神经纤维瘤病（neurofibromatosis，NF）是临床上常见的疾病，主要表现为多发性神经系统(中枢及外周)肿瘤、皮肤色素斑、血管系统及其他脏器病变。1882年，von Recklinghausen比较全面地描述了本病并命名为神经纤维瘤病。属于常染色体显性遗传疾病，有两种类型。Ⅰ型即周围型神经纤维瘤病病，亦称von Recklinghausen病（von Recklinghausen' disease），占NF病例的90%以上；Ⅱ型较为罕见，为中枢型神经纤维瘤病，其特征为双侧听神经瘤。

本病发病率约为1∶3000活产儿。现已了解Ⅰ型NF致病基因定位于第17号染色体(17q11.2)，Ⅱ型NF致病基因定位于第22号染色体。在Ⅰ型NF病例中，神经纤维蛋白(neurofibromin)的肿瘤抑制作用出现障碍或丧失。

儿童时期所见的神经纤维瘤病多为Ⅰ型。

病理改变

主要病理所见为沿粗大的末梢神经生长的肿瘤，如尺神经及桡神经。常见的肿瘤为神经纤维瘤及神经鞘瘤。中枢神经系统常见的肿瘤在神经纤维瘤病Ⅰ型中为视神经胶质瘤，在Ⅱ型中为听神经瘤及脑膜瘤。本病也可出现其他肿瘤如Wilms瘤、成神经细胞瘤和嗜铬细胞瘤等。

一般而言，不论中枢神经或末梢神经的神经纤维瘤多为良性，但也可恶性变，转变为神经纤维肉瘤，恶变率约为5%。

临床表现

1.皮肤表现

咖啡牛奶斑〔brown (café-au-lait) spots〕是本病的重要体征，出生时即可发现，为一些浅棕色(咖啡里混加牛奶的颜色)斑，大小、形状不一，与周围皮肤界限清楚，不隆起于皮肤，不脱屑，感觉无异常。除手掌、脚底和头皮外，躯体其他部位皮肤均可波及，在10岁以内可逐渐长大、增多。Whitehouse(1962)曾检查365例5岁以下小儿，发现正常小儿有时也可见1～2块咖啡牛奶斑，无诊断意义，但超过2个者仅占0.75%。6块以上直径大于5mm的咖啡牛奶斑则有诊断价值。

有时在腋窝、鼠鼷部或躯干其他部位见到一些直径1～3mm，似面部雀斑的浅棕色斑，成簇出现，数量较多，称为腋窝雀斑，也具有诊断价值。

皮肤异常的另一种表现是神经纤维瘤，在婴幼儿时期往往不明显，青春期后增多。表现为结节状隆起，有时有蒂，与皮肤色泽一致或呈暗红色，大小由数毫米至数厘米，数目多少不等，多见于躯干，四肢及头部较少。肿块呈多发性，少则几个，多者可成百上千难以计数。小如米粒，大似拳头，甚至可达数公斤以上。可松弛地悬挂于皮表，皱褶及松弛可致畸形明显。神经纤维瘤病沿神经干的走向生长时呈念珠状，或蚯蚓块状形结节。

2.眼部症状

虹膜部位可见到色素性虹膜错构瘤，又称为Lisch小体，一般检查不能发现，需在裂隙灯下观察，为一些略突起的褐色斑块，边界清晰，无特殊症状，不影响视力。5～6岁的患儿约1/2有此体征，随年龄增长而逐渐增多，到21岁时，几乎全部患者均有此体征。视网膜星形细胞瘤不常见，但其他视网膜错构瘤有时可见。

3.神经症状

神经纤维瘤当压迫周围神经时可引起疼痛或肢体活动障碍。丛状神经纤维瘤常波及面部，儿童时期也可见到，受侵的组织增厚肥大，常破坏面容及影响视力。颈部或纵隔的丛状神经纤维瘤可引起气道受阻。

