋白突变，而其他类型NF1则更多携带截短蛋白突变 [Ben-Shachar et al 2013]。

NF1变异的连续家族传递类型如沃森综合症（多个牛奶咖啡斑，肺动脉瓣狭窄，和智力障碍） [Allanson et al 1991, Tassabehji et al 1993]和家族性脊髓神经纤维瘤病 [Upadhyaya et al 2009, Pizzuti et al 2011, Burkitt Wright et al 2013] 表明等位基因异质性对NF1临床表型变异的作用。对家系内和不同家系间NF1表型的统计分析表明NF1突变等位基因对表型变异的仅有小量的贡献 [Sabbagh et al 2009, Sabbagh et al 2013]。NF1良性等位基因表达的差异可解释的表型变异度 [Jentarra et al 2012]。对患者家系临床特征的统计分析提示其他位点的修饰基因可从多方面影响NF1表型 [Pasmant et al 2012]。

NF1极度的临床变异性建议随机事件在决定患者表型的重要性。对这种解释的支持证据来自NF1患者神经纤维瘤、恶性周围神经鞘膜瘤、嗜铬细胞瘤、星形细胞瘤、胃肠道间质瘤，髓系恶性肿瘤、颌骨巨细胞肉芽肿和血管球瘤中在NF1基因位置发生的“二次打击”的变异或杂合性丢失（loss of heterozygosity） [Upadhyaya et al 2012]。在一些病例中，NF1基因杂合性丢失现象在生长于牛奶咖啡斑 [Maertens et al 2007, De Schepper et al 2008] 和胫骨假关节相关组织的黑素细胞中观察到[Stevenson et al 2006b, Lee et al 2012]。

NF1的临床变异性似乎是来自遗传、非遗传、以及随机因素的共同作用。NF1致病突变构成的复杂性和多样性将继续导致难以呈现基因型-表型的相关性（ genotype-phenotype correlation ）

外显率

儿童期后的患者几乎完全外显。.

命名

NF1以前称为周围型神经纤维瘤病，以区别于NF2（中央型神经纤维瘤病）–虽然NF1也可能累及中枢神经系统。

“神经纤维瘤病”一词有时在无更多的界定时也被使用在文献中特指NF1，但这种用法容易造成混淆，因为其他作者在使用术语“神经纤维瘤”时往往指一组疾病，包括NF2、神经鞘瘤病、以及其他临床上与NF1表型类似的疾病。

患病率

NF1是一种最常见的显性遗传病，发生率约为1/3000 [Lammert et al 2005, Evans et al 2010]。几乎一半患者为新生（de novo ）致病突变.。NF1基因突变率（~ 1:10000）是已知人类基因中最高的，其原因尚不清楚。

遗传（等位基因）相关疾病

一些个体或家庭有明确的NF1致病突变但与之相应的表型特征并不符合NIH制定NF1 诊断标准：

NF1全基因及旁侧区域重复没有导致NF1表型（由NF1微缺失或功能丧失突变所引起的症状），但可引起智力障碍和癫痫发作 [Grisart et al 2008, Moles et al 2012]。 NF1 微重复可造成多种表型，部分携带这种改变的个体表型正常。因为除NF1基因外还有多个基因包括在微重复区域，当出现异常表型时无从知道是由于NF1三体还是区域内其他基因重复所致。
带有NF1外显子17 [ 神经纤维瘤协会命名；或根据NCBI命名为第22外显子] 内三核苷酸框内缺失的温和变异(c.2970-2972 delAAT) 的个体罕有出现神经纤维瘤，其表现可能是仅有多个牛奶咖啡斑 [Upadhyaya et al 2007, Quintáns et al 2011] 。
家族性脊髓神经纤维瘤。患者有多个脊髓神经纤维瘤但少有出现NF1皮肤症状[Fauth et al 2009, Upadhyaya et al 2009, Pizzuti et al 2011, Burkitt Wright et al 2013]。虽然命名为家族性，本病也能发生在散发病例中 [Pascual-Castroviejo et al 2012, Ruggieri et al 2013]。
一例患有多发脊神经节细胞瘤（非神经纤维瘤）和多发皮下肿瘤的类似疾病患者 [Bacci et al 2010]。
一例患视神经胶质瘤但无其他NF1诊断特征的男性患者[Buske et al 1999]
一例脑颅皮肤脂肪过多症儿童患者 [Legius et al 1995]
豹斑综合征（ LEOPARD syndrome ），类似于努南综合征，区别在于患者有多发性雀斑、感觉神经性耳聋和更为高发的肥厚型心肌病和心电图改变；大多数病例是由于PTPN11致病突变所致。也有一例显示部分NF1症状的豹斑综合征患者被报道携带NF1致病突变 [Wu et al 1996]。

