Neurofibromatosis type 1
Neurofibromatosis type I, also known as Von Recklinghausen disease, is a common phakomatosis affecting 1 in 2500-3000 live births; it may be associated with several common ocular findings, including Lisch nodules, plexiform neurofibromas, optic pathway gliomas, retinal astrocytic hamartomas and choroidal nodules.
Mutations in the NF1 gene are associated with neurofibromatosis type 1 same as as Watson syndrome.
There is an increased susceptibility to tumor development in the central nervous system due to the loss of neurofibromin, an inactivator of the proto-oncogene Ras. NF1 has a broad clinical spectrum, which includes spinal tumors. Although the most common intramedullary tumor of the spinal cord in adults is ependymoma, few patients with NF1 accompanied by spinal ependymoma have been reported to date, and the localization of the tumors is cervical and thoracic in these cases.
NF1 microdeletion syndrome
Marques et al. identified the AP-1 transcription factor FOSL1 as a key regulator of the mesenchymal glioblastoma subtype.
They provided a mechanistic basis to the role of the neurofibromatosis type 1 gene (NF1), a negative regulator of the RAS/MAPK pathway, in Glioblastoma mesenchymal transformation through the modulation of FOSL1 expression. Depletion of FOSL1 in NF1-mutant human BTSCs and Kras-mutant mouse neural stem cells results in loss of the mesenchymal gene signature and reduction in stem cell properties and in vivo tumorigenic potential. This data demonstrates that FOSL1 controls Glioblastoma plasticity and aggressiveness in response to NF1 alterations 1).
Neurofibromatosis type 1 (NF1) is a common inherited complex multi-system disorder associated with the growth of various benign and malignant tumors, being Pilocytic Astrocytomas (PA) a common benign central nervous system (CNS) tumour occurring in this setting. Although this is a common association, simultaneous development of multiple lesions is an infrequent finding, especially in non-optic or hypothalamic locations 2).
Epidemiology
Neurofibromatosis type 1 is a genetic disorder impacting approximately 2.5 million people worldwide.
It occurs with approximately 1: 2000 to 1: 5000 in individuals.
About 40% of Neurofibromatosis type 1 patients develop spinal tumors, of whom some have familial spinal neurofibromatosis (FSNF), a variant form of NF1 in which patients present with multiple bilateral spinal tumors but have few other clinical features of the disease 3).
Clinical
The diagnosis of most NF1 patients is based on clinical manifestations.
Often leading to the development of numerous benign yet disfiguring cutaneous neurofibromas
Cognitive dysfunction accompanied by neurofibromatosis type 1 is one of the significant characteristics of this neurocutaneous disorder and has a serious impact on patients' quality of life. Although studies on cognitive function in children with neurofibromatosis type 1 have revealed that attentional impairment is a key deficit in these patients, few studies have examined their neuropsychological profile, especially whether the attentional function is also abnormal and specific in adult patients with neurofibromatosis type 1. In this study, we used the revised attention network test to examine the function of three attentional networks, orienting, and executive control in 20 adult patients with neurofibromatosis type 1 in comparison to 20 normal controls. Adult patients with neurofibromatosis type 1 showed significantly greater conflict effect for the executive control network, but no significant differences were found for the alerting and orienting network relative to normal controls. These results provide evidence that there is an attentional deficit that is specifically associated with the executive control network in adult patients with neurofibromatosis type 1 4).
Diagnosis
Requires at least two major criteria below : 2 or more neurofibromas or 1 plexiform neurofibroma, 6 or more café-au-lait patches, axillary or groin freckling, optic pathway glioma, lisch nodules in the Iris, a distinctive osseous lesion, a first degree relative with NF1.
Outcome
Spinal tumors occur in approximately 40% of patients with NF1.
see Hypothalamic glioma.
Case reports
A 40-year-old female patient with numerous cNF across her body underwent a single treatment using a 20 MHz dermatologically focused ultrasound device on seven selected cNF on the upper back. Each cNF was treated in a single session of 20-60 s without anesthesia due to manageable pain. Only one minimal adverse reaction in the form of depigmentation in a single treated tumor was noted from treatment or during the healing of a thin scab that formed on each cNF a few days after treatment. At the 12-month follow-up, four out of seven treated cNF showed full remission, two showed a partial or significant reduction in tumor volume, and two did not respond to treatment. The reason for the variability is not fully understood, but speculations include differences in tissue content, e.g., due to tumor age. The method is concluded to be a promising candidate for a new safe and minimally invasive treatment that can potentially be used for single-session removal/reduction of a large number of cNF. Further research should focus on refining treatment parameters and strategies to enhance response predictability 5).
A case report describes an 18-year-old woman with neurofibromatosis type 1 and prior right brachial plexus neurofibroma resection who reported intermittent, unilateral facial flushing after exertion 6).
Vaassen et al. reported an 11-year-old Neurofibromatosis type 1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of this patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1 7).
A 41 year-old female patient with neurofibromatosis type 1 and uncontrolled human immunodeficiency virus (HIV) type 1 infection presents with a first generalized seizure and associated headache and ataxia. Imaging studies revealed two large intra-axial tumours, nodular-cystic in the supratentorial compartment and solid in the infratentorial compartment. Both lesions were gross-totally removed in two surgeries performed with an interval of one-week. Despite their different imaging patterns, they were histologically and genetically identical.
Forte et al., present a unique case of two histologically and genetically identical pilocytic astrocytomas occurring simultaneously in supratentorial and infratentorial locations. They suggest that intrinsic tumour development predisposition associated to NF1 might have been enhanced by HIV-related immunosuppression in this case. Strict oncological surveillance is essential in patients with tumour predisposition syndromes combined with immunosuppression 8).
Yakar et al. reported the case of a patient with NF1 presenting to our clinic with low back pain and gait disturbance. The patient had an spinal extramedullary ependymoma at the L2-3 vertebra level. This report is the first case of NF1 with spinal ependymoma localized in the lumbar region 9)