在Ⅰ型NF，视神经胶质瘤是中枢神经系统最常见的肿瘤，约有15%的患者合并，表现为进行性视力丧失、视神经萎缩，其次为疼痛或眼球突出，视神经胶质瘤可为单侧或双侧。每个患者的病情发展不尽相同，有些表现为无痛性过程，但多数向周围脑组织侵犯，或沿视神经通路向后扩展。

肿瘤还可波及脊髓及神经根，出现一系列症状。

在Ⅰ型NF，患儿常有学习困难及行为障碍，但明显的智力低下及癫痫发作较结节性硬化症少见。出现惊厥的患儿中，约50%有颅内肿瘤。

4.其他系统

骨骼系统常见体格矮小，先天性骨发育不良，骨皮质变薄、钙化不全及病理骨折等。常可见蝶骨发育不良、胫骨假关节形成。有时还可见颈椎下段或胸椎后突畸形。

血管系统可见肾动脉或颈动脉狭窄，部分患者还可有Moyamoya综合征表现（以颈内动脉虹吸段及大脑中动脉、大脑前动脉起始部闭塞、狭窄为特征的血管病）。

中枢型神经纤维瘤病发生双侧性听神经瘤，约在患者20岁左右时出现临床症状。家族成员中可有胶质瘤或脑膜瘤病史，某些成员合并青少年型白内障。

检查与诊断

检查时可见肿瘤呈粉红色或灰白色，基底广、不易活动或带蒂，质较硬。需借依靠病理检查以确诊。

1.实验室检查

有癫痫发作的患者，脑电图检查多不正常，可表现为慢波增多，阵发性慢波、棘波及棘慢波。

2.影像学检查

可早期发现颅内肿瘤，故有中枢神经系统症状者应做头部CT扫描。

2.1 CT表现     ①Ⅰ型NF：头大，颞角脉络丛非肿瘤性孤立的钙化或沿整个脉络丛的钙化。蝶骨大翼发育不全，合并颞叶向眼眶疝出，搏动性凸眼，可并发脑膜瘤、神经鞘瘤及胶质瘤。②Ⅱ型NF：前庭耳蜗神经瘤，一些患者不伴有耳蜗前庭神经瘤，而有硬膜膨出，可使内耳道扩大。可伴有第Ⅲ－Ⅶ脑神经鞘瘤、单发或多发脑脊膜瘤、多发脊柱神经鞘瘤。

2.2 MRI表现    ①双侧听神经瘤，多数以一侧为重；②多对颅神经、周围神经的神经纤维瘤；③合并脑膜瘤或胶质瘤；④常伴骨骼畸形，如脊柱裂、颅骨缺损等。

诊断标准

Ⅰ型NF：
①有6处或大于5mm的皮肤牛奶咖啡斑（Six or more café-au-lait macules, 1.5 cm or larger in postpubertal patients, 0.5 cm or larger in prepubertal patients）；
②有一个丛状神经纤维瘤或2个以上任何类型的神经纤维瘤（Two or more neurofibromas or one or more plexiform neurofibromas）；
③2个或多个青色虹膜错构瘤（Two or more Lisch nodules－(benign hamartomas）；
④腋窝和腹股沟雀斑〔Freckling in the axillary or groin region (Crowe's sign)〕；
⑤视神经胶质瘤（Optic pathway tumor）；
⑥Ⅰ级胶质瘤；（A first-degree relative with NF1）
⑦蝶骨大翼发育不良为特征性表现〔A distinctive osseous lesion (long bone dysplasia/pseudoarthrosis or sphenoid wing dysplasia) 〕。

Other features of NF1 include: educational difficulty (40-60%), macrocephaly (38-45%), short stature (18-34%), scoliosis (10-30%) , headache (22%), seizures (5%-7%), neoplasms (5%), hemangiomas (5%-10%), sensorineural hearing loss (5%), precocious puberty (4%-5%), hypertension (4%), hydrocephalus (3-4%), and congenital heart disease (2%-4%) .

