神经纤维瘤病1型一定会脊柱侧弯吗（家族性神经纤维瘤病性脊柱侧凸）

神经纤维瘤病1型一定会脊柱侧弯吗（家族性神经纤维瘤病性脊柱侧凸）图5. 20210823躯干外观-右侧面图4. 20210823躯干外观-腹侧面2020年9月发现脊柱侧凸，就诊于兰大二院骨科，予以支具矫形治疗。为求进一步的治疗意见来我门诊就诊。查体：患儿发育正常，佩戴支具。去除支具后查看躯干部，见躯干多处咖啡斑，右侧躯干大块儿咖啡斑，12X10cm大小。双上肢、双下肢及会阴部未查。图3. 20210823躯干外观-背面

患儿女，2019年3月生。就诊时间2021年8月23日。

患儿之父诉，出生时看不出脊柱侧弯，2019年8月4月龄时，曾因肺部感染做胸部三维CT重建，当时胸椎还是直的(图1，图2)。

图1. 20190805肺部CT1-出生后4个月

图2. 20190805肺部CT2-出生后4个月

2020年9月发现脊柱侧凸，就诊于兰大二院骨科，予以支具矫形治疗。为求进一步的治疗意见来我门诊就诊。

查体：患儿发育正常，佩戴支具。去除支具后查看躯干部，见躯干多处咖啡斑，右侧躯干大块儿咖啡斑，12X10cm大小。双上肢、双下肢及会阴部未查。

图3. 20210823躯干外观-背面

图4. 20210823躯干外观-腹侧面

图5. 20210823躯干外观-右侧面

图6. 20210823躯干外观-左侧面

追问患者之父，家里是否还有其他人有同样的问题，患儿父亲说，患儿的母亲、患儿的姥姥、患儿母亲的舅爷、患儿的姐姐均有咖啡斑，患儿的姐姐曾于2014年1月份于兰大二院神经外科行脑瘤(室管膜瘤)切除后愈。患儿的姥姥因脊柱肿瘤住兰大二院神经外科做手术。手术日期应该是2021年8月25日。患儿的母亲及姥姥全身多处均有“疙瘩”。患儿姥姥脸部因大块儿“疙瘩”变形，右臂多处“疙瘩”。

以上内容根据患儿父亲描述，考虑此家族患有家族性遗传性神经纤维瘤病。且以女性显性遗传为主线。

图7. 2020年9月4日脊柱全长X线正位片显示T7-L1胸腰段脊柱侧凸，凸向右侧， Cobb角35度。

图8. 2020年9月4日脊柱全长X线侧位片。

图9. 2020年11月2日脊柱全长正侧位X线片，显示T8-12向右侧侧凸，Cobb角32度。

图10. 2021年5月17日Cobb角34度(开始支具治疗前拍摄)

图11. 我的门诊病历

说实话，这个门诊病例，很有研究价值。应该对其家族每一个相关个体，进行遗传学研究和临床病理学行为进行研究。

为此，我邀请南京鼓楼医院的邱勇教授，就该病例目前的情况，以及治疗状况，和未来的走向，做一评述，邱勇主任就该病例提供了他的个人意见。

邱勇(根据语音整理)：

”神经纤维瘤病合并脊柱侧凸以前认为在黄种人中间发病率不高，是白种人的常见病，在白种人中间是发病率最高的一种遗传性疾病。现在看来，在我们黄种人，或者在我们中国人也不少见，在综合症型脊柱侧凸中，神经纤维瘤病性脊柱侧凸应该是最常见的。此病为常染色体显性遗传，有50%的病人来自于基因突变，不一定有家族史，该病有诊断标准，请参考我们已出版的《脊柱畸形影像学与临床》。所以此病的诊断不一定要有家族史，但有家族史可以为诊断加分。50%的病人，基因突变后从此代开始往下遗传。并不是所有的神经纤维瘤病都合并有脊柱侧凸。对于神经纤维瘤病合并脊柱侧凸有多少比例，没有文献报道。因为在我们脊柱外科医生来看，神经纤维瘤病患者大都是因为合并了脊柱侧凸才来就诊的，所以，会感觉神经纤维瘤病合并脊柱侧凸发病率很高，但实际上，这是一种错觉，不能说神经纤维瘤病就一定合并脊柱侧凸。

《脊柱脊髓畸形-影像学与临床》 第8章 神经纤维瘤病合并脊柱侧凸

《脊柱脊髓畸形-影像学与临床》 第8章 神经纤维瘤病合并脊柱侧凸2

《脊柱脊髓畸形-影像学与临床》 第8章 神经纤维瘤病合并脊柱侧凸3

《脊柱脊髓畸形-影像学与临床》 第8章 神经纤维瘤病合并脊柱侧凸4

《脊柱脊髓畸形-影像学与临床》 第8章 神经纤维瘤病合并脊柱侧凸5

这个病例的治疗措施是对的，应该先进行支具治疗。这个病例有一个特点，就是现在年龄比较小，另外呢，从片子上面看，还没有表现出萎缩性改变，萎缩性改变不是特别的多，但是因为年龄比较小，所以我们不能讲她的弯型是类AIS， 类AIS就是AIS like。神经纤维瘤病型脊柱侧凸分为两种类型，一种是萎缩性脊柱侧凸，还有一种就是类AIS脊柱侧凸 所谓的类，就是类似了，类AIS就是它的弯型是像特发性脊柱侧凸AIS的。