对上述非典型表型的解释仍然不清楚。也许是因为其相对高的发病率，NF1（NF1致病突变导致）和另一常染色体显性遗传病（其他基因位点致病突变导致）在同一患者中发生的病例已被多次描述。已被报道与NF1同时发生在同一患者的第二种常染色体显性遗传病包括：努南综合征（ Noonan syndrome ；PTPN11基因突变相关）[Bertola et al 2005, Thiel et al 2009, Prada et al 2011]、遗传性乳腺癌 (BRCA1) [Campos et al 2013]、以及多发性内分泌腺瘤2型 (RET) [Ercolino et al 2014]。一例同时带有NF1 新生致病突变和染色体20q11.23区新生缺失突变的患者被报道 [Santoro et al 2013]。另有报道一个同时患有NF1和 Jalili综合征（常染色体隐性遗传锥杆营养不良和釉质发育不全）的儿童患者携带一个NF1杂合致病突变和一个CNNM4基因纯合致病突变 [Zobor et al 2012]。

有大约12%的NF1患者表现努南综合征表型 [Colley et al 1996]，包括眼距过宽、睑裂下倾、低位耳、颈蹼和肺动脉瓣狭窄。这类患者亲戚中的NF1患者则可能有或无努南综合征表型。NF1-努南表型的出现似乎有多种原因，包括：部分家系中有两种比较常见的常染色体显性遗传致病突变同NF1突变共分离 [Carey 1998, Bertola et al 2005, Thiel et al 2009, Prada et al 2011]。大多数NF1-努南综合征患者带有NF1基因胚系致病突变 [De Luca et al 2005, Hüffmeier et al 2006, Stevenson et al 2006a]。在PTPN11基因致病突变（而不是NF1）可见于大约半数的努南综合征患者，确少有在合并NF1-努南综合征患者中观察到 [De Luca et al 2005, Sarkozy et al 2007, Carcavilla et al 2011]。

局部或局域性神经纤维瘤患者的NF1表现只出现在身体的某一部分且父母双方均非该病患者 [Ruggieri & Huson 2001, Listernick et al 2003]。在某些病例中，疾病表现的异常分布可能是一个概率事件；在其他情况下，局部NF1的发生源于NF1体细胞突变嵌合 [Tinschert et al 2000, Vandenbroucke et al 2004, Consoli et al 2005, Maertens et al 2007, Messiaen et al 2011]。尽管如此，大多数被报道为NF1致病突变嵌合体的病例呈现轻微（而非局部性）神经纤维瘤 [Rasmussen et al 1998, Messiaen et al 2011]。已报道局域性NF1患者的孩子有典型的NF1表现 [Oguzkan et al 2004, Consoli et al 2005]；两个NF1表型差异的同卵双胞胎为发生在极早期后合子阶段的NF1致病突变的体细胞嵌合提供证据 [Kaplan et al 2010, Vogt et al 2011].