Ⅱ型NF：
①双侧第Ⅷ脑神经瘤；
②Ⅰ级胶质瘤或单侧第Ⅷ脑神经瘤；
③很少有皮肤改变。

治疗

位于皮肤或皮下等神经末梢处的肿瘤，可行单纯切除。对无包膜、边界不清、瘤组织内有血管窦腔及疏松蜂窝组织的神经纤维瘤病，激光治疗比传统手术治疗优越。对引起疼痛、影响功能及外表有恶变者，必须手术切除。多发性神经纤维瘤病由于肿瘤数量甚多，无临床症状者可不急于手术，引起临床症状者予以切除。

药物治疗：Gupta等（2003）报道采用反应停（thalidomide）治疗Ⅰ型NF的丛状神经纤维瘤，每天最大剂量200mg，连服1年。治疗12例患者（平均年龄5岁以上），4例患者肿瘤体积缩小在25%以下。不良反应为暂时性嗜睡，皮疹和轻度复发，未见严重不良反应，患者耐受性良好。

参考文献

1.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(1):130-132. (PDF)

2.Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007 Feb;44(2):81-8. Review.  (PDF)

Neurofibromatoses

Neurofibromatoses (NF) are genetic disorders of the nervous system that result in the growth of noncancerous tumors along nerves. NF also can cause abnormalities of skin and bone. There are two main forms of NF:
NF1, formerly called peripheral neurofibromatosis or von Recklinghausen's disease.
NF2, formerly called bilateral acoustic neurofibromatosis, central neurofibromatosis or vestibular schwannoma.

In both, severity of symptoms varies greatly. Many people thought that the deformities portrayed in the book, play and movie called The Elephant Man reflected an extreme case of NF1. Now, however, evidence indicates that the person portrayed had a different disorder called Proteus syndrome. Individuals with NF1 need not worry about becoming as disfigured as the Elephant Man.

How common is NF?

NF1 is one of the most common genetic disorders. It affects about 1 in 3,000 births in the United States (1, 2). NF2 is less common, occurring in about 1 in 25,000 births (1, 2). Both forms of NF are found in every racial and ethnic group throughout the world and affect both sexes equally. 

What causes NF?

NF1 and NF2 are caused by abnormalities in two different genes. The gene for NF1 is located on chromosome 17, and the gene for NF2 is on chromosome 22. In about 50 percent of cases, the abnormal gene for either NF1 or NF2 is inherited from one parent who has the disorder. In some cases, the affected parent may have such mild symptoms that he or she may be unaware of having the disorder. 

The remaining half of NF1 and NF2 cases are caused by new mutations (changes) in the causative genes (3). Thus, NF1 or NF2 can occur in a person who has no family history of the condition. The abnormal gene in each form of NF is autosomal dominant, so that any child of one parent with NF (the other parent is unaffected) has a 50-50 chance of inheriting the NF gene.  

What are the signs of NF1?

According to the National Institutes of Health (NIH), there are seven common signs of NF1 (4). NF1 is diagnosed in individuals who have two or more of these signs:

Six or more tan spots on the skin, called café-au-lait spots, that are wider than 1/5 inch before puberty or 3/5 inch after puberty (In French, café-au-lait means "coffee with milk"). These spots are usually present at birth or appear by 2 years of age. Café-au-lait spots may increase in size and number and darken with age.

Freckles that appear under the arms or in the groin, usually by 7 years of age.

Two or more benign (noncancerous) tumors (lumps), called neurofibromas, under the skin or deeper. (A person may have a single neurofibroma without having NF.) Neurofibromas grow on nerves and are made up of cells that surround nerves and of certain other cell types. These tumors usually develop at around the time of puberty, but they may develop at any age. An affected person may have any number of neurofibromas.  

A tumor on the optic (eye) nerve, called an optic glioma. This tumor rarely impairs sight. Most of these tumors, which are usually diagnosed by 7 years of age, cause no symptoms and require no treatment.

Two or more tiny tan or brown Lisch nodules, which are small clumps of pigment that appear in the iris (colored part of the eye). These usually appear at around puberty and cause no vision problems.