因为如果患者的弯型是类AIS 这种病人愈后比较好，她或他的治疗原则跟AIS没什么区别。遗憾的是大部分的神经纤维瘤病性脊柱侧凸都是萎缩性的。如果年龄越小，尽管他早期的表现为类AIS，但随着年龄的增长，他会出现一个mutation，就是突变吧，但这个突变不是基因突变，是影像学突变，也叫mutation，比如肋骨头脱位，铅笔样改变，椎体形态的改变等等，如果出现这种作用的话，它是加重的一个危险因素，所以这个病人在支具治疗过程中需要密切观察。这个病人，高度怀疑，高度可能性，最后是走向萎缩性脊柱侧凸，愈后可能比较差。

在我们目前治疗的病人中间，主要是外面来的一些病人，有一些治疗错误，有一个误区，就是当这个神经纤维瘤病脊柱侧凸伴有椎旁肿瘤的时候，这个肿瘤是不是要切除。伴有椎旁肿瘤，分为两种情况，一种是伴有丛状神经纤维瘤，病理学上以神经纤维瘤改变为主，它表现为成纤维细胞比较多，这种丛状神经纤维瘤，它的边界是不清楚的，所以手术是切不干净的。如果椎旁肿瘤是实体肿瘤的话，大部分是神经鞘瘤或者是雪旺氏细胞瘤。如果是实体肿瘤，它的边界比较清楚，是不是一定要切除？要不要切除，在英文文献里边，这个在国际上比较公认的，当这个实体肿瘤比较大，特别是出现一些周围的压迫症状，比如纵隔肿瘤，合并有巨大的这种纵隔肿瘤，或者是这个肿瘤进入到胸腔，或者造成腹膜后的压迫，比较大的这些实体肿瘤，是要切除的，即使切不干净，也要切除，即使切掉以后复发，也是要切除的，因为它引起压迫症状。如果它没有出现压迫症状，又不是特别大的肿瘤，其实是很多，我们脊柱外科目前的国际共识是这个肿瘤是不需要切的。

第二种情况，合并有椎管内外的神经源性肿瘤。因为神经纤维瘤病合并神经源性肿瘤，它除了组织学上神经纤维瘤或者雪旺氏细胞瘤以外，它还可以合并脊膜瘤，所以如果出现这种肿瘤，椎管内外都有肿瘤，且如果有神经症状的话，那肿瘤切除是绝对适应证。假如椎管内也有肿瘤，且肿瘤不是特别大，对这个椎管内肿瘤是不是要切除，争议就比较大，我们鼓楼医院的经验是，假如合并的椎管内肿瘤是孤立性的，比较大，这种病人估计未来可能有神经损害的话，我们主张是要做肿瘤切除的。

如果椎管内的肿瘤比较多，或者比较弥漫，又没有神经损害，我们脊柱外科医生偏向于不做，不做肿瘤切除，直接做脊柱的矫形手术。但神经外科医生很有可能就做肿瘤切除，他们的理由是这种椎管内的肿瘤，对骨骼结构的破坏特别大，特别是年龄比较小，或者是未成年的话，重要的生长过程中间可能造成神经损害。所以这种情况下，就看个人的经验。这种椎管的肿瘤切还是不切，争议比较大。我觉得呢，根据病人的情况，如果椎旁肿瘤是很多的丛状神经纤维瘤，这种肿瘤是不需要切的。我们遇到很多会诊的病人，就是外院做了手术的病人。到我们这来复诊，或者是出了问题来翻修，我们发现很多病人被做了这个肿瘤的切除，这种手术切除意义不是特别大。

第二个就是在国内误区，当伴有肋骨头脱位的时候，要不要做肋骨头的切除，再做矫形。这个在国际矫形界，基本上也是有共识，如果这个肋骨头脱位，主要在凸侧，如果没有神经损害的话，这个肋骨头也是不切的，这个我们在国内讲过多次，也发表过文章，但是大家真正做研究的也不是很多。看到一个肋骨头脱位，突向椎管，矫形以前就做个肋骨头切除，矫形还没做，病人的神经并发症已经出来，所以比较有共识的，就是当有脱位出现，出现神经损害的时候，那么这种肋骨头要切除，否则可以不切除。我们做过研究，在矫形过程中间肋骨头有部分复位。

如果大家感兴趣的话，可以去读我们的文献，我们的文章，英文、中文都有。国内有两个大佬，脊柱外科界也是比较有名的医生，在外面介绍的时候，就讲矫形前要做肋骨头的切除，在这种情况下，一般我就不发表意见，我不能说人家不看书啊。因为肋骨头进入椎管里边的话，如果没神经损害，不要去切了，没有必要切了，第一，绝大部分的病人，肋骨头突入椎管都是发生在凸侧，凸侧椎管的储备空间是比较大的。第二，神经纤维瘤病的病人，往往是椎管比较宽大，而不像先天性脊柱侧凸，所以允许有一定的活动度。

这个患者的最后一张片，正位片子，可以看到肋骨头已经在开始变细，这是第一个迹象。第二个有向后凸发展的趋势，跟老的片子比，第三，顶椎区椎体的凸侧有凹陷，这些都是发生mutation的一个不好的迹象。所以这个病人，最后的结局是这个脊柱侧凸过渡到萎缩性脊柱侧凸。

