. 2021 Aug;23(8):1506-1513.

doi: 10.1038/s41436-021-01170-5. Epub 2021 May 19.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Eric Legius^#¹, Ludwine Messiaen^#², Pierre Wolkenstein^#³, Patrice Pancza^#⁴, Robert A Avery⁵, Yemima Berman⁶, Jaishri Blakeley⁷, Dusica Babovic-Vuksanovic⁸, Karin Soares Cunha⁹, Rosalie Ferner¹⁰, Michael J Fisher¹¹, Jan M Friedman¹², David H Gutmann¹³, Hildegard Kehrer-Sawatzki¹⁴, Bruce R Korf², Victor-Felix Mautner¹⁵, Sirkku Peltonen^{16

17}, Katherine A Rauen¹⁸, Vincent Riccardi¹⁹, Elizabeth Schorry²⁰, Anat Stemmer-Rachamimov²¹, David A Stevenson²², Gianluca Tadini²³, Nicole J Ullrich²⁴, David Viskochil²⁵, Katharina Wimmer²⁶, Kaleb Yohay²⁷; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Susan M Huson^#²⁸, D Gareth Evans^#²⁹, Scott R Plotkin^#³⁰

Collaborators, Affiliations

Collaborators

International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC):
Alicia Gomes, Justin T Jordan, Victor Mautner, Vanessa L Merker, Miriam J Smith, David Stevenson, Monique Anten, Arthur Aylsworth, Diana Baralle, Sebastien Barbarot, Fred Barker 2nd, Shay Ben-Shachar, Amanda Bergner, Didier Bessis, Ignacio Blanco, Catherine Cassiman, Patricia Ciavarelli, Maurizio Clementi, Thierry Frébourg, Marco Giovannini, Dorothy Halliday, Chris Hammond, C O Hanemann, Helen Hanson, Arvid Heiberg, Pascal Joly, Michel Kalamarides, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Mia MacCollin, Conor Mallucci, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, Laura Papi, Allyson Parry, Juha Peltonen, Dominique Pichard, Bruce Poppe, Nilton Rezende, Luiz Oswaldo Rodrigues, Tena Rosser, Martino Ruggieri, Eduard Serra, Verena Steinke-Lange, Stavros Michael Stivaros, Amy Taylor, Jaan Toelen, James Tonsgard, Eva Trevisson, Meena Upadhyaya, Ali Varan, Meredith Wilson, Hao Wu, Gelareh Zadeh

Affiliations

¹ Department of Human Genetics, KU Leuven and University Hospital, Leuven, Belgium. eric.legius@uzleuven.be.
² Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
³ Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Service de Dermatologie, Créteil, France.
⁴ Children's Tumor Foundation, New York, NY, USA.
⁵ Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶ Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia and University of Sydney, Sydney, Australia.
⁷ Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, MD, USA.
⁸ Department of Clinical Genomics, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁹ Department of Pathology, Universidade Federal Fluminense, Niteroi, Brasil.
¹⁰ Neurology, Guy's and St. Thomas' Hospital and NHS Trust, London, UK.
¹¹ Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹³ Neurology, Washington University, St. Louis, MO, USA.
¹⁴ Institute of Human Genetics, University of Ulm, Ulm, Germany.
¹⁵ Neurology, University Hospital of Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Dermatology, University of Turku and Turku University Hospital, Turku, Finland.
¹⁷ Department of Dermatology and Venereology, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Pediatrics, University of California Davis, Sacramento, CA, USA.
¹⁹ The Neurofibromatosis Institute, La Crescenta, CA, USA.
²⁰ Medical Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²¹ Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
²² Medical Genetics, Stanford University, Stanford, CA, USA.
²³ Pediatric Dermatology, University of Milan, Milan, Italy.
²⁴ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
²⁵ Medical Genetics, University of Utah, Salt Lake City, UT, USA.
²⁶ Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
²⁷ NYU Langone Health, New York, NY, USA.
²⁸ Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, NHS Foundation Trust, Manchester, UK.
²⁹ Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.
³⁰ Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.

^# Contributed equally.

PMID: 34012067
PMCID: PMC8354850
DOI: 10.1038/s41436-021-01170-5

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Eric Legius et al. Genet Med. 2021 Aug.

. 2021 Aug;23(8):1506-1513.

doi: 10.1038/s41436-021-01170-5. Epub 2021 May 19.

