1型神经纤维瘤病NF1基因突变研究
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摘要
研究背景
第一部分神经纤维瘤病
神经纤维瘤病(Neurofibromatosis, NF),又称冯·雷克林豪森病(von Recklinghausen disease)。典型神经纤维瘤病表现为神经系统、骨骼和皮肤的发育异常。
临床类型NF1型：即传统的神经纤维瘤病,占总病例85%以上,表现为大量的神经纤维瘤和咖啡牛奶斑,可见Lisch小结,常不伴发中枢神经系统损害。NF2型：中枢型或听力型,为双侧听神经瘤,咖啡牛奶斑和皮肤神经纤维瘤很少,无Lisch小结。NF3型：混合型,兼有Ⅰ型和Ⅱ型的特征。NF4型：变异型,表现为弥漫性咖啡牛奶斑和神经纤维瘤,可见Lisch小结,可有或无中枢神经系统肿瘤。NF5型：节段型或局限型,神经纤维瘤和咖啡牛奶斑局限于身体的某些特定部位。NF6型：仅咖啡牛奶斑。NF7型：迟发型,30岁以后发病。
病因及发病机制本病NF1型至NF4型均为常染色体显性遗传,不同型别外显率不同,由畸变显性基因引起的神经外胚叶异常,常表现为不全型和单纯型,25%-50%的患者家族史阳性,男性较多见。一般认为NF5型由形成合子后的体细胞突变引起,常不遗传给后代。NF1基因位于17q11.2的中央周围区,编码神经纤维蛋白,该蛋白负调控Ras蛋白转导信号。NF2的基因位于染色体22q12.2,为一种肿瘤抑制基因,编码Merlin蛋白(神经鞘蛋白),该蛋白将肌动蛋白细胞骨架连接到细胞表面的糖蛋白上,起负生长调控作用,具有传导抑制信号的功能。已发现大量NFl基因的突变位点,到目前为止,已经验证的突变位点已达1500余个,突变位点涵盖了大部分NF1的外显子。
临床表现包括皮肤及皮肤以外的损害。
(一)皮肤损害包括皮肤色素斑,神经纤维瘤,及其他皮肤表现。
1.皮肤色素斑咖啡牛奶斑是NF1诊断标准的7个核心标准之一。常出生时即有,偶在出生后数月至1年内发生,常多发,除掌跖外,可不规则散在分布于体表任何部位,因大多数皮损呈咖啡色故称咖啡牛奶斑(Cafe au lait maecule),呈卵圆或不规则形,大小不一,多随年龄增长而增大、增多。尽管与咖啡加牛奶的颜色相似,但色素的变化从浅棕色至深棕色不等。要符合本病诊断的要求,患者需要六个或更多斑疹,直径>5mm(青春期前)或>15mm(青春期后)。不到1%的未患NF1的5岁以下儿童超过两个及以上的斑疹,如果出现多发性咖啡牛奶斑,将高度提示患有NF1。另一项研究发现,有6个或以上咖啡斑的大多数患者最终将达到NF1诊断标准,通常发生在6岁,这可能性随着咖啡斑的数量和典型形态学表现的增加而增加。一般人群咖啡斑的患病率在3%到36%之间(这取决于被研究的人群),另一方面,多发性咖啡斑存在于正常人群的比例一般为1%。腋窝或腹股沟处雀斑样色素沉着亦为本病的特征,称为Crowe征(Crowe's sign),是NF1核心诊断标准中最特异的一项。它被认为几乎可以确定诊断。但最近的另一项研究提出,斑点可能会出现于一些斑驳病患者,并不一定代表与1型神经纤维瘤病的并存。依据年龄相关的发生频率,它是仅次于咖啡牛奶斑,一般在3至5岁时发生在腋窝和／或腹股沟。其他部位包括颈部和胸部,嘴唇周围,甚至在成人躯干。然而,这些都不满足美国国立卫生研究院的诊断标准。大小从1到3mm大等,可同咖啡牛奶斑区分开来。泛发性色素沉着也可为NF1的皮肤色素改变。
2.神经纤维瘤被认为是NF1另外一个重要的诊断依据,是NF1最常见的表现。由于压迫神经,偶然引起疼痛和进行性功能缺失。神经纤维瘤可发生在身体的任何部位,可以有任何形状,任何大小。皮肤神经纤维瘤在青春期前常不很明显,在整个成人期可能持续生长,包括大小和数量。怀孕是另一个显著生长期。可分为三种类型,即皮肤型、皮下型和丛状型。①皮肤型表现为粉红色、橡胶样有蒂或无蒂的肿瘤,质软,数个至1000个以上,直径从数毫米至数厘米,甚至更大；可累及身体任何部位,但龟头罕见,女性的乳晕和乳头神经纤维瘤对NF1有诊断意义。②皮下神经纤维瘤可硬如象皮。皮肤型和皮下型神经纤维瘤在儿童期开始发生,青春期和妊娠时数量增多,在整个成年期可持续缓慢变大和增多。③丛状型神经纤维瘤出生时即有,对NF1有诊断意义。
3.其他皮肤表现青少年黄色肉芽肿,黑色素瘤,青少年黄色肉芽肿-NF1-青少年髓单核细胞白血病三联征等。
(二)皮肤以外的损害包括口腔损害,神经病变,眼部、骨骼、内分泌、内脏病变,并可能发生恶性肿瘤。1.口腔损害可有口腔肿瘤,发生于上腭、颊粘膜、舌和唇部；或表现为巨舌症。2.神经病变神经缺陷可为局限性或弥漫性、中枢性或外周性。(1)听神经瘤听神经在脑神经中最常受累,听神经瘤双侧发生时可引起感觉神经性耳聋。(2)视神经胶质瘤发生率约占NF1病例的15%,儿童期出现,80%患者无任何症状,少数出现突眼、视力下降或眼球活动受限,大多数病例为非进行性。(3)其他中枢神经系统病变包括脑积水、脑异位、神经胶质小结、神经管闭合、脊髓脊膜膨出、脑和脊髓肿瘤、神经鞘瘤、室管膜瘤、以及星形细胞瘤和脑膜瘤。(4)周围神经损害可出现感觉异常、神经根痛或臂丛麻痹、癫痫、智力障碍、共济失调等。
4.眼病变(1)Lisch小结为虹膜的黑素细胞错构瘤,呈半透明褐色斑点,每只眼平均有25个,常双侧发生,对视力无影响；大多数病例需用裂隙灯检查才能见到；初发于儿童期。Lisch小结很常见,6岁时,15%～20%的儿童和95%的成人有此表现,为美国国家卫生研究院的NF1重要诊断标准之一。(2)其他眼部损害包括脉络膜错构瘤、眼睑神经纤维瘤、双侧视神经萎缩和青光眼,无眼症等。
5.骨骼损害包括蝶骨发育不良,长骨皮质变薄(伴有或不伴有假关节),脊柱后侧凸,胫骨弓形,巨头,矮身材。神经纤维瘤病患者2,5二羟维生素D3血浆水平和骨密度明显下降。组织形态学分析不仅揭示了骨小梁体积下降,而且类骨质体积,成骨细胞和破骨细胞的数量增加。另外,钙含量显著下降。
6.内分泌异常可伴发肢端肥大症、粘液性水肿、性早熟或延迟、Addison病、甲状旁腺功能亢进、甲状腺髓样癌以及嗜铬细胞癌。
7.内脏病变本病根据病变部位,可分为3型：(1)周围型,以多发性皮肤肿瘤和丛状神经纤维瘤为特征,主要累及周围神经,可同时伴内脏和中枢神经系统病变；(2)中枢型,以中枢神经系统和神经根的各种肿瘤的并发为特征,这些肿瘤包括胶质瘤、脑膜瘤、神经鞘瘤和神经纤维瘤；(3)顿挫型,以肿瘤的数目较少为特点,全身仅几个,以后亦不增多。
8.恶变神经纤维肉瘤,或称恶性神经鞘瘤,可发生于神经纤维瘤病患者,但并不常见。在皮肤神经纤维瘤中者称外周恶性神经鞘瘤(malignant peripheral nerve sheath tumor,MPNST)),更为罕见。
组织病理：(1)咖啡牛奶斑表皮内角质形成细胞及黑素细胞中色素增加,黑素细胞及基底细胞内可见巨大球形黑素颗粒,散在分布,直径可达5μm,多巴(Dopa)反应示黑素细胞密度及活性增加。(2)神经纤维瘤瘤体无包膜,可扩展至皮下脂肪组织,界限常清楚,由神经衣和神经鞘细胞组成,瘤内尚有较多神经轴索增生,小血管丰富。神经鞘细胞呈细长梭形或略弯曲成波形,细胞界限不清,胞质染色呈淡伊红色,两端明显长短不一,排列成波形或涡轮状,间有少数成纤维细胞。特殊染色显示瘤内肥大细胞较多见,常有细长神经纤维穿插于其中,无弹性纤维。丛状神经纤维瘤病累及深部大神经,并见神经束不规则。早期局部神经衣呈黏液瘤样,间质增多,侵袭,并使有髓或无髓神经轴索分隔。神经鞘细胞和胶原纤维增生组成弯曲的条索,周围为黏液样无定形间质。晚期因肿瘤增大,导致正常神经形态无法分辨。
诊断标准包括多种,其中NF1主要使用1988年美国国立卫生研究院建立的关于神经纤维瘤病的诊断标准。基于1988年美国国立卫生研究院关于神经纤维瘤病的总结性报告,1型神经纤维瘤病(NFl)需达到以下标准中2条即可诊断：(1)6个或6个以上的咖啡牛奶色斑；(2)腋部或腹股沟区出现雀斑样改变；(3)2个或2个以上的神经纤维瘤；(4)2个或2个以上Lisch小结；(5)视神经胶质瘤(optic pathway gliomas, OPGs);(6)骨发育异常;(7)一级亲属罹患此病。NF2型神经纤维瘤病的诊断至少需以下1条：(1)CT和MRI检查证明双侧第8对脑神经发生肿瘤；(2)直系亲属患2型神经纤维瘤病以及任何一侧第8对脑神经发生肿瘤,或有以下肿瘤中2种或以上,如神经纤维瘤、脑膜瘤、神经胶质瘤、神经鞘瘤。