A variety of bone defects, such as bowing of the legs below the knee. These usually are present at birth or develop during the first year of life.  A family history of NF1 in a parent, sibling or child.

How is NF1 diagnosed?

NF1 is diagnosed by physical examination. The examiner may use a special lamp to check the skin, so that very light-colored café-au-lait spots can be noted. The examiner may recommend additional tests, including X-rays and other imaging tests [computerized tomography (CT scans) and magnetic resonance imaging (MRI)]. In some cases, genetic testing of a blood sample is needed to confirm the diagnosis.  

Some children under 8 years of age may have café-au-lait spots, but no other signs of NF1. These children should be monitored carefully to see if other signs of the disorder develop.

How does NF1 affect a person?

In many cases of NF1, symptoms are mild, and affected individuals live a normal life. Some characteristics of NF1, including café-au-lait spots, freckling and Lisch nodules, pose no risk to health. Some individuals have many skin neurofibromas on the face and body. Although skin neurofibromas are mainly of cosmetic concern, they can cause psychological distress.

Neurofibromas also can grow inside the body and can affect many organ systems. These deep neurofibromas (referred to as plexiform neurofibromas) affect about 30 percent of individuals with NF1 (1, 2). Some plexiform neurofibromas cause no symptoms, but others can result in serious problems, depending on the organ system involved.

Up to 60% of children with NF1 have learning disabilities (1, 5). Hyperactivity and problems with attention are common. Some affected children and adults have large heads, though this usually does not reflect a serious medical problem. Scoliosis (a progressive curvature of the spine) is common in NF1 and can begin at an early age. Short stature also is common. Eye tumors may cause bulging of the eye or visual difficulties. Less frequent complications include seizures and high blood pressure.

In about 3 percent of affected people, one or more fibromas become malignant and require treatment (surgery, chemotherapy and/or radiation therapy) (5). Individuals with NF1 appear to be at an increased risk of leukemia and certain rare cancers (5).

How is NF1 treated?

There is no cure for NF1, but there are ways to treat some of its effects. Surgery can remove painful or disfiguring skin tumors. However, they often grow back. Optic gliomas that affect vision can be treated with surgery and/or radiation. Scoliosis may be treated by surgery or by wearing a brace.

Since doctors don’t know how to prevent or stop neurofibromas from growing, surgery is often recommended to remove them.  Several surgical options exist, but there is no general agreement among doctors about when surgery should be performed or which surgical option is best.  Individuals considering surgery should carefully weigh the risks and benefits of all their options to determine which surgical treatment is right for them.  There are also surgical and chemical techniques that can reduce the size of eye tumors (optic gliomas) when vision is threatened.  In addition, some bone malformations, such as scoliosis, can be surgically corrected.  In the rare instances when tumors become malignant (3 to 5 percent of all cases), treatment may include surgery, radiation, or chemotherapy.   

Treatments for other conditions associated with NF1 are aimed at controlling or relieving symptoms.  Headache and epileptic seizures are treated with medications.  Since there is a higher than average risk for learning disabilities, children with NF1 should undergo a detailed neurological exam before they enter school.  Once these children enter school, if teachers or parents suspect there is evidence of a learning disability (or disabilities), they should request an evaluation that includes an IQ test and the standard range of tests to evaluate verbal and spatial skills. Children with learning disabilities are eligible for special education services under the provisions of the Individuals with Disabilities Education Act (IDEA).   

How does NF1 affect pregnancy?

Most women with NF1 have healthy pregnancies. However, neurofibromas may increase during pregnancy, apparently because of hormonal changes. This may sometimes contribute to pregnancy complications, such as compression of the umbilical cord or obstruction of the birth canal (requiring cesarean section) (1, 6). A pregnant woman with NF1 should be cared for by an obstetrician who is familiar with NF1, in close consultation with her NF specialist.

What are the signs of NF2?

