Neuro · Vol. 5, No. 1 · 2018 · pp. 3–4 · e-ISSN 2377-1607

Multiplicity as a Factor in Understanding NF1

Vincent M. Riccardi, MD, MBA

Department of Neurology,The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USAUnited States

DOI: https://doi.org/10.17140/noj-5-e009 · Published 2018-09-10 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2018 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Abstract

The NF1 locus on the long arm of chromosome 17 is a very special gene in the human genome. In terms of multiplicity, there are five pseudogenes on five other chromosomes; it influences the formation and/or behavior of many tissues; it is probably the locus with highest germinal mutation rate in humans (1 in 10,000), with a disease frequency of 1/2,500-1/3,000. There are several other multiplicities that persist in confounding our understanding of this very common autosomal dominant disorder. This editorial focuses on three considerations: 1) How many types of Neurofibromatosis (NF) are there? 2) How many types of NF1 neurofibromas are there? 3) What are the logical/causative relationships of the numerous pathogenetic and clinical elements of the full-blown syndrome or portions of it?

Keywords: phenotype; schwannomas; vestibular

Open Journal PUBLISHERS Editorial Multiplicity as a Factor in Understanding NF1 * Vincent M. Riccardi, MD, MBA* Department of Neurology,The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USA * *Corresponding author Vincent M. Riccardi, MD, MBA Department of Neurology,The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USA; E-mail: vmriccardi@charter.net Article information nd th th Received: August 2 , 2018; Accepted: August 4 , 2018; Published: September 10 , 2018 Cite this article Riccardi VM. Multiplicity as a factor in understanding NF1. Neuro Open J. 2018; 5(1): e3-e4. doi: 10.17140/NOJ-5-e009 he NF1 locus on the long arm of chromosome 17 is a very The point is that the numerical basis for NF classification special gene in the human genome. In terms of multiplicity, and nomenclature reflects was pre-genomic clinical heterogeneity, T there are five pseudogenes on five other chromosomes; it most useful in characterizing subtypes of what was originally influences the formation and/or behavior of many tissues; it is called Von Recklinghausen Disease. The only exceptions were probably the locus with highest germinal mutation rate in humans the two non-neurofibroma disorders: NF2 is a totally distinct (1 in 10,000), with a disease frequency of 1/2,500-1/3,000. There schwannoma-generating disorder, as is Schwannomatosis; and are several other multiplicities that persist in confounding our NF5 identified what we now know as the Legius syndrome. An understanding of this very common autosomal dominant disorder. important general point here is that a body-wide distribution This editorial focuses on three considerations: 1) How many types of multiple neurofibromas is virtually always a type of VRD or of Neurofibromatosis (NF) are there? 2) How many types of NF1. In addition, an intragenic mutation or a whole gene deletion NF1 neurofibromas are there? 3) What are the logical/causative (WGD) involving the NF1 locus consistently manifests as some 7,8 relationships of the numerous pathogenetic and clinical elements iteration of the VRD phenotype.7,8 of the full-blown syndrome or portions of it?

In other words, etiologically, there appears to be only TYPES OF NEUROFIBROMATOSIS (NF) one disorder that accurately warrants the diagnosis sensu strictu (phenotype attribution) of Neurofibromatosis or NF. For the 1 2,3 In 19821 and for the first two editions of my NF book.2,3 I identified time being, it would reserve the diagnostic or phenotypic label of seven to eight relatively distinctive types of NF. Based on careful Neurofibromatosis 1 or NF1 for an intragenic mutation or WGD literature reviews, the most common and most consistent phenotype involving the NF1 locus at 17q11.2.

was labeled as NF1. The next most consistent and somewhat .

common phenotype, with bilateral vestibular schwannomas as TYPES OF NEUROFIBROMAS the hallmark, was labeled NF2. The remainder of NF “types” were characterized as to the presence and/or distribution of AThe key to VRD or NF1 is the neurofibroma. And there is more neurofibromas, time of onset, idiosyncratic elements, and such. than one type of neurofibroma, although sadly there is not yet They were sequentially labeled NF3 through NF7 and NF-NOS consensus for their logical classification or names. Respecting (Not Otherwise Specified). Schwannomatosis, as a distinct entity that all neurofibromas are accurately and consistently considered was not considered in the earliest characterizations. In 1987, an NIH to be Peripheral Nerve Sheath Tumors (PNSTs), in 2007.9 It Consensus Conference adopted the NF1 and NF2 terminology as was proposed that there are three basic types of neurofibromas alternatives to “Von Recklinghausen disease (VRD)” and “Bilateral consistent with all prior classifications and routine histopathological Vestibular Schwannomas,” respectively.4 The respective gene loci designations: Endoneurial, Epineurial and Perineurial. Their similarities 5,6 have long been established on 17q11.2 and 22q12.2.5,6 and differences are emphasized in Table 1. Key elements for the cc Copyright 2018 by Riccardi VM. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which Neuro Open J. 2018; 5(1): e3-e4. doi: 10.17140/NOJ-5-e009 Plexiform nf (Pnf) are 1) the absence/presence of a Central

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