预防及治疗：目前无理想的治疗方法。主要对症处理,皮损严重妨碍美容、影响功能者,或肿瘤肿大、疼痛并疑有恶变时可行手术切除。恶性外周神经鞘瘤的标准治疗是手术完整切除。咖啡牛奶斑可选择激光(脉冲染料、YAG、红宝石)治疗。Kim等报道了一例采用切削术联合1444nm Nd: YAG激光成功治疗多发性皮肤神经纤维瘤。有癫痫发作者应仔细检查病灶,必要时考虑神经外科手术切除,但有复发可能。
第二部分1型神经纤维瘤病
1型神经纤维瘤病(NF1; OMIM#162200)是一种常见的神经皮肤疾病,以多发性咖啡斑,皮肤皱褶处雀斑样改变,Lisch结节,神经纤维瘤为特征。NFl基因编码神经纤维蛋白,已被证实为NFl的致病基因。神经纤维瘤病的发病率约为1/3500。少见的临床表现包括恶性肿瘤,丛状神经纤维瘤,视神经胶质瘤,学习能力障碍,青少年黄色肉芽肿和骨异常。约50%恶性外周神经鞘瘤(MPNSTs)与1型神经纤维瘤相关皮损有关。
90%的NF1病例可发生咖啡斑(Cafe-au-lait, CAL),表现为圆形的淡棕色均一的斑疹,直径从1～2mm至20cm不等。最近报道了一例非常罕见的巨大咖啡斑,边界不规则,累及后背的下半部分,右侧面,双侧臀部和大腿。1型神经纤维瘤病另外一个显著特点是神经纤维瘤,可发生在身体任何部位,形状和大小不一。一般来说,神经纤维瘤瘤体在皮肤内呈圆拱形,质软,饱满,皮肤色至轻度色素沉着,而位于皮下者呈坚实的结节状。神经纤维瘤还可发生在产道,若在宫颈可导致宫颈狭窄和下腹部疼痛。
NFl基因,定位于染色体17q11.2,在基因组DNA中约280kb,含有60个外显子,编码神经纤维蛋白,该蛋白由2818个氨基酸残基组成。神经纤维蛋白为Ras的GTP酶活化蛋白GTPase activating protein, GAP),广泛的表达于多种组织中。迄今为止,已有超过1000个不同的突变被发现,并列于人类突变基因数据库中。大多数突变都导致了截短蛋白(truncated proteins)表达。
研究目的
本研究旨在对1型神经纤维瘤病的致病基因NFl突变及其表型-基因型相关性进行研究。借鉴模式生物的研究成果,利用人类样本明确人类自身NFl基因在1型神经纤维瘤病发病中的基因结构及表达变化,丰富NF1基因突变数据库,为进一步深入阐明NFl基因的生物学功能及1型神经纤维瘤病的遗传咨询,产前诊断,基因诊断和未来的基因治疗奠定基础。利用本研究检测结果,结合既往文献,分析NFl的基因型-表型潜在相关性。
研究材料和方法
抽取两个1型神经纤维瘤病家系、三个散发病例及100例无亲缘关系的正常对照的外周血,提取DNA,设计引物,对NF1基因编码的外显子及外显子内含子交界区域进行基因扩增,PCR产物纯化,并采用Sanger法进行测序,利用BioEdit软件分析比对研究对象的基因序列有无杂合突变,并与基因数据库正常序列进行比对,分析有无纯合突变,同时与SNP数据库和100例正常对照的序列比对排除多态性。通过比较临床和突变数据来分析NF1基因型和表型的潜在相关性。
结果
(1)临床发现
所有患者出生时即出现咖啡斑。家系1先证者,女,3.5岁,躯干、四肢和臀部可见散在分布的咖啡斑,大小不等。其父亲,姑和祖母病情严重,皮损典型,全身可见大量神经纤维瘤和咖啡斑。该家系中所有患者5-6岁时出现神经纤维瘤,10岁以后迅速进展。家系2所有患者神经纤维瘤出现在3岁左右,后逐渐增多,10余岁时达到最多。两个散发病例发病时间分别为23岁和24岁,虽然发病较晚,但病情进展迅速,神经纤维瘤生长快,部分瘤体巨大。神经纤维瘤组织病理学检查,可见神经纤维瘤的典型特征,如梭形细胞增生,粘液样背景和大量的肥大细胞。
(2)NFl在1型神经纤维瘤病中的基因变异
在两个1型神经纤维瘤病家系和3个散发病例中共发现3个新的突变,分别为c.601T>A, c.871G>T, c.1448A>G,这些新的突变仅在患者中发现,家系中未患病成员及正常对照均为野生型。这些突变分别位于外显子4、内含子6和外显子10,分别导致的氨基酸改变为F201I, E291X, D485G。
结论
(1)NFl基因的突变c.601T>A, c.871G>T, c.1448A>G可能为相应患者1型神经纤维瘤病发病原因；
(2)我们的数据显示NFl基因外显子4,6,10的突变可能影响NF1蛋白的结构和功能,并可能最终影响其生理学功能。
Background
Part I Neurofibromatosis
Neurofibromatosis, also known as Von Recklinghausen's disease, is characterized by dysplasia of nervous system, skeletal system and skin.
Clinical classification
Clinically, neurofibromatosis can be classified into seven different types, including Neurofibromatosis type-1(NF1), NF2, NF3, NF4, NF5, NF6and NF7. NF1is the most common, counting for85%of all the cases, characterized by multiple cafe-au-lait, skinfold freckling, Lisch nodules, and neurofibromas, and involvement in central nervous system (CNS) is not common. NF2, mainly involving in CNS, is bilateral acoustic neuroma, presenting few cafe-au-lait and neurofibromas, and no Lisch nodules. NF3combines the features of both NF1and NF2. The types from NF4to NF7are very rare.
Manifestations
Cutaneous manifestations
Skin pigment spots:The Cafe-au-lait macule (CALM) is one of the seven cardinal diagnostic criteria of NF1CALMs are discrete, well circumscribed, round or oval, uniformly pigmented patches. Despite the analogy of the color to coffee with milk, the pigmentation varies from light to dark brown. To fulfill this requirement, patients need six or more macules>5mm (prepuberty) or>15mm (postpuberty) in diameter. Less than1%of children under5years of age without NF1have more than two; when multiple macules are present, this is highly suggestive of NF1Another study found that the majority of patients with6or more CALMs will eventually meet diagnostic criteria for NF1, typically by age6years, and this likelihood increases with increasing number and typical morphologic appearance of CALMs. The prevalence of CALMs in the general population has varied between3%and36%-depending on the population studied-but the presence of multiple CALMs in an otherwise normal population is generally1%.