Almost all individuals with NF2 develop tumors that grow on the nerve from the ear to the brain, called the eighth cranial nerve (one of the 12 pairs of nerves that emerge from the brain.) These tumors are called schwannomas because they come from Schwann cells, which support and protect nerve cells. They often cause pressure on the acoustic (hearing) nerves, resulting in hearing loss. Many persons with NF2 also develop tumors on nerve tissues elsewhere in the body, including the brain and spinal cord. They also may develop a special type of cataract (clouding of the eye's lens) early in life. Persons with NF2 have few, or no, café-au-lait spots or neurofibromas, although they may have a small number of skin tumors (also called schwannomas).

How is NF2 diagnosed?

As with NF1, NF2 usually is diagnosed by physical examination. The examiner may recommend a number of imaging tests, including MRI, to look at the brain and spinal cord. MRI can detect tiny tumors, allowing for early diagnosis. In some cases, genetic testing is done to help confirm the diagnosis.

When NF2 is diagnosed, hearing tests (audiometry and brainstem auditory evoked response test) are recommended to determine how well the eighth cranial nerve is functioning. The individual also should be examined by an ophthalmologist (eye specialist) to look for cataracts and other eye problems that can contribute to vision loss. 

How does NF2 affect a person?

Symptoms of NF2 usually appear in the teens or early twenties and include hearing loss, ringing in the ears, dizziness, facial numbness, balance problems and headaches (2).

Occasionally, spinal cord tumors can cause numbness or weakness in parts of the body, such as the legs. Some individuals may have weakness in one arm or leg if tumors grow in nerves in the armpit or groin. Cataracts can result in vision loss.

How is NF2 treated?

As is the case in NF1, there is no cure for NF2, but surgery and radiation treatment can help control symptoms. MRI scans can detect very small tumors, sometimes allowing for early treatment. However, surgery on the eighth cranial nerve can sometimes result in additional hearing loss, so individuals and families must carefully weigh the risks and benefits of surgery. Sometimes removing part of a tumor, followed by radiation treatment, or radiation treatment alone, can help relieve symptoms. 

Is genetic testing available to help diagnose NF1 and NF2?

Yes. Genetic testing is available, and it can help confirm the diagnosis of NF1 and NF2. Genetic testing also can be conducted before birth and to help identify individuals with a family history of these disorders who do not yet show symptoms. However, genetic tests cannot predict the degree of severity of either form of NF.

Genetic counseling may be helpful to people with NF who are considering having children. Genetic counselors can explain the risks to offspring and discuss prenatal testing.  Genetic counselors can be found at medical centers throughout the country.     

Are there other forms of NF?

Occasionally, cases of NF occur that are not consistent with NF1 or NF2. Less is known about these conditions, including their genetic causes.

One recently identified, uncommon form of NF is called schwannomatosis. Affected individuals develop schwannomas, as do many people with NF2. However, the schwannomas do not develop on the eighth cranial nerve, so affected individuals do not develop hearing loss. The main symptom of schwannomatosis is pain, which can occur in any part of the body. Affected individuals also may have some other neurological problems, such as numbness, tingling, or weakness in fingers and toes (4). Schwannomas often can be surgically removed to relieve pain (although tumors sometimes grow back).

Does the March of Dimes conduct research on NF?

The March of Dimes has funded NF studies, including basic research on the causes of these and other nervous system diseases. For example, researchers are studying genetically controlled events in the embryo that are crucial to development of the body's nervous system and factors that regulate growth and maintenance of nerves.

References

1.Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007 Feb;44(2):81-8. Epub 2006 Nov 14. Review.   

2. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007 Apr;6(4):340-51.

3.Yohay KH. The genetic and molecular pathogenesis of NF1 and NF2. Semin Pediatr Neurol. 2006 Mar;13(1):21-6. 

4.National Institutes of Neurological Disorders and Stroke. Neurofibromatosis Fact Sheet. National Institutes of Health, updated 4/16/07. http://www.ninds.nih.gov/disorders/neurofibromatosis/detail_neurofibromatosis.htm

5.Tonsgard JH. Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol. 2006 Mar;13(1):2-7. Review. 

6.Friedman JM. Neurofibromatosis 1. Gene Reviews. University of Washington at Seattle, updated 1/31/07.