鉴别诊断

有超过100种遗传病和多个先天畸形综合征被描述具有包括牛奶咖啡斑或其他神经纤维瘤病1型特征，其中有少数几种曾与NF1相混淆。

常与NF1混淆的疾病

Legius综合征, 一种显性遗传病，由SPRED1基因杂合致病突变所致，患者的临床表现包括多个牛奶咖啡斑、腋窝斑点、巨头，部分患者的面容类似努南综合征 [Brems et al 2012] 。患者的症状可能达到NF1诊断标准，但常不发生Lisch结节、神经纤维瘤和中枢神经系统肿瘤。而大多数的NF1患者在儿童后期或青春期前也不出现皮肤多发性神经纤维瘤和Lisch结节，因此有时仅根据身体特征不可能将legius综合征与NF1区别开来，检查父母 legius综合征或NF1的特征表现有助于区分这两个病。但对于散发病例，有必要在青春期后重新评估或通过分子检测进行诊断。
Lynch综合征是由于相关基因的纯合或复合杂合致病突变导致结构性错配修复缺陷所致疾病 [Wimmer 2012]，患者的皮肤表现与NF1非常类似，甚至可达到 NIH制定的NF1诊断标准。然而，Lynch综合征致病突变纯合子患者通常比杂合子更早形成典型的Lynch综合征肿瘤，这可与NF1相区别。在Lynch综合征中，父母往往是近亲（consanguineous ），父母双方或一方经常通常有Lynch症状和/或家族史。双方父母通常都没有NF1临床表现。这些患者的血中通常检测不到NF1致病突变。
花斑特质 (Piebald trait，OMIM) (皮肤色素沉着和色素脱失区以一个深染的边界相间，白额）。部分患者符合NF1诊断标准[Stevens et al 2012].
神经纤维瘤病2型（双侧前庭神经鞘瘤、颅和周围神经鞘瘤，皮肤神经鞘瘤，脑膜瘤，青少年后囊下白内障）。NF2在遗传和临床上均不同于NF1 。
神经鞘瘤 (Schwannomatosis， OMIM) (颅、脊髓、或外周神经多发性神经鞘瘤，通常无NF2出现的前庭、眼或皮肤症状）Merker et al 2012]
多发性牛奶咖啡斑 (一种无其他神经纤维瘤病表现的常染色体显性遗传特征) (OMIM). 在所报道的家系中没有检测SPRED1致病突变；因此，并不知道该病是否区别于有类似症状的legius综合征。
豹皮综合征（ LEOPARD syndrome ）（多发性雀斑、眼距过宽、耳聋、先天性心脏病）
McCune-Albright 综合征 (大不规则边缘牛奶咖啡斑，多骨型纤维性发育不良l)
努南综合征 Noonan syndrome ( 矮小，先天性心脏缺损，颈蹼，特征面容)
婴儿肌纤维变性（Infantile myofibrosis） (OMIM, OMIM) (多发性皮肤、皮下组织、骨骼肌、骨骼和内脏肿瘤)
Proteus综合征（多组织错构瘤性过度生长 , 结缔组织色素痣, 表皮色素痣, 骨肥大)
多发性眼窝神经纤维瘤，疼痛性周围神经瘤，独特面容，及马凡综合征体质 [Babovic-Vuksanovic et al 2012]。

管理

Evaluations Following Initial Diagnosis初诊后评估

推荐采用以下评价以确定神经纤维瘤1型（NF1）严重程度和需求：

关注个人病史特别是NF1特征表现
在体检中特别关注皮肤、骨骼、心血管系统和神经系统
眼科评价中包括虹膜裂隙灯检查
儿童发育评价
其他临床症状或体征的研究
临床遗传咨询

此外，应获取患者家族史，特别是要关注NF1特征，应对父母双方进行身体检查和眼科检查（包括裂隙灯检查）以确定疾病是遗传自父母还是由新生突变所致。这对于遗传咨询是必要的，并可能有助于鉴别非NF1基因突变所引起的类似症状疾病，如legius综合征或结构性错配修复缺陷 (参见鉴别诊断).