Skin fold freckling, also known as Crowe's sign, is the most specific of the cardinal criteria for NF1. It is considered nearly pathognomonic. But another study recently proposed that freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type1. It is second only to CALMs in terms of age-related frequency and generally occurs between3and5years of age in either the axillae and/or groin. Other sites include under the neck and breasts, around the lips, and even the trunk in adults; however, none of these fulfill the NIH diagnostic criterion. Their size varies from1to3mm, distinguishing them from CALMs. Generalized hyperpigmentation also is one of skin pigmentary lesions of NF1.
Cutaneous neurofibromas. The neurofibroma is considered as another hallmark sign of NF1. neurofibromas are the most common manifestations of neurofibromatosis type-1. They occasionally cause pain or progressive loss of function due to nerve compression. Neurofibromas can occur anywhere on the body and widely varies in their shape and size. Cutaneous neurofibromas usually do not become apparent until puberty and may continue to increase in size and number throughout adulthood. Outside of puberty, pregnancy is the other major time associated with increased growth. There are three types including skin one, hypodermal one and plexiform one. The latter occurs at birth and is important for diagnosis.
Other cutaneous findings include juvenile xanthogranuloma, Melanoma, triad of juvenile xanthogranuloma (JXG), NF1, and juvenile myelomonocytic leukemia (JMML).
Noncutaneous manifestations
Oral lesions include oral tumor, at the site of the palate, buccal mucosa, tongue and the lips; or show acroglossia.
Neuropathy
Neuropathy, possibly localized or diffuse, central or peripheral, includes acoustic neuroma, optic glioma, hydrocephaly, heterotopic brain, glial nodule, neural tube closure, bulging meningomyelocele, brain and spinal cord tumors, schwannoma, ependymoma and astrocytoma and meningioma. Peripheral nerve lesions can appear abnormal sensation, nerve root pain or brachial plexus paralysis, epilepsy, mental retardation, ataxia, etc.
Ocular disorders
Ocular disorders, such as lisch nodules, optic gliomas and anterior segment defects, are typical with clinical presentation of NF1. Anophthalmia is a rare eye malformation in NF1. Ophthalmic features of NF2are also prominent and include reduced visual acuity and cataract. The two most common problems are lisch nodules, optic gliomas.
Lisch nodules are small, dome-shaped hyperpigmented macules of the iris that cause no impairment of vision. They are a common finding (by6years of age,15%to20%of children have them;95%of adults have them) and are included as one of the cardinal NIH diagnostic criteria.
Bony abnormalities
Bony abnormalities in NF1are variable and include scoliosis, sphenoid wing or long bone dysplasia, and, more recently, osteopenia/osteoporosis. Patients with NF1display significantly lower25-(OH)-cholecalciferol serum levels and decreased bone mineral density(BMD). Histomorphometric analysis not only reveal a reduced trabecular bone volume in biopsies from NF1patients, but also a significantly increased osteoid volume and increased numbers of osteoblasts and osteoclasts. Moreover, qBEI analysis revealed a significant decrease of the calcium content in biopsies from NF1patients.
5. Endocrine abnormalities lead to acromegaly, myxedema, precocious puberty or delay, Addison's disease, hyperparathyroidism, medullary thyroid carcinoma and chromaffin cells carcinoma.