继续支具治疗。但是支具治疗无法阻止这种疾病转归，进展成萎缩型脊柱侧凸是不可避免的，支具只是控制，这个病人的手术命运，最后是跑不了的，仅仅是什么时候手术以及手术的术式而已。”

对该病例，我也在www. pubmed.gov里查阅了一些相关文献，罗列如下，前面4条我做了翻译。

1. A de Goede-Bolder M H Cnossen D Dooijes A M van den Ouweland M F Niermeijer. [From gene to disease; neurofibromatosis type 1]. Review Ned Tijdschr Geneeskd. 2001 Sep 8;145(36):1736-8. [Article in Dutch]

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease characterised by café-au-lait spots freckling in the axillary or inguinal region dermal and plexiform neurofibromas and Lisch nodules. Complications are severe in one third of patients and the clinical variability is pronounced even within families. The NF1 gene has been localised to chromosome 17q11.2 and encodes the protein neurofibromin. The gene is proposed to be a tumour suppressor gene. Inactivation of neurofibromin leads to a disruption in cell growth regulation. Mutation analysis is possible but laborious and therefore NF1 is generally a clinical diagnosis based on diagnostic criteria.

1型神经纤维瘤病（NF1）是一种常染色体显性遗传性疾病，其特征为咖啡斑、腋窝或腹股沟雀斑、真皮和丛状神经纤维瘤以及Lisch结节。三分之一的患者有严重的并发症。临床变异明显，即使是家族性遗传中也是如此。NF1基因定位于染色体17q11.2，编码神经纤维蛋白(neurofibromin)。该基因被认为是一种肿瘤抑制基因。神经纤维蛋白失活导致细胞生长调节中断。可以进行基因突变分析，但费力费时费事，因此NF1的诊断通常是基于诊断标准的临床诊断。

2. Marek W Karwacki Wojciech Woźniak. [Neurofibromatosis--an inborn genetic disorder with susceptibility to neoplasia]. Review Med Wieku Rozwoj. Jul-Sep 2006;10(3 Pt 2):923-48. [Article in Polish]

Abstract

Among different subtypes of neurofibromatosis (Nf) type 1 (Nf-1) predominates in frequency (approximately 97% of Nfs' patients) with an incidence of approximately 1 in 3500 live births. Nf-2 comprises 2% of the Nf population and is a very rare disease (1:40 000). Both are autosomal dominant disorders with 100% penetration variable expression and 50% rate of new (de novo) mutations. The protein products of both NF1 andNF2 genes are best known and the genes serve as tumour suppressors. Mutations result in a predisposition to develop a variety of tumours of the central and peripheral nervous systems as well as other malignancies. Nf-2 is a multisystem genetic disorder associated with bilateral vestibular schwannomas spinal cord schwannomas meningiomas gliomas and juvenile cataracts with a paucity of cutaneous features which are seen more consistently in Nf-1. In contrast to Nf-1 Nf-2 is associated with significant morbidity and decreased life span and a higher incidence of CNS tumours. However morbidity and mortality rates in Nf-1 are not negligible. The cardinal features of Nf-1 are cafe-au-lait spots axillary and inguinal freckling cutaneous neurofibromas and iris hamartomas (Lisch nodules). Optic gliomas and both malignant and benign peripheral nerve sheet tumours are the most common malignancies arising in Nf-1 patients. Among neurological symptoms epilepsy intellectual disability and learning difficulty are also observed. Bone dysplasia results in scoliosis. There is no known medical treatment beneficial to both groups of patients. The mainstay of care for Nf patients is anticipatory guidance and early detection and symptomatic treatment of disease complications.

在神经纤维瘤病（Nf）的不同亚型中，1型（Nf-1）的发病率最高（约97%的Nfs患者），约3500例活产中有1例发生。Nf-2占Nf人群的2%，是一种非常罕见的疾病（1:40000）。两者都是常染色体显性遗传疾病，具有100%的穿透率、可变表达和50%的新（再发）突变率。NF1和NF2基因的蛋白质产物已为人所知，这些基因具有肿瘤抑制作用。突变导致易患多种中枢和外周神经系统肿瘤以及其他恶性肿瘤。Nf-2是一种多系统遗传性疾病，与双侧前庭神经鞘瘤、脊髓神经鞘瘤、脑膜瘤、胶质瘤和青少年白内障相关，皮肤特征较少，而皮肤特征在Nf-1中更常见。与Nf-1相反，Nf-2与显著的发病率和寿命缩短以及CNS肿瘤的高发病率相关。然而，Nf-1的发病率和死亡率不容忽视。Nf-1的主要特征是咖啡斑、腋窝和腹股沟雀斑、皮肤神经纤维瘤和虹膜错构瘤（Lisch结节）。视神经胶质瘤以及恶性和良性周围神经肿瘤是Nf-1患者最常见的恶性肿瘤。在有神经症状的癫痫中，还观察到智力残疾和学习困难。骨发育不良导致脊柱侧凸。目前尚无对这两组患者都有治疗作用的药物。Nf患者的主要照护是期望性指导，以及疾病并发症的早期发现和对症治疗。

3. Rony Cohen Avinoam Shuper. [Developmental manifestation in children with neurofibromatosis type 1]. Review Harefuah. 2010 Jan;149(1):49-52 61. [Article in Hebrew]

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that primarily involves the skin and the nervous system. It affects about 1 in 4000 individuals. NF1 is caused by a mutation in the nfl gene located on chromosome 17q11.2. Neurofibromin the protein products of the normal nf1 gene acts as a tumor suppressor and limits cell growth. Mutation in this gene leads to cell overgrowth and an increased risk of developing benign and malignant tumor. The diagnosis of NF1 is made in an individual with any two of the following clinical features: café-au-lait spots intertriginous freckling Lisch nodules neurofibromas optic glioma distinctive bone lesions and first degree family relative with NF1. Learning and developmental disorders are the most common neurologic complication of neurofibromatosis type 1 and can be responsible for significant lifetime morbidity. This report provides a review on cognitive and developmental manifestation of children with NF1 and the importance of early diagnosis and treatment.

