The neurofibromatoses (NF) are a group of genetic disorders that interfere negatively with the quality of life (QoL) and influence physical, emotional and social statuses. Studying the effects of neurofibromatoses on various aspects of QoL seems important to implement beneficial strategies in increasing the QoL of NF patients. The aim of this study was to review the literature on quality of life in patients with NF and quantitatively evaluate the effects of Neurofibromatosis on various aspects of quality of life by synthesizing available studies.

The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should be clinically examined and undergo follow-up in accordance with the standard NF1 guidelines, as MNF1 patients more often may develop more benign phenotypes and thereby less disease-associated complications including cognitive impairment. We discussed the need for a specific MNF1 follow-up guideline with focus on frequency of plexiform neurofibromas and NF1-associated complications.

Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive "active-site" mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.

Neurofibromatoses (NF; NF1, NF2, and schwannomatosis) are hereditary tumor predisposition syndromes with a risk for poor quality of life (QOL) and no evidence-based treatments.

Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases.

Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1.

Neurofibromatoses (NF) are rare genetic conditions associated with substantial psychosocial burden and impaired quality of life (QoL). We developed the first NF-tailored mind-body program (the Relaxation Response Resiliency Program for NF) and adapted it for delivery via live videoconferencing to decrease participation barriers and increase its reach. In a pilot randomized controlled trial (RCT), we found that the Relaxation Response Resiliency Program for NF had excellent feasibility and acceptability when delivered via live videoconferencing; furthermore, the Relaxation Response Resiliency Program for NF showed proof of concept in improving QoL compared with an NF-tailored health education control program (the Health Enhancement Program for NF). A fully powered trial is needed to ascertain the efficacy and durability of the Relaxation Response Resiliency Program for NF delivered via secure live videoconferencing among geographically diverse patients.

Neurofibromatosis type 1 (NF1) is a cancer predisposing syndrome. Studies suggest that women < 50 years old (y.o.) with NF1 have an increased breast cancer (BC) incidence and BC associated mortality. However, this has not been widely recognized secondary to small study populations.

Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.

MAP/ERK kinase 1 and 2 (MEK 1/2) inhibitors (MEKi) are investigated in several trials to treat lesions that arise from pathogenic variants of the Neurofibromatosis type 1 and type 2 genes (NF1, NF2). These trials showed that MEKi are capable to shrink volume of low grade gliomas and plexiform neurofibromas in NF1. Targeting other lesions being associated with a high morbidity in NF1 seems to be promising. Due to involvement of multiple pathways in NF2 associated lesions as well as in malignant tumors, MEKi are also used in combination therapies. This review outlines the current state of MEKi application in neurofibromatosis and associated benign and malignant lesions.