Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

doi:10.1016/j.gim.2022.05.007

. 2022 Sep;24(9):1967-1977.

doi: 10.1016/j.gim.2022.05.007. Epub 2022 Jun 9.

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

Scott R Plotkin¹, Ludwine Messiaen², Eric Legius³, Patrice Pancza⁴, Robert A Avery⁵, Jaishri O Blakeley⁶, Dusica Babovic-Vuksanovic⁷, Rosalie Ferner⁸, Michael J Fisher⁹, Jan M Friedman¹⁰, Marco Giovannini¹¹, David H Gutmann¹², Clemens Oliver Hanemann¹³, Michel Kalamarides¹⁴, Hildegard Kehrer-Sawatzki¹⁵, Bruce R Korf², Victor-Felix Mautner¹⁶, Mia MacCollin¹⁷, Laura Papi¹⁸, Katherine A Rauen¹⁹, Vincent Riccardi²⁰, Elizabeth Schorry²¹, Miriam J Smith²², Anat Stemmer-Rachamimov²³, David A Stevenson²⁴, Nicole J Ullrich²⁵, David Viskochil²⁶, Katharina Wimmer²⁷, Kaleb Yohay²⁸; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Susan M Huson²⁹, Pierre Wolkenstein³⁰, D Gareth Evans²²

Collaborators, Affiliations

Collaborators

International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC):
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, Alicia Gomes, Dorothy Halliday, Chris Hammond Helen Hanson Arvid Heiberg, Pascal Joly, Justin T Jordan, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Conor Mallucci, Vanessa L Merker, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, 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 Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA. Electronic address: splotkin@mgh.harvard.edu.
² Department of Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL.
³ Department of Human Genetics, Member of ERN GENTURIS, KU Leuven and University Hospital, Leuven, Belgium.
⁴ Children's Tumor Foundation, New York, NY.
⁵ Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA.
⁶ Comprehensive Neurofibromatosis Center, Johns Hopkins Medicine, The Johns Hopkins Hospital, Baltimore, MD.
⁷ Department of Clinical Genomics, Mayo Clinic College of Medicine and Science, Rochester, MN.
⁸ Neurology, Guy's and St. Thomas' Hospital and NHS Trust, London, United Kingdom.
⁹ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
¹⁰ Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles, CA.
¹² Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO.
¹³ Institute of Translational and Stratified Medicine, Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom.
¹⁴ Department of Neurosurgery, Hospital Pitie-Salpetriere, Sorbonne Université, Paris, France.
¹⁵ Institute of Human Genetics, University of Ulm, Ulm, Germany.
¹⁶ Department of Neurology, University Hospital of Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Pediatric Neurology, Bend, OR.
¹⁸ The Department of Experimental and Clinical, Medical Genetics Unit, Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy.
¹⁹ Department of Pediatrics, University of California Davis, Sacramento, CA.
²⁰ The Neurofibromatosis Institute, La Crescenta, CA.
²¹ Medical Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
²² Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Member of ERN GENTURIS, Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
²³ Department of Pathology, Massachusetts General Hospital, Boston, MA.
²⁴ Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.
²⁵ Department of Neurology, Boston Children's Hospital, Boston, MA.
²⁶ Medical Genetics, University of Utah, Salt Lake City, UT.
²⁷ Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
²⁸ Departments of Neurology and Pediatrics, NYU Langone Health, New York, NY.
²⁹ Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
³⁰ Service de Dermatologie, Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Créteil, France.

PMID: 35674741
DOI: 10.1016/j.gim.2022.05.007

Free article

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

Scott R Plotkin et al. Genet Med. 2022 Sep.

Free article

. 2022 Sep;24(9):1967-1977.

doi: 10.1016/j.gim.2022.05.007. Epub 2022 Jun 9.