1型神经纤维瘤病（NF1）是一种常染色体显性遗传性疾病，主要累及皮肤和神经系统。大约每4000人中就有1人受累。NF1由位于染色体17q11.2上的nfl基因突变引起。神经纤维蛋白(neurofibromin)是正常nf1基因的蛋白质产物，起到肿瘤抑制和限制细胞生长的作用。该基因突变导致细胞过度生长，并增加发生良性和恶性肿瘤的风险。NF1的诊断基于以下任何两种临床特征：咖啡斑、肋间雀斑、Lisch结节、神经纤维瘤、视神经胶质瘤、独特的骨病变和NF1相关的单层级家族遗传。学习和发育障碍是1型神经纤维瘤病最常见的神经系统并发症，可导致显著的终生发病。本报告对NF1儿童的认知和发育表现以及早期诊断和治疗的重要性进行了综述。

4. Veruschka Ramanjam Colleen Adnams Alvin Ndondo Graham Fieggen Karen Fieggen Jo Wilmshurst. Clinical phenotype of South African children with neurofibromatosis 1. J Child Neurol. 2006 Jan;21(1):63-70. doi: 10.1177/08830738060210011501.

Abstract

Forty-eight children with neurofibromatosis 1 presenting between 2000 and 2004 were reviewed for their clinical phenotype and data were compared with published reports. The median age at presentation was 4 years (range 10 days to 12 years). The male to female ratio was similar (22 male:26 female). There were frequencies of café au lait spots axillary freckling Lisch nodules and new mutations comparable to those cited in the literature. Fewer patients had neurofibromas (4%) but more patients had plexiform neurofibromas of the head and neck (16%). Three patients of the 22 who had neuroimaging had optic gliomas (14%). The most consistent disability with maximum impact related to the patient's cognitive level of functioning. School problems defined as learning and behavioral problems observed in the classroom were reported in 70% of school-aged children (n = 21) compared with international figures of 29.8% to 45%. This high prevalence has reinforced the clinic service policy of formal neuropsychology assessments in all children with reported school problems. In addition earlier referral of children to the service (preschool n = 18) has enabled formal developmental assessments and planning of specific educational placement to optimize learning. This is the first description of the neurofibromatosis 1 phenotype from the African continent. The multidisciplinary approach to management has proved beneficial in the South African context. The combined clinic has resulted in a holistic approach to patient care early detection of pathology consistent therapies across the specialties and better patient attendance and compliance. (J Child Neurol 2006;21:63-70).

5. K North. Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic. J Child Neurol. 1993 Oct;8(4):395-402. doi: 10.1177/088307389300800421.

Abstract

Neurofibromatosis type 1 is a common multisystem disorder best managed in a multidisciplinary clinic. In 1991 the first Australian neurofibromatosis clinic was established at the Children's Hospital Camperdown and the clinical characteristics of the first 150 families are reviewed. Two hundred individuals were assessed; there was an equal sex distribution and 55% of cases were sporadic. Advanced paternal age appeared to predispose to new mutations in the neurofibromatosis gene. Café-au-lait spots and axillary freckling were important to the diagnosis of neurofibromatosis type 1 during childhood and neurofibromas and Lisch nodules although often not appearing until after puberty were present in almost all patients over 30 years of age. Short stature (27%) macrocephaly (43%) scoliosis (20.5%) and learning disabilities (45%) were common associated features. The prevalence of disease complications was similar to the major US and European studies.

6. J H Chaglassian E J Riseborough J E Hall. Neurofibromatous scoliosis. Natural history and results of treatment in thirty-seven cases. J Bone Joint Surg Am. 1976 Jul;58(5):695-702.

Abstract

Of 400 patients with the diagnosis of neurofibromatosis on their hospital records 141 actually had the disease. The presence of at least two of the following features was considered diagnostic: positive family history; positive biopsy; a minimum of six cafe-au-lait spots each with a diameter of at least 1.5 centimeters; and multiple subcutaneous neurofibromas. Scoliosis was present in thirty-seven patients (26 per cent) most commonly associated with cafe-au-lait spots (thirty-five patients). In many of the patients with scoliosis there were associated medical and surgical problems. Although no standard pattern of spinal deformity could be identified a sharp single right thoracic curve involving more than five vertebrae was the most common. For the whole group the initial measurement of the scoliosis averaged 42 degrees. Double curves were more sever buth kyphosis was uncommon and no cases of paraplegia were recorded. In patients with progressive scoliosis the best results were obtained with early Harrington instrumentation and posterior spine fusion. Progression of the scoliosis was observed both before treatment and postoperatively. The amount of progression was not necessarily related to the severity of other manifestations of neurofibromatosis and was not significantly dependent on the length of the curve.