Malignancy
Neurofibrosarcoma, also known as malignant schwannoma, can occur on patients with neuroflbromatosis, but it is not common. In the skin, the tumor is named as malignant peripheral nerve sheath tumor(MPNST)and rarer.
Hostopathologically
Cafe-Au-Lait Maecula Increased pigment is seen in keratinocytes and melanocytes of epidermis. Giant global melanin granules may be seen in melanocytes and basal cells with diffused distribution. The granules are about5μM in diameter, and Dopa reaction shows increased density and activities of melanocytes.
Neurofibroma No envelope exists on the tumors, which may spread to the hypodermal fatty tissues and have a clear bound, composed of nerve garment and Schwann cells. Within the tumor, hyperplasia of neural axon and richness of small blood vessels is showed. Schwann cells are in long and thin spindle shape or slightly bent into waveform with unclear boundary. Plasma of the cells is stained in color of light eosin.They have an obviously different length on both ends, are arranged in waveform or turbine with few fibroblasts in it. Special staining frequently shows mast cells and no elastic fiber. Plexiform neurofibromatosis involves in deep large nerve, in which irregular nerve tracts are seen. The early-stage local nerve envelope appears myxoid, more interstitial substances and have an invasive, and makes medullated and non-medullated neuraxon divide. Nerve sheath cells and collagen fiber hyperplasia forms bending cords, surrounded by myxoid amorphous stroma. Morphologically, the normal nerve can not be distinguished at advanced stage due to enlargement in size of tumors.
Diagnostic criteria
Based on the1988National Institutes of Health Consensus Development Conference on Neurofibromatosis, the diagnosis of NF1is made in an individual with any2of the following clinical features:(1)6or more cafe-au-lait spots,(2) axillary or groin freckling,(3)2or more Lisch nodules,(4)2or more neurofibromas,(5) optic pathway gliomas (OPGs),(6) bone dysplasia, and (7) a first-degree family relative with NF1
The diagnosis of NF2is made in an individual with any1of the following clinical features:(1) the tests of CT and MRI show tumor involving in the bilateral vestibular nerves;(2) a first-degree family relative with NF2and at least one side eighth of cranial nerves is involved, or2or more tumors as following:neurofibroma, meningioma, glioma and schwannom
Management
Up to now, there is no perfect therapy for treating neurofibromatosis. Surgical intervention is the only effective means of treatment for progressive pain, disfigurement, functional compromise, and malignancy. Complete surgical resection is the standard treatment for malignant peripheral nerve sheath tumors. Cafe-au-lait spots can be treated by laser therapies, including pulse-dye laser, YAG laser and ruby laser. Kim, H. J. et al. reported a successful treatment of multiple cutaneous neuroflbromas using a combination of shave excision and laser photothermocoagulation with a1,444-nm Neodymium-Doped Yttrium Aluminum Garnet (Nd:YAG) laser, carefully checking lesions should be taken if of onset of epilepsy. If necessary, neurosurgery may be considered to resect the lesions which is possibly recurrent.
Part Ⅱ Neurofibromatosis type1
Neurofibromatosis type1(NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple cafe-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. The incidence has been estimated to be1in3500individuals. The less frequent manifestations include malignancies, plexiform neurofibromas, optic glioma, learning difficulties, juvenile xanthogranuloma and skeletal abnormalities. About50%of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type1associated lesions.
Cafe-au-lait (CAL) spots occur in more than90%of NF1cases, and manifested as well-circumscribed, light-brown, homogenous patches that range from1to2mm to greater than20cm in diameter, with the majority being under10cm. A giant cafe-au-lait macule with irregular borders, involving the lower part of the back, right flank and both buttocks and thighs were reported recently, which is rather unusual. Neurofibromas, another one of the hallmark signs of NF1, can occur anywhere on the body and there is a wide variation in their shape and size. Generally, the'cutaneous'or'dermal'tumors are dome-shaped, soft, fleshy, and skin colored to slightly hyperpigmented, and the'subcutaneous' tumors are of the firm, nodular variety. Neurofibromas, beside skin, also appear in the gynecologic tract, including the cervix, resulting in cervical stenosis and lower abdominal pain.
NF1gene, mapped on chromosome17ql1.2, spans approximately280kb of genomic DNA, contains60exons and encodes neurofibromin which is composed of2818amino acid residues. Neurofibromin that functions as a GTPase activating protein (GAP) for Ras is widely expressed in many tissues. To date, more than1,000different NF1mutations have been found and listed in the Human Gene Mutation Database. The majority of these NF1mutations lead to truncated protein products.
Objectives
To identify the mutations of NF1gene and the correlation of genotype and phenotype in human samples on the basis of research results of model organisms for further illuminating the biological function of NF1gene, expand the data of NF1gene mutation and proivide a foundation of genetic consultation, prenatal diagnosis, genetic diagnosis and the future genetic treatment in neurofibromatosis type1.
Materials and methods
The NF1gene of two families with neurofibromatosis type1and three sporadic cases and100unrelated controls were amplified by polymerase chain reaction(PCR) and then were sequenced. The genes of subjects of the study were analysed by software BioEdit. The correlation study between the genotypes and phenotypes in these patients was exerted by comparing the data of clinic and mutations.
results
Clinical findings
Patient1, a3.5-year-old girl, was the proband in family1. She presented with cafe-au-lait spots involving trunk, extremities and buttocks. Her father, aunt, grandmother have more typical and severe manifestation of many neurofibromas and cafe-au-lait spots over their bodies. In the family, all patients had cafe-au-lait spots at birth, and the neurofibromas appeared in5or6years old, and rapidly developed at teenage age. The other three patients [the proband in family2, and the two sporadic patients] also had the typical clinical features of neurofibromatosis. In family2, all patients had cafe-au-lait spots at birth, and the neurofibromas developed in about3years old, and gradually developed at teenage age. Patient3was a46year-old male, sporadic case, who had onset at the age of20s. However, the neurofibromas developed very swiftly and the size of the tumors was very giant partly. On histological examination of skin biopsies taken from one patient, the typical features of neurofibromas and spindle cell proliferations were seen, with a mucinous background and many mast cells.
Experimental findings
The sequencing of PCR products showed three novel mutations in NF1gene, c.601T>A in exon4, c.871G>T in exon6, c.1448A>G in exon10, respectively leading to amino acid changes, F201I, E291X, D485G. No any change was found in unaffected individuals in these families and unrelated controls.
Conclusions
(1) These mutations c.601T>A, c.871G>T, c.1448A>G of NF1gene may be pathogenic causes for neurofibromatosis type1.
(2) Our data indicates that the mutations in exon4,6,10of NF1gene possibly change the structure and function of NF1protein and ultimately affect their physiological function.