常规头颅MRI扫描用于NF1诊断的价值存有争议。

支持者认为这样的研究对于在患者有明显临床症状前，识别头颅部位的结构异常、肿瘤或血管疾病，建立诊断、及评价颅外并发症的发生都是有用的。
反对者的意见集中在：常规头颅MRI扫描所发现的特征如UBO等的临床意义不明确、成像费用的昂贵、及对小儿镇静的要求。虽然对无症状NF1患者的临床管理不会受到颅内病变如UBO或个体视神经增粗的影响，但是，尽管长期缺乏相关症状，发现这种病变可能导致经常重复的MRI检查，对个人和家庭除增加额外花费和引起焦虑外，没有任何利益。

症状的治疗

美国儿科学会 [Hersh 2008]、全国遗传咨询师协会[Radtke et al 2007], 以及多个专家组 [Ferner et al 2007, Williams et al 2009, Ferner & Gutmann 2013]已联合推出NF1病人管理指南。

NF1患者在眼部、中枢或外周神经系统、脊柱或长骨、或心血管系统异常的个体应该被转诊到合适的专科治疗。

离散的皮肤或皮下组织有碍美观或造成不方便的神经纤维瘤（例如，在腰或领口处）可以手术切除，如果小的话也可以用激光或电灼去除。

丛状神经纤维瘤的手术治疗往往不令人满意，因为其与神经紧密接触而且容易从手术去除的位置复发 [Fadda et al 2007, Serletis et al 2007, Prada et al 2012, Nguyen et al 2013a]。
对于小部分儿童期发生的浅表丛状神经纤维瘤，有可能在肿瘤还相当小时采用手术切除而不产生任何神经功能缺损 [Friedrich et al 2005]。
放射治疗在这些遗传易感个体有诱导恶性外周神经鞘肿瘤风险，应忌用 [Evans et al 2002]。
在一例合并精原细胞瘤的NF1患者采用卡铂化疗两周期后一丛状神经纤维瘤的体积减少了54% [Hummel et al 2011]。
一个II期临床试验报告约25%患有大丛状神经纤维瘤的NF1患者经酪氨酸激酶抑制剂伊马替尼治疗后疗效显著[Robertson et al 2012]，进一步的研究正在进行中。I

疼痛、神经功能缺失的发展、或丛状神经纤维瘤的变大可能预示着恶性周围神经鞘膜瘤，需要立即评估 [Valeyrie-Allanore et al 2005]。核磁共振、PET、或PET/CT检查 [Ferner et al 2008, Matsumine et al 2009, Warbey et al 2009, Salamon et al 2013]有助于鉴别良性和恶性周围神经鞘膜瘤，但最终需由肿瘤组织学检查确诊。尽可能完全的手术切除是唯一可能治愈恶性周围神经鞘膜瘤的治疗手段 [Friedrich et al 2007, Dunn et al 2013]。有时也采用辅助化疗或放疗，貌似在部分（但非大多数）NF1患者中取得疗效[Gottfried et al 2006, Chaudhary & Borker 2012, Zehou et al 2013]。

大多数NF1患者在MRI检测发现的视神经胶质瘤是无症状的，不需要治疗 [Segal et al 2010, Oh et al 2011, Cassiman et al 2013]。尽管疗效不一，化疗仍是儿童NF1患者渐进性视神经胶质瘤治疗的一个选择[Rosenfeld et al 2010, Ardern-Holmes & North 2011, Fisher et al 2012]。视神经胶质瘤的手术治疗通常采用在盲眼位置保持美观的姑息治疗，放射治疗因其诱导恶性肿瘤或烟雾病的风险而应通常避免 [Evans et al 2002, Ullrich et al 2007a]。

NF1患者合并脑干和小脑星形细胞瘤的自然病程应该在确定肿瘤治疗方案时加以考虑 [Vinchon et al 2000, Rosser & Packer 2002, Ullrich et al 2007a]。

营养不良性脊柱侧凸的NF1患儿常常要求外科治疗，这可能是复杂和困难的 [Shen et al 2005, Tsirikos et al 2005, Stoker et al 2012, Kawabata et al 2013]。非营养不良性脊柱侧凸的NF1患者的治疗与原发性脊柱侧凸类似。胫骨假关节的外科治疗困难且常常疗效不佳 [Stevenson et al 2013]。

监管

NF1病人管理指南已经由美国儿科学会 [Hersh 2008]、全国遗传咨询师协会 [Radtke et al 2007]、及各专家组发布 [Ferner et al 2007, Williams et al 2009, Ferner & Gutmann 2013]。