Authors

Collaborators

International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC):
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, Alicia Gomes, Dorothy Halliday, Chris Hammond Helen Hanson Arvid Heiberg, Pascal Joly, Justin T Jordan, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Conor Mallucci, Vanessa L Merker, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, 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 Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA. Electronic address: splotkin@mgh.harvard.edu.
² Department of Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL.
³ Department of Human Genetics, Member of ERN GENTURIS, KU Leuven and University Hospital, Leuven, Belgium.
⁴ Children's Tumor Foundation, New York, NY.
⁵ Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA.
⁶ Comprehensive Neurofibromatosis Center, Johns Hopkins Medicine, The Johns Hopkins Hospital, Baltimore, MD.
⁷ Department of Clinical Genomics, Mayo Clinic College of Medicine and Science, Rochester, MN.
⁸ Neurology, Guy's and St. Thomas' Hospital and NHS Trust, London, United Kingdom.
⁹ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
¹⁰ Department of Medical Genetics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles, CA.
¹² Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO.
¹³ Institute of Translational and Stratified Medicine, Peninsula Medical School, University of Plymouth, Plymouth, United Kingdom.
¹⁴ Department of Neurosurgery, Hospital Pitie-Salpetriere, Sorbonne Université, Paris, France.
¹⁵ Institute of Human Genetics, University of Ulm, Ulm, Germany.
¹⁶ Department of Neurology, University Hospital of Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Pediatric Neurology, Bend, OR.
¹⁸ The Department of Experimental and Clinical, Medical Genetics Unit, Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy.
¹⁹ Department of Pediatrics, University of California Davis, Sacramento, CA.
²⁰ The Neurofibromatosis Institute, La Crescenta, CA.
²¹ Medical Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
²² Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Member of ERN GENTURIS, Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
²³ Department of Pathology, Massachusetts General Hospital, Boston, MA.
²⁴ Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA.
²⁵ Department of Neurology, Boston Children's Hospital, Boston, MA.
²⁶ Medical Genetics, University of Utah, Salt Lake City, UT.
²⁷ Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
²⁸ Departments of Neurology and Pediatrics, NYU Langone Health, New York, NY.
²⁹ Clinical Genetics, (Formerly) Manchester Center for Genomic Medicine, Manchester University Hospitals, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
³⁰ Service de Dermatologie, Assistance Publique-Hôpital Paris (AP-HP), Hôpital Henri-Mondor, UPEC, Créteil, France.

PMID: 35674741
DOI: 10.1016/j.gim.2022.05.007

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.

Keywords: NF2; Neurofibromatosis; SMARCB1; Schwannomatosis; lztr1.

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Conflict of interest statement

Conflict of Interest R.A.A., C.O.H., and K.A.R declare no conflicts of interest. D.B.-V. is a scientific advisor for AstraZeneca, L.P. and receives grant support from the Department of Defense and SpringWorks Therapeutics. J.B. is a member of the Children’s Tumor Foundation Medical Advisory Committee and the Clinical Care Advisory Board. D.G.E. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe and has received consultancy fees from AstraZeneca, SpringWorks Therapeutics, and Recursion. R.F. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe and is a medical advisor for AstraZeneca. M.J.F. is a member of the Children’s Tumor Foundation Medical Advisory Committee. J.M.F. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board. M.G. receives grant support from NF2 Therapeutics, Inc and is a consultant for Puma Biotechnology. D.H.G. declares no conflicts of interest. M.K. is a paid consultant for Regeneron Pharmaceuticals. S.M.H. declares no conflicts of interest. H.K.-S. declares no conflicts of interest. 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. E.L. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe. V.-F.M. is a member of the Children’s Tumor Foundation Clinical Care Advisory Board-Europe. M.M. declares no conflicts of interest. L.P. declares no conflicts of interest. L.M. directed the Medical Genomics Laboratory at University of Alabama, Birmingham, which specializes in genetic testing for all forms of the neurofibromatosis, until April 2021. 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, United States) and Europe; is cofounder of NFlection Therapeutics, Inc and NF2 Therapeutics, Inc; and is a consultant for Akouos, AstraZeneca, and SonALASense. V.R. declares no conflicts of interest. 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. M.J.S declares no conflicts of interest. A.S.-R. declares no conflicts of interest. D.A.S. is a consultant for Alexion Pharmaceuticals, Inc. N.J.U is a member of the Children’s Tumor Foundation Clinical Care Advisory Board, serves on the board of Neurofibromatosis Northeast, and received a consultant fee from Astra Zeneca. D.V. is a member of the Children’s Tumor Foundation Medical Advisory Committee and Clinical Care Advisory Board, is a member of the AstraZeneca speaker’s bureau, and is on the Sanofi-Genzyme—MPS Board of Advisors. K.W. declares no conflicts of interest. 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, is on the Scientific Advisory Board for iNFixion Bioscience, is member of the Programmatic Review Committee for the Department of Defense, Congressionally Directed Medical Research Program, and Neurofibromatosis Research Program.

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Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

Collaborators

Affiliations

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation

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Collaborators

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Abstract

Conflict of interest statement

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