第一部分神经纤维瘤病
神经纤维瘤病(Neurofibromatosis, NF),又称冯·雷克林豪森病(von Recklinghausen disease)。典型神经纤维瘤病表现为神经系统、骨骼和皮肤的发育异常。
临床类型NF1型：即传统的神经纤维瘤病,占总病例85%以上,表现为大量的神经纤维瘤和咖啡牛奶斑,可见Lisch小结,常不伴发中枢神经系统损害。NF2型：中枢型或听力型,为双侧听神经瘤,咖啡牛奶斑和皮肤神经纤维瘤很少,无Lisch小结。NF3型：混合型,兼有Ⅰ型和Ⅱ型的特征。NF4型：变异型,表现为弥漫性咖啡牛奶斑和神经纤维瘤,可见Lisch小结,可有或无中枢神经系统肿瘤。NF5型：节段型或局限型,神经纤维瘤和咖啡牛奶斑局限于身体的某些特定部位。NF6型：仅咖啡牛奶斑。NF7型：迟发型,30岁以后发病。
病因及发病机制本病NF1型至NF4型均为常染色体显性遗传,不同型别外显率不同,由畸变显性基因引起的神经外胚叶异常,常表现为不全型和单纯型,25%-50%的患者家族史阳性,男性较多见。一般认为NF5型由形成合子后的体细胞突变引起,常不遗传给后代。NF1基因位于17q11.2的中央周围区,编码神经纤维蛋白,该蛋白负调控Ras蛋白转导信号。NF2的基因位于染色体22q12.2,为一种肿瘤抑制基因,编码Merlin蛋白(神经鞘蛋白),该蛋白将肌动蛋白细胞骨架连接到细胞表面的糖蛋白上,起负生长调控作用,具有传导抑制信号的功能。已发现大量NFl基因的突变位点,到目前为止,已经验证的突变位点已达1500余个,突变位点涵盖了大部分NF1的外显子。
临床表现包括皮肤及皮肤以外的损害。
(一)皮肤损害包括皮肤色素斑,神经纤维瘤,及其他皮肤表现。
1.皮肤色素斑咖啡牛奶斑是NF1诊断标准的7个核心标准之一。常出生时即有,偶在出生后数月至1年内发生,常多发,除掌跖外,可不规则散在分布于体表任何部位,因大多数皮损呈咖啡色故称咖啡牛奶斑(Cafe au lait maecule),呈卵圆或不规则形,大小不一,多随年龄增长而增大、增多。尽管与咖啡加牛奶的颜色相似,但色素的变化从浅棕色至深棕色不等。要符合本病诊断的要求,患者需要六个或更多斑疹,直径>5mm(青春期前)或>15mm(青春期后)。不到1%的未患NF1的5岁以下儿童超过两个及以上的斑疹,如果出现多发性咖啡牛奶斑,将高度提示患有NF1。另一项研究发现,有6个或以上咖啡斑的大多数患者最终将达到NF1诊断标准,通常发生在6岁,这可能性随着咖啡斑的数量和典型形态学表现的增加而增加。一般人群咖啡斑的患病率在3%到36%之间(这取决于被研究的人群),另一方面,多发性咖啡斑存在于正常人群的比例一般为1%。腋窝或腹股沟处雀斑样色素沉着亦为本病的特征,称为Crowe征(Crowe's sign),是NF1核心诊断标准中最特异的一项。它被认为几乎可以确定诊断。但最近的另一项研究提出,斑点可能会出现于一些斑驳病患者,并不一定代表与1型神经纤维瘤病的并存。依据年龄相关的发生频率,它是仅次于咖啡牛奶斑,一般在3至5岁时发生在腋窝和／或腹股沟。其他部位包括颈部和胸部,嘴唇周围,甚至在成人躯干。然而,这些都不满足美国国立卫生研究院的诊断标准。大小从1到3mm大等,可同咖啡牛奶斑区分开来。泛发性色素沉着也可为NF1的皮肤色素改变。
2.神经纤维瘤被认为是NF1另外一个重要的诊断依据,是NF1最常见的表现。由于压迫神经,偶然引起疼痛和进行性功能缺失。神经纤维瘤可发生在身体的任何部位,可以有任何形状,任何大小。皮肤神经纤维瘤在青春期前常不很明显,在整个成人期可能持续生长,包括大小和数量。怀孕是另一个显著生长期。可分为三种类型,即皮肤型、皮下型和丛状型。①皮肤型表现为粉红色、橡胶样有蒂或无蒂的肿瘤,质软,数个至1000个以上,直径从数毫米至数厘米,甚至更大；可累及身体任何部位,但龟头罕见,女性的乳晕和乳头神经纤维瘤对NF1有诊断意义。②皮下神经纤维瘤可硬如象皮。皮肤型和皮下型神经纤维瘤在儿童期开始发生,青春期和妊娠时数量增多,在整个成年期可持续缓慢变大和增多。③丛状型神经纤维瘤出生时即有,对NF1有诊断意义。
3.其他皮肤表现青少年黄色肉芽肿,黑色素瘤,青少年黄色肉芽肿-NF1-青少年髓单核细胞白血病三联征等。
(二)皮肤以外的损害包括口腔损害,神经病变,眼部、骨骼、内分泌、内脏病变,并可能发生恶性肿瘤。1.口腔损害可有口腔肿瘤,发生于上腭、颊粘膜、舌和唇部；或表现为巨舌症。2.神经病变神经缺陷可为局限性或弥漫性、中枢性或外周性。(1)听神经瘤听神经在脑神经中最常受累,听神经瘤双侧发生时可引起感觉神经性耳聋。(2)视神经胶质瘤发生率约占NF1病例的15%,儿童期出现,80%患者无任何症状,少数出现突眼、视力下降或眼球活动受限,大多数病例为非进行性。(3)其他中枢神经系统病变包括脑积水、脑异位、神经胶质小结、神经管闭合、脊髓脊膜膨出、脑和脊髓肿瘤、神经鞘瘤、室管膜瘤、以及星形细胞瘤和脑膜瘤。(4)周围神经损害可出现感觉异常、神经根痛或臂丛麻痹、癫痫、智力障碍、共济失调等。
4.眼病变(1)Lisch小结为虹膜的黑素细胞错构瘤,呈半透明褐色斑点,每只眼平均有25个,常双侧发生,对视力无影响；大多数病例需用裂隙灯检查才能见到；初发于儿童期。Lisch小结很常见,6岁时,15%～20%的儿童和95%的成人有此表现,为美国国家卫生研究院的NF1重要诊断标准之一。(2)其他眼部损害包括脉络膜错构瘤、眼睑神经纤维瘤、双侧视神经萎缩和青光眼,无眼症等。
5.骨骼损害包括蝶骨发育不良,长骨皮质变薄(伴有或不伴有假关节),脊柱后侧凸,胫骨弓形,巨头,矮身材。神经纤维瘤病患者2,5二羟维生素D3血浆水平和骨密度明显下降。组织形态学分析不仅揭示了骨小梁体积下降,而且类骨质体积,成骨细胞和破骨细胞的数量增加。另外,钙含量显著下降。
6.内分泌异常可伴发肢端肥大症、粘液性水肿、性早熟或延迟、Addison病、甲状旁腺功能亢进、甲状腺髓样癌以及嗜铬细胞癌。
7.内脏病变本病根据病变部位,可分为3型：(1)周围型,以多发性皮肤肿瘤和丛状神经纤维瘤为特征,主要累及周围神经,可同时伴内脏和中枢神经系统病变；(2)中枢型,以中枢神经系统和神经根的各种肿瘤的并发为特征,这些肿瘤包括胶质瘤、脑膜瘤、神经鞘瘤和神经纤维瘤；(3)顿挫型,以肿瘤的数目较少为特点,全身仅几个,以后亦不增多。
8.恶变神经纤维肉瘤,或称恶性神经鞘瘤,可发生于神经纤维瘤病患者,但并不常见。在皮肤神经纤维瘤中者称外周恶性神经鞘瘤(malignant peripheral nerve sheath tumor,MPNST)),更为罕见。
组织病理：(1)咖啡牛奶斑表皮内角质形成细胞及黑素细胞中色素增加,黑素细胞及基底细胞内可见巨大球形黑素颗粒,散在分布,直径可达5μm,多巴(Dopa)反应示黑素细胞密度及活性增加。(2)神经纤维瘤瘤体无包膜,可扩展至皮下脂肪组织,界限常清楚,由神经衣和神经鞘细胞组成,瘤内尚有较多神经轴索增生,小血管丰富。神经鞘细胞呈细长梭形或略弯曲成波形,细胞界限不清,胞质染色呈淡伊红色,两端明显长短不一,排列成波形或涡轮状,间有少数成纤维细胞。特殊染色显示瘤内肥大细胞较多见,常有细长神经纤维穿插于其中,无弹性纤维。丛状神经纤维瘤病累及深部大神经,并见神经束不规则。早期局部神经衣呈黏液瘤样,间质增多,侵袭,并使有髓或无髓神经轴索分隔。神经鞘细胞和胶原纤维增生组成弯曲的条索,周围为黏液样无定形间质。晚期因肿瘤增大,导致正常神经形态无法分辨。
诊断标准包括多种,其中NF1主要使用1988年美国国立卫生研究院建立的关于神经纤维瘤病的诊断标准。基于1988年美国国立卫生研究院关于神经纤维瘤病的总结性报告,1型神经纤维瘤病(NFl)需达到以下标准中2条即可诊断：(1)6个或6个以上的咖啡牛奶色斑；(2)腋部或腹股沟区出现雀斑样改变；(3)2个或2个以上的神经纤维瘤；(4)2个或2个以上Lisch小结；(5)视神经胶质瘤(optic pathway gliomas, OPGs);(6)骨发育异常;(7)一级亲属罹患此病。NF2型神经纤维瘤病的诊断至少需以下1条：(1)CT和MRI检查证明双侧第8对脑神经发生肿瘤；(2)直系亲属患2型神经纤维瘤病以及任何一侧第8对脑神经发生肿瘤,或有以下肿瘤中2种或以上,如神经纤维瘤、脑膜瘤、神经胶质瘤、神经鞘瘤。