推荐如下:

由熟悉本病和患者的医生进行年度体检
在儿童早期每年进行眼科检查，对年龄较大儿童和成人则可减少检查次数
（在儿童中）通过筛选问卷调查进行定期的发育评估
定期血压监测
其他的检查（如MRI)仅针对明显的临床体征或症状
由适当的专科医生对有中枢神经系统、骨骼系统或心血管系统异常的患者进行监测

禁忌药物/状况

限制对大多数NF1患者没有必要，但可针对于某些特定的症状如胫骨发育不良或发育不良性脊柱侧弯；在这些病例中，限制取决于患者症状本身，而不是因为NF1。

NF1患者的放疗似乎与治疗区域恶性周围神经鞘膜瘤的高发风险相关 [Evans et al 2002, Sharif et al 2006].

亲属患病风险评估

参见有关风险亲属遗传咨询相关检查问题。

妊娠管理

虽然大多数NF1 女性患者妊娠正常，但仍有发生严重并发症的可能 [Chetty et al 2011, Terry et al 2013]。

许多NF1女性患者在妊娠期出现神经纤维瘤数量和体积的快速增长。
孕期可能会首次发生高血压症状，如以前患有高血压则可能加重。
大的盆腔或生殖器处神经纤维瘤可能增加分娩复杂性，比其他妇女似乎有更大的剖腹产需要。

研究中的治疗方法

多种针对丛状和脊髓神经纤维瘤的治疗方法正在临床试验中评估[Ferner & Gutmann 2013, Lin & Gutmann 2013]。初步研究表明一种mTOR通路抑制剂西罗莫司（sirolimus ）在治疗丛状神经纤维瘤引发的疼痛中有效 [Hua et al 2014] (参见注释)。

针对面部弥漫性丛状神经纤维瘤和牛奶咖啡斑的射频疗法已经在几个小规模的临床试验中显示出应用前景 [Baujat et al 2006, Yoshida et al 2007].

已有几个针对NF1患者恶性周围神经鞘膜瘤治疗方法的对照试验 [Ferner & Gutmann 2013, Lin & Gutmann 2013] (参见注释)。

几个视神经胶质瘤治疗的对照试验已用于NF1患者 [Schnur 2012, Ferner & Gutmann 2013, Lin & Gutmann 2013] (参见注释)。

注释:NIH ClinicalTrials.gov 网站列出了正在进行中的NF1临床试验。

其他

NF1女性患者采用激素避孕似乎不会刺激神经纤维瘤的生长 [Lammert et al 2006].

遗传咨询

遗传咨询是向个人和家庭提供遗传疾病的性质、传递和影响等信息，以帮助他们作出明智的医疗和个人决定的过程。下一节涉及遗传风险评估及家族史和遗传检测的应用，以阐明家庭成员的遗传状态。这一部分并不是为了解决个人可能面临的所有自身的、文化的或伦理的问题、也不能代替遗传专家的咨询。—ED.

遗传方式

神经纤维瘤病1型（NF1）为常染色体显性（ autosomal dominant ）遗传方式。

家系成员患病风险

先证者父母

大约50%的NF1患者有一个受累的父母，另外50%是NF1基因新生致病突变所致。
对一个明显的新生致病突变先证者父母的评估建议包括病史和体检，特别要注意NF1相关的皮肤和其他症状。此外，应对父母双方进行眼科检查（包括裂隙灯检查）以发现Lisch结节或其他NF1眼科症状。

注: 由于没有在家庭成员中检出NF1或父母在NF1症状表现之前已早逝，可能造成无家族史的情况。

先证者同胞的风险取决于先证者父母任何一方是否为NF1。
如果父母一方受累，同胞患病风险为50%。
如果经过仔细的病史、身体及眼科检查，父母双方均不符合NF1 临床诊断标准，则先证者同胞患NF1的风险较低，但仍高于一般人群，这是由于父母有生殖系嵌合的可能性。注：NF1致病突变生殖系嵌合体已经在一位育有两个典型的NF1患儿的表型正常父亲[Lázaro et al 1995] 和一位育有一位有NF1典型表现的局部性神经纤维瘤女性患者 [Consoli et al 2005]中证实。

