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Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study.

Forde, C; Burkitt-Wright, E; Turnpenny, PD; Haan, E; Ealing, J; Mansour, S; Holder, M; Lahiri, N; Dixit, A; Procter, A; et al. Forde, C; Burkitt-Wright, E; Turnpenny, PD; Haan, E; Ealing, J; Mansour, S; Holder, M; Lahiri, N; Dixit, A; Procter, A; Pacot, L; Vidaud, D; Capri, Y; Gerard, M; Dollfus, H; Schaefer, E; Quelin, C; Sigaudy, S; Busa, T; Vera, G; Damaj, L; Messiaen, L; Stevenson, DA; Davies, P; Palmer-Smith, S; Callaway, A; Wolkenstein, P; Pasmant, E; Upadhyaya, M (2022) Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study. Eur J Hum Genet, 30 (3). pp. 291-297. ISSN 1476-5438 https://doi.org/10.1038/s41431-021-01015-4
SGUL Authors: Mansour, Sahar

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Abstract

Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual-a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with 'classical', clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype-phenotype association is fundamental to accurate prognostication for families and caregivers.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2021
Keywords: 0604 Genetics, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Eur J Hum Genet
ISSN: 1476-5438
Language: eng
Dates:
DateEvent
March 2022Published
13 December 2021Published Online
22 November 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
PubMed ID: 34897289
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113939
Publisher's version: https://doi.org/10.1038/s41431-021-01015-4

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