预防及治疗：目前无理想的治疗方法。主要对症处理,皮损严重妨碍美容、影响功能者,或肿瘤肿大、疼痛并疑有恶变时可行手术切除。恶性外周神经鞘瘤的标准治疗是手术完整切除。咖啡牛奶斑可选择激光(脉冲染料、YAG、红宝石)治疗。Kim等报道了一例采用切削术联合1444nm Nd: YAG激光成功治疗多发性皮肤神经纤维瘤。有癫痫发作者应仔细检查病灶,必要时考虑神经外科手术切除,但有复发可能。
第二部分1型神经纤维瘤病
1型神经纤维瘤病(NF1; OMIM#162200)是一种常见的神经皮肤疾病,以多发性咖啡斑,皮肤皱褶处雀斑样改变,Lisch结节,神经纤维瘤为特征。NFl基因编码神经纤维蛋白,已被证实为NFl的致病基因。神经纤维瘤病的发病率约为1/3500。少见的临床表现包括恶性肿瘤,丛状神经纤维瘤,视神经胶质瘤,学习能力障碍,青少年黄色肉芽肿和骨异常。约50%恶性外周神经鞘瘤(MPNSTs)与1型神经纤维瘤相关皮损有关。
90%的NF1病例可发生咖啡斑(Cafe-au-lait, CAL),表现为圆形的淡棕色均一的斑疹,直径从1～2mm至20cm不等。最近报道了一例非常罕见的巨大咖啡斑,边界不规则,累及后背的下半部分,右侧面,双侧臀部和大腿。1型神经纤维瘤病另外一个显著特点是神经纤维瘤,可发生在身体任何部位,形状和大小不一。一般来说,神经纤维瘤瘤体在皮肤内呈圆拱形,质软,饱满,皮肤色至轻度色素沉着,而位于皮下者呈坚实的结节状。神经纤维瘤还可发生在产道,若在宫颈可导致宫颈狭窄和下腹部疼痛。
NFl基因,定位于染色体17q11.2,在基因组DNA中约280kb,含有60个外显子,编码神经纤维蛋白,该蛋白由2818个氨基酸残基组成。神经纤维蛋白为Ras的GTP酶活化蛋白GTPase activating protein, GAP),广泛的表达于多种组织中。迄今为止,已有超过1000个不同的突变被发现,并列于人类突变基因数据库中。大多数突变都导致了截短蛋白(truncated proteins)表达。
研究目的
本研究旨在对1型神经纤维瘤病的致病基因NFl突变及其表型-基因型相关性进行研究。借鉴模式生物的研究成果,利用人类样本明确人类自身NFl基因在1型神经纤维瘤病发病中的基因结构及表达变化,丰富NF1基因突变数据库,为进一步深入阐明NFl基因的生物学功能及1型神经纤维瘤病的遗传咨询,产前诊断,基因诊断和未来的基因治疗奠定基础。利用本研究检测结果,结合既往文献,分析NFl的基因型-表型潜在相关性。
研究材料和方法
抽取两个1型神经纤维瘤病家系、三个散发病例及100例无亲缘关系的正常对照的外周血,提取DNA,设计引物,对NF1基因编码的外显子及外显子内含子交界区域进行基因扩增,PCR产物纯化,并采用Sanger法进行测序,利用BioEdit软件分析比对研究对象的基因序列有无杂合突变,并与基因数据库正常序列进行比对,分析有无纯合突变,同时与SNP数据库和100例正常对照的序列比对排除多态性。通过比较临床和突变数据来分析NF1基因型和表型的潜在相关性。
结果
(1)临床发现
所有患者出生时即出现咖啡斑。家系1先证者,女,3.5岁,躯干、四肢和臀部可见散在分布的咖啡斑,大小不等。其父亲,姑和祖母病情严重,皮损典型,全身可见大量神经纤维瘤和咖啡斑。该家系中所有患者5-6岁时出现神经纤维瘤,10岁以后迅速进展。家系2所有患者神经纤维瘤出现在3岁左右,后逐渐增多,10余岁时达到最多。两个散发病例发病时间分别为23岁和24岁,虽然发病较晚,但病情进展迅速,神经纤维瘤生长快,部分瘤体巨大。神经纤维瘤组织病理学检查,可见神经纤维瘤的典型特征,如梭形细胞增生,粘液样背景和大量的肥大细胞。
(2)NFl在1型神经纤维瘤病中的基因变异
在两个1型神经纤维瘤病家系和3个散发病例中共发现3个新的突变,分别为c.601T>A, c.871G>T, c.1448A>G,这些新的突变仅在患者中发现,家系中未患病成员及正常对照均为野生型。这些突变分别位于外显子4、内含子6和外显子10,分别导致的氨基酸改变为F201I, E291X, D485G。
结论
(1)NFl基因的突变c.601T>A, c.871G>T, c.1448A>G可能为相应患者1型神经纤维瘤病发病原因；
(2)我们的数据显示NFl基因外显子4,6,10的突变可能影响NF1蛋白的结构和功能,并可能最终影响其生理学功能。
Background
Part I Neurofibromatosis
Neurofibromatosis, also known as Von Recklinghausen's disease, is characterized by dysplasia of nervous system, skeletal system and skin.
Clinical classification
Clinically, neurofibromatosis can be classified into seven different types, including Neurofibromatosis type-1(NF1), NF2, NF3, NF4, NF5, NF6and NF7. NF1is the most common, counting for85%of all the cases, characterized by multiple cafe-au-lait, skinfold freckling, Lisch nodules, and neurofibromas, and involvement in central nervous system (CNS) is not common. NF2, mainly involving in CNS, is bilateral acoustic neuroma, presenting few cafe-au-lait and neurofibromas, and no Lisch nodules. NF3combines the features of both NF1and NF2. The types from NF4to NF7are very rare.
Manifestations
Cutaneous manifestations
Skin pigment spots:The Cafe-au-lait macule (CALM) is one of the seven cardinal diagnostic criteria of NF1CALMs are discrete, well circumscribed, round or oval, uniformly pigmented patches. Despite the analogy of the color to coffee with milk, the pigmentation varies from light to dark brown. To fulfill this requirement, patients need six or more macules>5mm (prepuberty) or>15mm (postpuberty) in diameter. Less than1%of children under5years of age without NF1have more than two; when multiple macules are present, this is highly suggestive of NF1Another study found that the majority of patients with6or more CALMs will eventually meet diagnostic criteria for NF1, typically by age6years, and this likelihood increases with increasing number and typical morphologic appearance of CALMs. The prevalence of CALMs in the general population has varied between3%and36%-depending on the population studied-but the presence of multiple CALMs in an otherwise normal population is generally1%.
