ABSTRACT
PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.
Subject(s)
Neurilemmoma , Neurofibromatoses , Neurofibromatosis 1 , Neurofibromatosis 2 , Skin Neoplasms , Consensus , Humans , Neurilemmoma/diagnosis , Neurilemmoma/genetics , Neurilemmoma/pathology , Neurofibromatoses/diagnosis , Neurofibromatoses/genetics , Neurofibromatosis 1/genetics , Neurofibromatosis 2/diagnosis , Neurofibromatosis 2/genetics , Skin Neoplasms/geneticsABSTRACT
PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
Subject(s)
Neurofibromatosis 1 , Cafe-au-Lait Spots/genetics , Consensus , Genetic Testing , Humans , Neurofibromatosis 1/diagnosis , Neurofibromatosis 1/geneticsABSTRACT
The neurofibromatoses (NF) are a group of rare genetic disorders that can affect all races equally at an incidence from 1:3000 (NF1) to a log unit lower for NF2 and schwannomatosis. Since the research community is reporting an increasing number of malignant cancers that carry mutations in the NF genes, the general interest of both the research and pharma community is increasing and the authors saw an opportunity to present a novel, fresh approach to drug discovery in NF. The aim of the paper is to challenge the current drug discovery approach to NF, whereby existing targeted therapies that are either in the clinic or on the market for other disease indications are repurposed for NF. We offer a suggestion for an alternative drug discovery approach. In the new approach, selective and tolerable targeted therapies would be developed for NF and later expanded to patients with more complex diseases such as malignant cancer in which the NF downstream pathways are deregulated. The Children's Tumor Foundation, together with some other major NF funders, is playing a key role in funding critical initiatives that will accelerate the development of better targeted therapies for NF patients, while these novel, innovative treatments could potentially be beneficial to molecularly characterized cancer patients in which NF mutations have been identified.