先证者后代

NF1患者的每个孩子均有50%的几率遗传到NF1基因致病突变。
由于NF1的外显率为100%，遗传到NF1致病突变的孩子将出现NF1症状，但疾病的表现程度则可能比其患者父母更轻或更严重。

先证者其他家系成员
如果一个先证者的父母一方受累，他的其他家系成员也可能有发病风险。

遗传咨询相关问题

有可能出现一个家庭多个新生致病突变的情形。Upadhyaya 等 [2003]报告了在一个家系中检测到三个不同的NF1致病突变，建议在假定同一致病突变存在于患者家庭的所有成员时需要审慎。另一报道中一个家系发现2个不同的致病突变 [Klose et al 1999]。

有关家系中 新生 致病突变的考虑。 当一个常染色体显性遗传先证者的父母双方均无NF1临床症状时存在先证者为新生致病突变的可能性。尽管如此，也需要探究可能的非医学原因，包括替代的父源或母源（如辅助生殖）、或是未公开的收养。

家庭计划

确定遗传风险和探讨产前或植入前遗传诊断（ preimplantation genetic diagnosis ）可能性的最佳时机是妊娠前。
遗传咨询（包括后代和生育选择的潜在风险的讨论）应提供给年轻的患者或高风险个体。

产前测试

分子遗传检测。在进行产前检查前必须确定患者家系成员的致病等位基因 [van Minkelen et al 2014].

超声检查。 已有报道通过产前超声检查对特别严重的NF1进行产前诊断 [McEwing et al 2006], 但在大多数情况下，超声检查不太可能检出NF1胎儿。

疾病（如NF1）严重程度和发病年龄的不同，相应产前测试的要求也不尽相同。医疗专业人员和家庭对产前检查可能存在不同的关注角度，特别是当测试的目的是考虑是否终止妊娠而不是早期诊断时。虽然大多数中心将考虑父母的选择决定产前测试，对这些问题的讨论是适当的。

NF1的植入前遗传学诊断(PGD) 已被报道[Spits et al 2005, Altarescu et al 2006, Vanneste et al 2009, Chen et al 2011] ，并可成为部分致病突变已确定家庭的一个选择。

资源

GeneReviews 工作人员已选定下列疾病相关支持组织和/或登记处以保障患者及其家人的利益。GeneReviews 不对其他组织提供的信息负责。有关选择信息的标准请单击此处。

儿童肿瘤基金会（Children's Tumor Foundation）

95 Pine Street

16th Floor

New York NY 10005

Phone: 800-323-7938 (toll-free); 212-344-6633

Fax: 212-747-0004

Email: info@ctf.org

http://www.ctf.org/
My46 特征概况 (My46 Trait Profile)

Neurofibromatosis type 1
医学遗传基本参考书国家图书馆（National Library of Medicine Genetics Home Reference）

Neurofibromatosis 1
全国罕见疾病组织（National Organization for Rare Disorders, NORD)

Neurofibromatosis Type 1 (NF1)
神经纤维瘤网络 (Neurofibromatosis Network）

213 South Wheaton Avenue

Wheaton IL 60187

Phone: 800-942-6825

Fax: 630-510-8508

Email: admin@nfnetwork.org

http://www.nfnetwork.org/home
Medline Plus

Neurofibromatosis
RAS通路网（RASopathiesNet）

244 Taos Road

Atlandena CA 91001

Phone: 626-676-7694

Email: lisa@rasopathies.org

rasopathiesnet.org

分子遗传学

在分子遗传学和OMIM表中的信息可能不同于 GeneReview：下表可能包含更多的最新信息。—ED.

表 A.

神经纤维瘤病1型：基因与数据库

Gene	Chromosome Locus	Protein	Locus Specific	HGMD
NF1	17q11?.2	Neurofibromin	NF1 database	NF1

: 数据编辑自以下标准参考资料：基因引自 HGNC;染色体座位、位置名、关键区域、互补群依据 OMIM; 蛋白质根据 UniProt. 有关这些数据库（位点特异，HGMD）的描述点击此处。

表 B.

