C2 neurofibromas in neurofibromatosis type 1: genetic and imaging characteristics

Restricted access


C2 nerve root neurofibromas have been reported frequently in patients with neurofibromatosis type 1 (NF1), although their genetic and imaging characteristics are unexplored. The aim of this study was to characterize genetic and spinal imaging findings in a large cohort of NF1 patients with C2 neurofibromas.


The authors performed a review of national NF1 referrals between 2009 and 2016. Inclusion criteria were at least 1 C2 root neurofibroma and cervical-spine or whole-spine MRI scans available for analysis. Blinded imaging review was performed by a neuroradiologist with an interest in NF1.


Fifty-four patients with 106 C2 neurofibromas were included. The median age was 32.5 years (range 15–61 years), and there were slightly more male patients (33 vs 21 female patients). Splice-site (30%) and missense (20%) variants were frequent. Spinal neurofibromas were distributed in all spine regions (65%) or in the cervical spine alone (22%). Most (93%) C2 neurofibromas were visible on MRI scans of the head. Intradural invasion and cord compression in the cervical spine included the C2 level in 95% and 80% of patients, respectively. Compared with all other cervical spine neurofibromas in these patients, C2 neurofibromas had higher rates of intraspinal extension (75% vs 32%; OR 6.20, 95% CI 3.85–9.97; p < 0.001), intradural invasion (53% vs 26%; OR 3.20, 95% CI 2.08–4.92; p < 0.001), and cord compression (25% vs 13%; OR 2.26, 95% CI 1.35–3.79; p = 0.002). However, C2 neurofibromas had lower rates of extraforaminal growth beyond the transverse process (12% vs 62%; OR 0.09, 95% CI 0.05–0.16; p < 0.001).


C2 neurofibromas are associated with an aggressive intraspinal phenotype, limited growth outside the spinal canal, and an uncommon genetic profile. These observations require future study.

ABBREVIATIONS NF1 = neurofibromatosis type 1; PFS = progression-free survival.

Article Information

Correspondence Mueez Waqar: Salford Royal NHS Foundation Trust, Manchester, United Kingdom. mwaqar@doctors.org.uk.

INCLUDE WHEN CITING Published online October 19, 2018; DOI: 10.3171/2018.7.SPINE171340.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    Spine segmental neurofibroma patterns in patients with C2 neurofibromas. A: Intradural invasion patterns. These were similar between the cervical and lumbosacral spine. Intradural invasion was rare in the thoracic spine. B: Cord compression patterns. In general, radiological cord compression was rare outside of the cervical spine.

  • View in gallery

    Features in patients with C2 neurofibromas as seen on coronal (A–C) and axial (D and E) images. A: Multilevel segmental spinal neurofibromas were common, as in this 39-year-old man with extensive segmental neurofibromas throughout the whole spine, including plexiform neurofibromatous involvement of the brachial plexi and lumbar and sacral plexi. B: Isolated neurofibromas were rare, as in this 61-year-man male with an isolated, unilateral left-sided C2 neurofibroma (arrow), without neurofibromas elsewhere in the spine. C: Some neurofibromas had intraspinal growth without intradural invasion, as in this 52-year-old woman with an extensive right-sided C2 neurofibroma causing cord compression (arrow). D: Intradural invasion was present in a significant proportion, as in this 45-year-old man with bilateral C2 neurofibromas with intradural invasion (1%–25%; arrow). E: Radiological cord compression was commonly associated with C2 neurofibromas, as in this 19-year-old woman with progressive myelopathy (arrow) due to bilateral C2 neurofibromas. Figure is available in color online only.



Abe JTakami TNaito KYamagata TArima HOhata K: Surgical management of solitary nerve sheath tumors of the cervical spine: a retrospective case analysis based on tumor location and extension. Neurol Med Chir (Tokyo) 54:9249292014


Ars EKruyer HGaona ACasquero PRosell JVolpini V: A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 62:8348411998


Atit RPCrowe MJGreenhalgh DGWenstrup RJRatner N: The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts. J Invest Dermatol 112:8358421999


Burkitt Wright EMSach ESharif SQuarrell OCarroll TWhitehouse RW: Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis. J Med Genet 50:6066132013


El-Sissy MHMahmoud M: C2 root nerve sheath tumors management. Acta Neurochir (Wien) 155:7797842013


Evans DGBowers NBurkitt-Wright EMiles EGarg SScott-Kitching V: Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine 7:2122202016


Evans DGHoward EGiblin CClancy TSpencer HHuson SM: Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152A:3273322010


Ferner REHuson SMThomas NMoss CWillshaw HEvans DG: Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44:81882007


Friedrich REHagel CBrehme ZKluwe LMautner VF: Ki-67 proliferation-index (MIB-1) of neurofibromas in neurofibromatosis type 1 patients. Anticancer Res 23 (2A):9539552003


George BLot G: Neurinomas of the first two cervical nerve roots: a series of 42 cases. J Neurosurg 82:9179231995


Goel AMuzumdar DNadkarni TDesai KDange NChagla A: Retrospective analysis of peripheral nerve sheath tumors of the second cervical nerve root in 60 surgically treated patients. J Neurosurg Spine 8:1291342008


Janjua MBZhou PLGreenfield JPBaaj AAFrempong-Boadu A: C2 and greater occipital nerve: the anatomic and functional implications in spinal surgery. Cureus 9:e10742017


Jinnai TKoyama T: Clinical characteristics of spinal nerve sheath tumors: analysis of 149 cases. Neurosurgery 56:5105152005


Leonard JRFerner REThomas NGutmann DH: Cervical cord compression from plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry 78:140414062007


Lim JKWong HK: Variation of the cervical spinal Torg ratio with gender and ethnicity. Spine J 4:3964012004


Lot GGeorge B: Cervical neuromas with extradural components: surgical management in a series of 57 patients. Neurosurgery 41:8138221997


Miyakoshi NHongo MKasukawa YMisawa AShimada Y: Bilateral and symmetric C1-C2 dumbbell ganglioneuromas associated with neurofibromatosis type 1 causing severe spinal cord compression. Spine J 10:e11e152010


Nguyen RDombi EAkshintala SBaldwin AWidemann BC: Characterization of spinal findings in children and adults with neurofibromatosis type 1 enrolled in a natural history study using magnetic resonance imaging. J Neurooncol 121:2092152015


Ribeiro SNapoli IWhite IJParrinello SFlanagan AMSuter U: Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Reports 5:1261362013


Riccardi VM: The genetic predisposition to and histogenesis of neurofibromas and neurofibrosarcoma in neurofibromatosis type 1. Neurosurg Focus 22(6):E32007


Ruggieri MPolizzi ASpalice ASalpietro VCaltabiano RD’Orazi V: The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet 87:4014102015


Taleb FSGuha AArnold PMFehlings MGMassicotte EM: Surgical management of cervical spine manifestations of neurofibromatosis Type 1: long-term clinical and radiological follow-up in 22 cases. J Neurosurg Spine 14:3563662011


Thakkar SDFeigen UMautner VF: Spinal tumours in neurofibromatosis type 1: an MRI study of frequency, multiplicity and variety. Neuroradiology 41:6256291999


Tsirikos AISaifuddin ANoordeen MH: Spinal deformity in neurofibromatosis type-1: diagnosis and treatment. Eur Spine J 14:4274392005


Upadhyaya MSpurlock GKluwe LChuzhanova NBennett EThomas N: The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 10:2512632009




All Time Past Year Past 30 Days
Abstract Views 130 130 88
Full Text Views 65 65 35
PDF Downloads 46 46 17
EPUB Downloads 0 0 0


Google Scholar