7. S M Huson P S Harper D A Compston. Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales Brain. 1988 Dec;111 ( Pt 6):1355-81. doi: 10.1093/brain/111.6.1355.

Abstract

A population-based study in south-east Wales (population 668 100) identified 135 patients with von Recklinghausen neurofibromatosis (prevalence 20/10(5]. In addition to multiple café-au-lait spots and/or dermal neurofibromas freckling was present in the axilla (67%) groin (44%) or submammary areas (29% of adult females). Although not a criterion for diagnosis Lisch nodules were almost invariably present in the iris (93% of patients overall; 96% of those aged greater than or equal to 20 yrs). The complications of von Recklinghausen neurofibromatosis in this cohort (n = 135 unless stated) were plexiform neurofibromas (40/125) severe mental retardation (1) epilepsy (6) optic glioma (2) spinal neurofibroma (2) aqueduct stenosis (2) meningioangiomatosis (1) scoliosis requiring surgery (6) pseudoarthrosis (3) delayed puberty (2) visceral and endocrine tumours (6) and congenital glaucoma (1). There were no cases of acoustic neuroma. Considering all living family members aged greater than or equal to 18 yrs together with their deceased relatives the frequency of CNS and malignant tumours related to the disease was 4.4-5.2%. Uncomplicated von Recklinghausen neurofibromatosis is disfiguring but not a major cause of morbidity. The management of the disease relates to its complications which can be divided into three categories: those which occur in childhood and cause lifelong morbidity (moderate-severe mental handicap facial plexiform neurofibromas orthopaedic) those which can occur at any time but are 'treatable' (benign disorders of the nervous system visceral and endocrine tumours renal artery stenosis) and malignant or CNS tumours. The combined frequency for each category based on this survey was 12% 16% and 4.4-5.2% respectively.

8. S M Huson 1 D A Compston P S Harper. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. II. Guidelines for genetic counselling. Review J Med Genet. 1989 Nov;26(11):712-21. doi: 10.1136/jmg.26.11.712.

Abstract

The age of appearance and diagnostic value of the major defining features of von Recklinghausen neurofibromatosis (NF-1) have been studied in 168 cases from 73 families. In assessing children of an affected patient those who have inherited the gene can be distinguished from their normal sibs on the basis of whether or not café au lait (CAL) spots are present by the age of five years. Lisch nodules appear before cutaneous neurofibromas and are a useful clinical aid in the assessment of unusual cases those in whom the diagnosis is equivocal and children with multiple CAL spots but no family history of NF-1. Sixty-nine of the families were identified through a population based study in south east Wales and the frequency of complications in 135 affected subjects from these families has been used to develop figures for genetic counselling. For these purposes the complications of NF-1 can be usefully divided into four categories: intellectual handicap (33%) (moderate/severe retardation 3.2% minimal retardation/learning difficulties 29.8%); complications developing in childhood and causing lifelong morbidity (8.5%); 'treatable' complications which can develop at any age (15.7%); and malignant or CNS tumours (4.4 to 5.2%).

9. D F Easton M A Ponder S M Huson B A PonderAn analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993 Aug;53(2):305-13.

Abstract

Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression. To determine whether variation in expression has an inherited component we examined 175 individuals in 48 NF families including six MZ twin pairs. Three quantitative traits were scored--number of café-au-lait patches number of cutaneous neurofibromas and head circumference; and five binary traits were scored--the presence or absence of plexiform neurofibromas optic gliomas scoliosis epilepsy and referral for remedial education. For café-au-lait patches and neurofibromas correlation was highest between MZ twins less high between first-degree relatives and lower still between more distant relatives. The high correlation between MZ twins suggests a strong genetic component in variation of expression but the low correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits with the exception of plexiform neurofibromas also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects but there were insufficient data to rule out other models including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals. We conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other "modifying" loci and that these modifying genes are trait specific.

10. Borivoj Petrak Sarka Bendova Tomas Seeman Tibor Klein Jiri Lisy Tomas Zatrapa Tana Marikova. Mid-aortic syndrome with renovascular hypertension and multisystem involvement in a girl with familiar neurofibromatosis von Recklinghausen type 1. Case Reports Neuro Endocrinol Lett. 2007 Dec;28(6):734-8.

Abstract

Objectives: Neurofibromatosis von Recklinghausen type 1 (NF1) is an autosomal dominant neurocutaneous disorder affecting one in 3 000-4 000 individuals. Mid-aortic syndrome (MAS) is a rare condition characterized by segmental narrowing of abdominal aorta and stenosis of its major branches - mainly renal arteries including manifestation of renovascular hypertension. MAS can be caused by different diseases including NF1.

Main findings: A 9 years old girl with primary diagnosis of NF1 combined with renovascular hypertension due to MAS suffered of bilateral optic and chiasm glioma pubertas praecox speech disorder light mental retardation and scoliosis. We have found a mutation in exone 34 of the NF1 gene (17q11.2). Her father has been also diagnosed with NF1 and hypertension developed at early age. He has the same mutation in exone 34 of NF1 gene. The girl is currently treated with conservative antihypertensive medication with positive effect. Bilateral optic and chiasm glioma are asymptomatic at the time and they had been without progress over period of time. Any vascular surgery neurosurgical and oncological therapy are not indicated at the present time.

Conclusion: This article is a summary of clinical findings in patient with NF1 due to NF1 gene mutation in exone 34. It confirms the importance of complex multidisciplinar approach to examination and taking care of NF1 patients and their families.