Skin fold freckling, also known as Crowe's sign, is the most specific of the cardinal criteria for NF1. It is considered nearly pathognomonic. But another study recently proposed that freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type1. It is second only to CALMs in terms of age-related frequency and generally occurs between3and5years of age in either the axillae and/or groin. Other sites include under the neck and breasts, around the lips, and even the trunk in adults; however, none of these fulfill the NIH diagnostic criterion. Their size varies from1to3mm, distinguishing them from CALMs. Generalized hyperpigmentation also is one of skin pigmentary lesions of NF1.
Cutaneous neurofibromas. The neurofibroma is considered as another hallmark sign of NF1. neurofibromas are the most common manifestations of neurofibromatosis type-1. They occasionally cause pain or progressive loss of function due to nerve compression. Neurofibromas can occur anywhere on the body and widely varies in their shape and size. Cutaneous neurofibromas usually do not become apparent until puberty and may continue to increase in size and number throughout adulthood. Outside of puberty, pregnancy is the other major time associated with increased growth. There are three types including skin one, hypodermal one and plexiform one. The latter occurs at birth and is important for diagnosis.
Other cutaneous findings include juvenile xanthogranuloma, Melanoma, triad of juvenile xanthogranuloma (JXG), NF1, and juvenile myelomonocytic leukemia (JMML).
Noncutaneous manifestations
Oral lesions include oral tumor, at the site of the palate, buccal mucosa, tongue and the lips; or show acroglossia.
Neuropathy
Neuropathy, possibly localized or diffuse, central or peripheral, includes acoustic neuroma, optic glioma, hydrocephaly, heterotopic brain, glial nodule, neural tube closure, bulging meningomyelocele, brain and spinal cord tumors, schwannoma, ependymoma and astrocytoma and meningioma. Peripheral nerve lesions can appear abnormal sensation, nerve root pain or brachial plexus paralysis, epilepsy, mental retardation, ataxia, etc.
Ocular disorders
Ocular disorders, such as lisch nodules, optic gliomas and anterior segment defects, are typical with clinical presentation of NF1. Anophthalmia is a rare eye malformation in NF1. Ophthalmic features of NF2are also prominent and include reduced visual acuity and cataract. The two most common problems are lisch nodules, optic gliomas.
Lisch nodules are small, dome-shaped hyperpigmented macules of the iris that cause no impairment of vision. They are a common finding (by6years of age,15%to20%of children have them;95%of adults have them) and are included as one of the cardinal NIH diagnostic criteria.
Bony abnormalities
Bony abnormalities in NF1are variable and include scoliosis, sphenoid wing or long bone dysplasia, and, more recently, osteopenia/osteoporosis. Patients with NF1display significantly lower25-(OH)-cholecalciferol serum levels and decreased bone mineral density(BMD). Histomorphometric analysis not only reveal a reduced trabecular bone volume in biopsies from NF1patients, but also a significantly increased osteoid volume and increased numbers of osteoblasts and osteoclasts. Moreover, qBEI analysis revealed a significant decrease of the calcium content in biopsies from NF1patients.
5. Endocrine abnormalities lead to acromegaly, myxedema, precocious puberty or delay, Addison's disease, hyperparathyroidism, medullary thyroid carcinoma and chromaffin cells carcinoma.