OMIM中神经纤维瘤病 1型条目 (View All in OMIM)

162200	NEUROFIBROMATOSIS, TYPE I; NF1
613113	NEUROFIBROMIN 1; NF1

Gene structure. NF1是一个很大的基因（~ 350Kb，60个外显子）至少包括三个不同剪切转录本。 [Upadhyaya & Cooper 2012]。特别之处是 NF1的一个内含子包含有至少三个基因的编码序列。有关基因和蛋白质信息的详情，请参见表 A, 基因。

致病性变异. 已有超过1000种NF1基因致病突变被证实。大多数致病突仅在一个特定的家庭中发现。也有很多致病突变被多次报道，但在被研究家庭中没有任何一个突变超过百分之几的发生率。已发现很多不同类型的致病突变，包括无义突变、氨基酸替换、缺失 (可包括一个或几个碱基、多个外显子，或整个基因缺失）、插入、剪切突变、3'非翻译区改变、及大范围的染色体重排。大多数报道的NF1患者的种系致病突变常常改变mRNA剪接进而导致基因产物的严重截短。

Table 2.

在本章GeneReview中讨论的NF1致病突变

DNA碱基改变	预测的蛋白改变	参考序列
c.2970_2972 delAAT	p.Met992del	NM_001042492?.1 NP_001035957?.1

: 变异分类注释：表中所列出变异由作者提供。GeneReviews工作人员没有对变异分类进行独立验证。
: 命名注释： GeneReviews采用人类基因组变异协会（Human Genome Variation Society；www?.hgvs.org ) 标准命名协定。参见快速参考获取解释。.

正常基因产物。其蛋白产物为神经纤维瘤蛋白（neurofibromin），计算的分子量约为327Kd，功能尚不完全清楚。通过激活Ras GTP酶从而控制细胞的增殖和作为肿瘤抑制因子 [Gottfried et al 2010, Upadhyaya & Cooper 2012]。神经纤维瘤蛋白还具有其他功能，包括腺苷酸环化酶活性和细胞内环腺苷酸生成的调节。

非正常基因产物。NF1 基因中的功能丧失（ loss-of-function ）突变导致神经纤维瘤病1型 [Upadhyaya & Cooper 2012].

癌症与良性肿瘤

几种肿瘤呈现增高发生率的NF1患者有可能携带一个或两个NF1体细胞（而非生殖细胞）变异等位基因，这些个体可能并没有NF1的临床表现。这种发生在缺乏NF1特征临床表现而携带NF1突变的个体发生的散发NF1相关肿瘤包括恶性外周神经鞘瘤 [Bottillo et al 2009]、嗜铬细胞瘤 [Vicha et al 2013]、青少年单核细胞白血病 [Yoshimi et al 2010, Sakaguchi et al 2013]、神经胶质瘤[Purow & Schiff 2009]、和乳腺癌 [Cancer Genome Atlas Network 2012]。

NF1体细胞突变体也可以在肺腺癌、卵巢癌、结肠癌、黑色素瘤和成人急性髓细胞白血病中发现，这是NF1患者中是罕见的 [Laycock-van Spyk et al 2011, Patil & Chamberlain 2012, Yap et al 2014]。

参考文献

Al Freihi SH, Edward DP, Nowilaty SR, Abouammoh MA, Morales J. Iris neovascularization and neovascular glaucoma in neurofibromatosis type 1: report of 3 cases in children. J Glaucoma. 2013;22:336–41. [PubMed: 22138687]
Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, Huson SM. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991;28:752–6. [PMC free article: PMC1017110 ] [PubMed: 1770531]
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Chapter Notes

Revision History

4 September 2014 (me) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
2 June 2009 (me) Comprehensive update posted live
31 January 2007 (me) Comprehensive update posted to live Web site
5 October 2004 (me) Comprehensive update posted to live Web site
30 September 2002 (me) Comprehensive update posted to live Web site
2 October 1998 (pb) Review posted to live Web site
Spring 1996 (jmf) Original submission

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