11. R Perrotta 1 M S Tarico D Virzì G Manzo S Curreri. [Morpho-functional iterative surgery in a patient with von Recklinghausen disease]. Case Reports G Chir. Nov-Dec 2010;31(11-12):543-8. [Article in Italian]

Abstract

Neurofibromatosis 1 is an autosomal dominant disease with an estimated incidence 1:2500 to 1:3000 live newborns. The disease presents with multiple cutaneous and non cutaneous lesions. NF1 occurs with equal frequency in males and females and has been identified in all ethnic group. The morbidity and the mortality caused by NF1 are the result of complications that may involve any of the body systems. This disease has been linked with mutations of the NF1 gene which encodes tumor suppressor neurofibromin. At least half of patients with NF1 will have only cutaneous involvement that is not considered to be a major medical problem even though it can be a source of psychologic burden as a result of cosmetic disfigurement. The cardinal features of the disorder are cafè-au-lait spots axillary freckling cutaneous neurofibromas and Lisch nodules but there are a lot of wide variety of complications affecting almost every system of the body including the eyes (optic glioma) the nervous system (intracranial tumors) the skeleton (short stature scoliosis) the endocrine and cardiovascular system (hypertension). Manifestations of NF1 vary at different times in an individual's life. Substantial variability exists among affected members of a single family. This variability confounds clinical management and the severity of the disease cannot be predicted. We present a case in young woman 24 years-old treated by reiterative plastic surgery.

12. B Quintáns J Pardo B Campos F Barros V Volpini A Carracedo M J Sobrido. Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing. Case Reports Case Rep Neurol. 2011 Apr 11;3(1):86-90. doi: 10.1159/000327557.

Abstract

Neurofibromatosis type 1 (NF1) is a multisystem disease with autosomal dominant inheritance and complete penetrance diagnosed by clinical findings. Cutaneous neurofibromas are present in almost all adult patients in the dermis epidermis or along the peripheral nerves. Plexiform neurofibromas are subcutaneous or deep lesions involving nerve plexuses or roots. Neurofibromas can degenerate into malignant tumors with important prognostic implications. NF1 shows a broad clinic variability even within a single family. Exceptions are cases reporting the in-frame microdeletion c.2970_2972delAAT presenting with the typical pigmentary features of NF1 but no cutaneous or plexiform neurofibromas. We report a patient with a de novo c.2970_2972delAAT mutation who had few café-au-lait spots only 2 of which measured >15 mm axillary and submammary freckling a flat angioma extending over the neck arm and trunk a high arched palate micrognathia macrocephaly pes cavus and scoliosis. There was complete absence of observable cutaneous neurofibromas as well as external plexiform neurofibromas. She had had epileptic seizures since childhood; however a diagnosis of NF1 had not been confirmed until she was 38 partly due to the paucity of characteristic cutaneous stigmata. We confirm the association of the c.2970_2972delAAT mutation in NF1 with a particular clinical phenotype especially with lack of detectable neurofibromas. For an appropriate management of patients and family counseling molecular study of the NF1 gene should be considered in patients not fulfilling NIH criteria when other features suggestive of NF1 are present. In the absence of neurofibromas starting NF1 testing with the screening of exon 17 may be worthwhile.

Keywords: De novo mutation; Diagnosis; Genotype-phenotype correlation; NF1; Neurofibromas; Neurofibromatosis; c.2970_2972delAAT.

13. S Alwan L Armstrong H Joe P H Birch J Szudek J M Friedman. Associations of osseous abnormalities in Neurofibromatosis 1. Am J Med Genet A. 2007 Jun 15;143A(12):1326-33. doi: 10.1002/ajmg.a.31754.

Abstract

The characteristic sites of Neurofibromatosis 1-associated osseous manifestations are the long bones (usually the tibia and fibula) vertebrae and sphenoid wing. Although these focal bony lesions may cause profound clinical consequences a minority of people with NF1 are affected. However most people with NF1 are shorter than expected for their age gender and family. The pathogenesis of NF1 focal osteopathy and its relationship if any to short stature are unknown. We examined associations between the occurrence of various osseous lesions in 3377 NF1 probands from the Children's Tumor Foundation NF International Database. Using logistic regression analysis among 260 NF1 probands who had undergone radiological examination of both the spine and skull we found associations between the occurrence of sphenoid wing and long bone osteopathy (conditional odds ratio [OR] = 6.1; 95% confidence interval [CI] = 1.7-22.3; P = 0.006) and between sphenoid wing and vertebral osteopathy (OR = 16.9; 95% CI = 5.3-53.3; P < 0.001) after adjusting for age and gender. Similar findings were observed from all 3377 NF1 probands using a multivariate probit regression model. In a separate analysis we found lower age- and gender-standardized height in patients who had characteristic vertebral or sphenoid wing lesions than in people who did not (P < 0.05). We found no relationship between height and tibial osteopathy. We conclude that some people with NF1 are more likely to develop osseous manifestations than others and speculate that there may be a common pathogenetic mechanism responsible for the development of osseous abnormalities and that of the vertebrae and long bones.

14. Adila Alkindy Nadia Chuzhanova Usha Kini David N Cooper Meena Upadhyaya. Genotype-phenotype associations in neurofibromatosis type 1 (NF1): an increased risk of tumor complications in patients with NF1 splice-site mutations? Hum Genomics. 2012 Aug 13;6(1):12. doi: 10.1186/1479-7364-6-12.