Malignancy
Neurofibrosarcoma, also known as malignant schwannoma, can occur on patients with neuroflbromatosis, but it is not common. In the skin, the tumor is named as malignant peripheral nerve sheath tumor(MPNST)and rarer.
Hostopathologically
Cafe-Au-Lait Maecula Increased pigment is seen in keratinocytes and melanocytes of epidermis. Giant global melanin granules may be seen in melanocytes and basal cells with diffused distribution. The granules are about5μM in diameter, and Dopa reaction shows increased density and activities of melanocytes.
Neurofibroma No envelope exists on the tumors, which may spread to the hypodermal fatty tissues and have a clear bound, composed of nerve garment and Schwann cells. Within the tumor, hyperplasia of neural axon and richness of small blood vessels is showed. Schwann cells are in long and thin spindle shape or slightly bent into waveform with unclear boundary. Plasma of the cells is stained in color of light eosin.They have an obviously different length on both ends, are arranged in waveform or turbine with few fibroblasts in it. Special staining frequently shows mast cells and no elastic fiber. Plexiform neurofibromatosis involves in deep large nerve, in which irregular nerve tracts are seen. The early-stage local nerve envelope appears myxoid, more interstitial substances and have an invasive, and makes medullated and non-medullated neuraxon divide. Nerve sheath cells and collagen fiber hyperplasia forms bending cords, surrounded by myxoid amorphous stroma. Morphologically, the normal nerve can not be distinguished at advanced stage due to enlargement in size of tumors.
Diagnostic criteria
Based on the1988National Institutes of Health Consensus Development Conference on Neurofibromatosis, the diagnosis of NF1is made in an individual with any2of the following clinical features:(1)6or more cafe-au-lait spots,(2) axillary or groin freckling,(3)2or more Lisch nodules,(4)2or more neurofibromas,(5) optic pathway gliomas (OPGs),(6) bone dysplasia, and (7) a first-degree family relative with NF1
The diagnosis of NF2is made in an individual with any1of the following clinical features:(1) the tests of CT and MRI show tumor involving in the bilateral vestibular nerves;(2) a first-degree family relative with NF2and at least one side eighth of cranial nerves is involved, or2or more tumors as following:neurofibroma, meningioma, glioma and schwannom
Management
Up to now, there is no perfect therapy for treating neurofibromatosis. Surgical intervention is the only effective means of treatment for progressive pain, disfigurement, functional compromise, and malignancy. Complete surgical resection is the standard treatment for malignant peripheral nerve sheath tumors. Cafe-au-lait spots can be treated by laser therapies, including pulse-dye laser, YAG laser and ruby laser. Kim, H. J. et al. reported a successful treatment of multiple cutaneous neuroflbromas using a combination of shave excision and laser photothermocoagulation with a1,444-nm Neodymium-Doped Yttrium Aluminum Garnet (Nd:YAG) laser, carefully checking lesions should be taken if of onset of epilepsy. If necessary, neurosurgery may be considered to resect the lesions which is possibly recurrent.
Part Ⅱ Neurofibromatosis type1
Neurofibromatosis type1(NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple cafe-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. The incidence has been estimated to be1in3500individuals. The less frequent manifestations include malignancies, plexiform neurofibromas, optic glioma, learning difficulties, juvenile xanthogranuloma and skeletal abnormalities. About50%of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type1associated lesions.
Cafe-au-lait (CAL) spots occur in more than90%of NF1cases, and manifested as well-circumscribed, light-brown, homogenous patches that range from1to2mm to greater than20cm in diameter, with the majority being under10cm. A giant cafe-au-lait macule with irregular borders, involving the lower part of the back, right flank and both buttocks and thighs were reported recently, which is rather unusual. Neurofibromas, another one of the hallmark signs of NF1, can occur anywhere on the body and there is a wide variation in their shape and size. Generally, the'cutaneous'or'dermal'tumors are dome-shaped, soft, fleshy, and skin colored to slightly hyperpigmented, and the'subcutaneous' tumors are of the firm, nodular variety. Neurofibromas, beside skin, also appear in the gynecologic tract, including the cervix, resulting in cervical stenosis and lower abdominal pain.
NF1gene, mapped on chromosome17ql1.2, spans approximately280kb of genomic DNA, contains60exons and encodes neurofibromin which is composed of2818amino acid residues. Neurofibromin that functions as a GTPase activating protein (GAP) for Ras is widely expressed in many tissues. To date, more than1,000different NF1mutations have been found and listed in the Human Gene Mutation Database. The majority of these NF1mutations lead to truncated protein products.
Objectives
To identify the mutations of NF1gene and the correlation of genotype and phenotype in human samples on the basis of research results of model organisms for further illuminating the biological function of NF1gene, expand the data of NF1gene mutation and proivide a foundation of genetic consultation, prenatal diagnosis, genetic diagnosis and the future genetic treatment in neurofibromatosis type1.
Materials and methods
The NF1gene of two families with neurofibromatosis type1and three sporadic cases and100unrelated controls were amplified by polymerase chain reaction(PCR) and then were sequenced. The genes of subjects of the study were analysed by software BioEdit. The correlation study between the genotypes and phenotypes in these patients was exerted by comparing the data of clinic and mutations.
results
Clinical findings
Patient1, a3.5-year-old girl, was the proband in family1. She presented with cafe-au-lait spots involving trunk, extremities and buttocks. Her father, aunt, grandmother have more typical and severe manifestation of many neurofibromas and cafe-au-lait spots over their bodies. In the family, all patients had cafe-au-lait spots at birth, and the neurofibromas appeared in5or6years old, and rapidly developed at teenage age. The other three patients [the proband in family2, and the two sporadic patients] also had the typical clinical features of neurofibromatosis. In family2, all patients had cafe-au-lait spots at birth, and the neurofibromas developed in about3years old, and gradually developed at teenage age. Patient3was a46year-old male, sporadic case, who had onset at the age of20s. However, the neurofibromas developed very swiftly and the size of the tumors was very giant partly. On histological examination of skin biopsies taken from one patient, the typical features of neurofibromas and spindle cell proliferations were seen, with a mucinous background and many mast cells.
Experimental findings
The sequencing of PCR products showed three novel mutations in NF1gene, c.601T>A in exon4, c.871G>T in exon6, c.1448A>G in exon10, respectively leading to amino acid changes, F201I, E291X, D485G. No any change was found in unaffected individuals in these families and unrelated controls.
Conclusions
(1) These mutations c.601T>A, c.871G>T, c.1448A>G of NF1gene may be pathogenic causes for neurofibromatosis type1.
(2) Our data indicates that the mutations in exon4,6,10of NF1gene possibly change the structure and function of NF1protein and ultimately affect their physiological function.
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