Authors

Collaborators

International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC):
Alicia Gomes, Justin T Jordan, Victor Mautner, Vanessa L Merker, Miriam J Smith, David Stevenson, Monique Anten, Arthur Aylsworth, Diana Baralle, Sebastien Barbarot, Fred Barker 2nd, Shay Ben-Shachar, Amanda Bergner, Didier Bessis, Ignacio Blanco, Catherine Cassiman, Patricia Ciavarelli, Maurizio Clementi, Thierry Frébourg, Marco Giovannini, Dorothy Halliday, Chris Hammond, C O Hanemann, Helen Hanson, Arvid Heiberg, Pascal Joly, Michel Kalamarides, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Mia MacCollin, Conor Mallucci, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, Laura Papi, Allyson Parry, Juha Peltonen, Dominique Pichard, Bruce Poppe, Nilton Rezende, Luiz Oswaldo Rodrigues, Tena Rosser, Martino Ruggieri, Eduard Serra, Verena Steinke-Lange, Stavros Michael Stivaros, Amy Taylor, Jaan Toelen, James Tonsgard, Eva Trevisson, Meena Upadhyaya, Ali Varan, Meredith Wilson, Hao Wu, Gelareh Zadeh

Affiliations

¹ Department of Human Genetics, KU Leuven and University Hospital, Leuven, Belgium. eric.legius@uzleuven.be.
² Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
³ Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Service de Dermatologie, Créteil, France.
⁴ Children's Tumor Foundation, New York, NY, USA.
⁵ Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶ Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia and University of Sydney, Sydney, Australia.
⁷ Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, MD, USA.
⁸ Department of Clinical Genomics, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁹ Department of Pathology, Universidade Federal Fluminense, Niteroi, Brasil.
¹⁰ Neurology, Guy's and St. Thomas' Hospital and NHS Trust, London, UK.
¹¹ Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹³ Neurology, Washington University, St. Louis, MO, USA.
¹⁴ Institute of Human Genetics, University of Ulm, Ulm, Germany.
¹⁵ Neurology, University Hospital of Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Dermatology, University of Turku and Turku University Hospital, Turku, Finland.
¹⁷ Department of Dermatology and Venereology, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Pediatrics, University of California Davis, Sacramento, CA, USA.
¹⁹ The Neurofibromatosis Institute, La Crescenta, CA, USA.
²⁰ Medical Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²¹ Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
²² Medical Genetics, Stanford University, Stanford, CA, USA.
²³ Pediatric Dermatology, University of Milan, Milan, Italy.
²⁴ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
²⁵ Medical Genetics, University of Utah, Salt Lake City, UT, USA.
²⁶ Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
²⁷ NYU Langone Health, New York, NY, USA.
²⁸ Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, NHS Foundation Trust, Manchester, UK.
²⁹ Department of Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.
³⁰ Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.

^# Contributed equally.

PMID: 34012067
PMCID: PMC8354850
DOI: 10.1038/s41436-021-01170-5

Abstract

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.

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Conflict of interest statement

D.V.-B. is a scientific advisor for AstraZeneca Pharmaceuticals, LP, and receives grant support for the Department of Defense and SpringWorks Therapeutics. J.B. and M.J.F. are members of the Children’s Tumor Foundation Medical Advisory Committee. D.G.E., E.L., V.-F.M., S.P. are members of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe. R.F. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe and is a medical advisor for AstraZeneca. J.M.F. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board. B.R.K. is a member of the Children’s Tumor Foundation Medical Advisory Committee (Chair) and is on the medical advisory boards of Genome Medicine and Infixion Bioscience. L.M. is director of the Medical Genomics Laboratory at University of Alabama, Birmingham, which specializes in genetic testing for all forms of the neurofibromatoses. P.P. is employed by the Children’s Tumor Foundation. S.R.P. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board (Chair, US) and Europe, and is co-founder of NFlection Therapeutics; is consultant for AstraZeneca and SonalaSense. E.S. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board and receives Department of Defense funding as a site for NF Clinical Trials Consortium. N.J.U. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board and serves on the board of NF Northeast. D.V. is member of the Children’s Tumor Foundation and Medical Advisory Committee, is a member of the AstraZeneca speakers bureau, and is on Sanofi-Genzyme–MPS Board of Advisors. P.W. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board–Europe (Chair). K.Y. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board; received a consultant fee from AstraZeneca Pharmaceuticals; is on the Scientific Advisory Board for Infixion Bioscience; and is a member of the Programmatic Review Committee for the Department of Defense, Congressionally Directed Medical Research Program, NF Research Program. The other authors declare no competing interests.

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Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Collaborators

Affiliations

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

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Abstract

Conflict of interest statement

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