Abstract

Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder with an increased susceptibility to develop both benign and malignant tumors but with a wide spectrum of inter and intrafamilial clinical variability. The establishment of genotype-phenotype associations in NF1 is potentially useful for targeted therapeutic intervention but has generally been unsuccessful apart from small subsets of molecularly defined patients. The objective of this study was to evaluate the clinical phenotype associated with the specific types of NF1 mutation in a retrospectively recorded clinical dataset comprising 149 NF1 mutation-known individuals from unrelated families. Each patient was assessed for ten NF1-related clinical features including the number of café-au-lait spots cutaneous and subcutaneous neurofibromas and the presence/absence of intertriginous skin freckling Lisch nodules plexiform and spinal neurofibromas optic gliomas other neoplasms (in particular CNS gliomas malignant peripheral nerve sheath tumors (MPNSTs) juvenile myelomonocytic leukemia rhabdomyosarcoma phaechromocytoma gastrointestinal stromal tumors juvenile xanthogranuloma and lipoma) and evidence of learning difficulties. Gender and age at examination were also recorded. Patients were subcategorized according to their associated NF1 germ line mutations: frame shift deletions (52) splice-site mutations (23) nonsense mutations (36) missense mutations (32) and other types of mutation (6). A significant association was apparent between possession of a splice-site mutation and the presence of brain gliomas and MPNSTs (p = 0.006). If confirmed these findings are likely to be clinically important since up to a third of NF1 patients harbor splice-site mutations. A significant influence of gender was also observed on the number of subcutaneous neurofibromas (females p = 0.009) and preschool learning difficulties (females p = 0.022).

15. JM Friedman Margaret P Adam Holly H Ardinger Roberta A Pagon Stephanie E Wallace Lora JH Bean Ghayda Mirzaa Anne Amemiya editors. Neurofibromatosis 1. In: GeneReviews® [Internet]. Seattle (WA): University of Washington Seattle; 1993–2021. 1998 Oct 2 [updated 2019 Jun 6].

Excerpt

Clinical characteristics: Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots axillary and inguinal freckling multiple cutaneous neurofibromas iris Lisch nodules and choroidal freckling. About half of people with NF1 have plexiform neurofibromas but most are internal and not suspected clinically. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas malignant peripheral nerve sheath tumors scoliosis tibial dysplasia and vasculopathy.

Diagnosis/testing: The diagnosis of NF1 is usually based on clinical findings. Heterozygous pathogenic variants in NF1 are responsible for neurofibromatosis 1. Molecular genetic testing of NF1 is rarely needed for diagnosis.

Management: Treatment of manifestations: Referral to specialists for treatment of complications involving the eye central or peripheral nervous system cardiovascular system endocrine system spine or long bones; surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of plexiform neurofibromas is often unsatisfactory. Complete surgical excision when possible of malignant peripheral nerve sheath tumors. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Dystrophic scoliosis often requires surgical management whereas nondystrophic scoliosis can usually be treated conservatively. Methylphenidate treatment often benefits children with attention-deficit/hyperactivity disorder.

Surveillance: Annual physical examination by a physician familiar with the disorder; annual ophthalmologic examination in children less frequently in adults; regular developmental assessment of children; regular blood pressure monitoring; MRI for follow up of clinically suspected intracranial tumors and other internal tumors. Begin annual mammography in women at age 30 with consideration of annual breast MRI in women between ages 30 and 50 years.

Genetic counseling: NF1 is inherited in an autosomal dominant manner. Half of affected individuals have NF1 as the result of a de novo NF1 pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the altered NF1 allele but the disease manifestations are extremely variable even within a family. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in a family is known.

Copyright © 1993-2021 University of Washington Seattle. GeneReviews is a registered trademark of the University of Washington Seattle. All rights reserved.

16. Jian-Tao Liang Li-Rong Huo Yu-Hai Bao Zhen-Yu Wang Feng Ling. Cerebral vasculopathy in a Chinese family with neurofibromatosis type I mutation. Neurosci Bull. 2013 Dec;29(6):708-14. doi: 10.1007/s12264-013-1388-x. Epub 2013 Nov 11.

Abstract

Neurofibromatosis type I (NF1) is a hereditary autosomal dominant neurocutaneous syndrome that is attributed to NF1 gene mutation. NF1 has been associated with scoliosis macrocephaly pseudoarthrosis short stature mental retardation and malignancies. NF1-associated vasculopathy is an uncommon and easily-overlooked presentation. Examination of a Chinese family affected by NF1 combined with cerebral vessel stenosis and/or abnormality suggested a possible relationship between NF1 and vessel stenosis. To determine which NF1 gene mutation is associated with vascular lesions particularly cerebral vessel stenosis we examined one rare family with combined cerebral vessel lesions or maldevelopment. Vascular lesions were detected using transcranial Doppler sonography and digital subtraction angiography in family members. Next denaturing high-performance liquid chromatography and sequencing were used to screen for NF1 gene mutations. The results revealed a nonsense mutation c.541C>T in the NF1 gene. This mutation truncated the NF1 protein by 2659 amino-acid residues at the C-terminus and co-segregated with all of the patients but was not present in unaffected individuals in the family. Exceptionally three novel mutations were identified in unaffected family members but these did not affect the product of the NF1 gene. Thus the nonsense mutation c.541C>T located in the NF1 gene could constitute one genetic factor for cerebral vessel lesions.

17. S P Cai N Fan J Chen Z L Xia Y Wang X M Zhou Y Yin T L Wen Q J Xia X Y Liu H Y Wang. A novel NF1 frame-shift mutation (c.702_703delGT) in a Chinese family with neurofibromatosis type 1. Genet Mol Res. 2014 Jul 24;13(3):5395-404. doi: 10.4238/2014.July.24.19.

Abstract

This study aimed to characterize the clinical features of a Chinese pedigree with neurofibromatosis type 1 (NF1) and to identify mutations in the NF1 gene. In this three-generation family containing 8 members 5 had been diagnosed with NF1 and the others were asymptomatic. All members of the family underwent complete medical examinations. Molecular genetic analyses were performed on all subjects included in the study. All exons of NF1 were amplified by polymerase chain reaction sequenced and compared with a reference database. Possible changes in function of the protein induced by amino acid variants were predicted by bioinformatic analysis. In this family the 5 patients presented different clinical phenotypes but all manifested typical café-au-lait macules. One novel frame-shift mutation c.702_703delGT in exon 7 of NF1 was identified in all affected family members but not in the unaffected family members or in 102 normal controls. This mutation generates a premature stop codon at amino acid position 720. Additionally a synonymous mutation c.702 G>A was found in 3 family members including 2 affected and 1 normal individuals. In conclusion our study suggests that a novel c.702_703delGT frame-shift mutation in NF1 is likely to be responsible for the pathogenesis of NF1 in this family. To the best of our knowledge it is the first time that a c.702_703delGT mutation has been identified in a family with neurofibromatosis type 1.

18. Ying-Hao Huang Qin-Bo Yang Yun-Hua Deng Nian-Wen Yu Qing Wang Mu-Gen Liu. [NF1 mutation analysis in a Chinese family with neuro- fibromatosis type]. Yi Chuan. 2008 Mar;30(3):309-12. doi: 10.3724/sp.j.1005.2008.00309. [Article in Chinese]

Abstract

A Chinese family affected with autosomal dominant disorder-neurofibromatosis type I was identified in this study. Linkage analysis was performed and DNA sequencing for whole coding region of NF1 was carried out to identify the disease-causing mutation. The disease gene of the Chinese NF1 family was linked to NF1 locus and a nonsense mutation G1336X in the NF1 gene was identified. This mutation truncates the NF1 protein by 1 483 amino acid residues at the C-terminus and is co-segregate with all the patients but not present in unaffected individuals in the family. The present study demonstrated that G1336X mutation in the NF1 gene cause Neurofibromatosis type I in the family. To our knowledge this mutation is firstly reported in Chinese population.

19. Qinbo Yang Changzheng Huang Xiaoying Yang Yinfu Feng Qing Wang Mugen Liu. The R1947X mutation of NF1 causing autosomal dominant neurofibromatosis type 1 in a Chinese family. J Genet Genomics. 2008 Feb;35(2):73-6. doi: 10.1016/S1673-8527(08)60011-9.

Abstract

Neurofibromatosis type 1 is a common autosomal dominant disorder with a high rate of penetrance. It is caused by the mutation of the tumor suppressor gene NF1 which encodes neurofibromin. The main function of neurofibromin is down-regulating the biological activity of the proto-oncoprotein Ras by acting as a Ras-specific GTPase activating protein. In this study we identified a Chinese family affected with neurofibromatosis type 1. The known gene NF1 associated with NF1 was studied by linkage analysis and by direct sequencing of the entire coding region and exon-intron boundaries of the NF1 gene. The R1947X mutation of NF1 was identified which was co-segregated with affected individuals in the Chinese family but not present in unaffected family members. This is the first report which states that the R1947X mutation of NF1 may be one of reasons for neurofibromatosis type 1 in Chinese population.

20. Jian-Tao Liang Li-Rong Huo Yu-Hai Bao Zhen-Yu Wang and Feng Ling. Cerebral vasculopathy in a Chinese family with neurofibromatosis type I mutation. Neurosci Bull. 2013 Dec; 29(6): 708–714.

Abstract

Neurofibromatosis type I (NF1) is a hereditary autosomal dominant neurocutaneous syndrome that is attributed to NF1 gene mutation. NF1 has been associated with scoliosis macrocephaly pseudoarthrosis short stature mental retardation and malignancies. NF1-associated vasculopathy is an uncommon and easily-overlooked presentation. Examination of a Chinese family affected by NF1 combined with cerebral vessel stenosis and/or abnormality suggested a possible relationship between NF1 and vessel stenosis. To determine which NF1 gene mutation is associated with vascular lesions particularly cerebral vessel stenosis we examined one rare family with combined cerebral vessel lesions or maldevelopment. Vascular lesions were detected using transcranial Doppler sonography and digital subtraction angiography in family members. Next denaturing high-performance liquid chromatography and sequencing were used to screen for NF1 gene mutations. The results revealed a nonsense mutation c.541C>T in the NF1 gene. This mutation truncated the NF1 protein by 2659 aminoacid residues at the C-terminus and co-segregated with all of the patients but was not present in unaffected individuals in the family. Exceptionally three novel mutations were identified in unaffected family members but these did not affect the product of the NF1 gene. Thus the nonsense mutation c.541C>T located in the NF1 gene could constitute one genetic factor for cerebral vessel lesions.

Keywords: neurofibromatosis type I cerebral vessel stenosis stroke mutation