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Revision of Diagnostic Criteria for Neurofibromatosis

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Revision of Diagnostic Criteria for Neurofibromatosis Revision of Diagnostic Criteria for Neurofibromatosis Gareth Evans, MD, St. Mary’s Hospital/University of Manchester, UK Susan Huson, MD, Consultant Geneticist, UK Eric Legius, MD, PhD, University of Leuven, Belgium Ludwine Messiaen, PhD, University of AlaBama, Birmingham, USA Scott Plotkin, MD, PhD, Massachusetts General Hospital, USA Pierre Wolkenstein, MD, PhD, Hôpital Henri-Mondor, France 2019 NF Conference San Francisco, CA September 21, 2019 Revision of the Diagnostic Criteria of the Neurofibromatoses 92 medical specialists 20 countries 5 continents We want your feedback! Send email to: [email protected] Participants in revision process: Leadership team Clinical Epidemiology Health Services Research: Ophthalmology: • Gareth Evans • Nilton Rezende • Vanessa Merker • Robert Avery • Sue Huson • Catherine Cassiman • Eric Legius Clinical Genetics: Internal Medicine: Pathology: • Ludwine Messiaen • Dorothy Halliday • Luiz Oswaldo Carneiro • Karin Cunha • Scott Plotkin • Maurizio Clementi Rodrigues • Anat Stemmer-Rachamimov • Pierre Wolkenstein • Arvid Heiberg • Patrice Pancza • Joanne Ngeow Scientists: Pediatrics: • Shay Ben-Schachar • Miriam Smith • Outside Experts: • Bruce Korf • Marco Giovannini Rianne Oostenbrink • • Monique Anten • Mimi Berman • Eduard Serra Robert Listernick • Jaan Toelen • Betty Schorry • Juha Peltonen Pediatric Hematology and • Arthur Aylsworth • Gareth Evans Oncology: • Meredith Wilson • Ignacio Blanco Molecular Genetics: • Michael Fisher • Helen Hanson • Dusica Babovic-Vuksanovic •Laura Papi • Christopher Moertel • Daniela Kroshinsky • Kate Rauen •Ludwine Messiaen • Ali Varan • Pascal Joly • Jan Friedman •Meena Upadhyaya • • Conor Mallucci • David Viskochil •Hildegard Kehrer-Sawatzki Matthias KaraJanis • Roger Packer • Fred Barker, II • David Stevenson •Katharina Wimmer • • Diana Baralle • Eric Legius •Conxi Lazaro Kaleb Yohay • Verena Steinke-Lange • Sue Huson Pediatric Neurology: • Theirry Frebourg Neurology: • David Gutmann • Bruce Poppe Dermatology: • Rosalie Ferner • Mia MacCollin • Gianluca Tadini • Oliver Hanemann • Tena Rosser • Pierre Wolkenstein • Victor Mautner • Martino Ruggieri • Sebestien Barbarot • Allyson Parry • • Lu Le Nicole Ullrich • • Didier Bessis Neuro-Oncology: James Tonsgard • Dominique Pichard • Jaishri Blakeley Pediatric Neuroradiologist: • Siirku Peltonen • Justin Jordan • Stavros Stivaros • Scott Plotkin Genetic Counselor: • Amanda Bergner Neuro-Surgery: • Amy Mueller • Michel Kalamarides • Amy Taylor • Michael Link • Alicia Gomes • Hao Wu • Zadeh Gelerah • Patricia Caviarelli Rationale for revising the diagnostic criteria • No updates since criteria were established during NIH Consensus Conference in 1987 • Current criteria were established prior to • Recognition of schwannomatosis as distinct from NF2 • Discovery of the genes that cause NF1, NF2, and schwannomatosis • Ability to perform genetic testing • New clinical information about NF1, NF2, and schwannomatosis • To clarify historical confusion between NF1 and NF2 Guiding principles for the revision process • Ideally, revised diagnostic criteria would: • Accurately and clearly delineate among NF1, NF2, and schwannomatosis • Represent best consensus among NF experts • Reflect input from patients, families, and foundations • Exclusively address issues of diagnosis (rather than clinical management) • Be broadly representative of medical specialties and national groups • Usable by general doctors as well as NF specialists • Recognize advances in genetics over last 30 years without requiring genetic analysis for diagnosis • Be acceptable in different countries and health care systems, now and in the coming years Milestones for revising the diagnostic criteria Planning revision process Creating first draft of revised criteria June 2018 May 2018 November 2017 Revision 4 workshop in NYC June 2017 Guiding First expert 3 Delphi 2 principles of ▪ Experts meet in revision process ▪ Working groups in person to review NF Conference ▪ Leadership team 1 NF1, NF2, SWN, Delphi results formulates guiding genetics proposed ▪ Working groups ▪ NF clinicians and principles of revision changes to existing present revised investigators process diagnostic criteria criteria recognize need to ▪ Choose Delphi ▪ Leadership team ▪ Expert debate revise diagnostic process to manage created a proposed criteria criteria at the annual consensus process questionnaire based ▪ After conference, CTF meeting ▪ Key areas: NF1, on continued discussion ▪ CTF agrees to support Legius, NF2, SWN, recommendations among working the revision process mosaicism ▪ Used Delphi method groups ▪ Formation of ▪ Goals: To clarify to analyze leadership team wording, to include agreement among molecular biology, to 70 international NF add new suggested experts criteria Milestones for revising the diagnostic criteria Creating second draft of revised criteria Creating third draft of revised criteria June 2019 May 2019 November 2018 Patient and family October 2018 Expert feedback 8 engagement (US) (non-NF Joint Global 7 ▪ Present criteria Neurofibromatosis specialists) developed by 6 Meeting (Paris) Second expert ▪ Present revised international experts Delphi to patients, families, 5 ▪ Present draft criteria to international experts and foundations recommendations for ▪ Questionnaire to who do not focus on ▪ Solicit feedback on revised criteria to the NF changes and assess consensus international ▪ Goal: assess ability implications of these regarding revised community of non-NF experts to changes criteria ▪ Solicit feedback from use revised criteria ▪ In preparation for attendees ▪ Incorporate ▪ Presentation available worldwide recommendations into criteria for comment from patients, foundations ▪ Incorporate suggestions into next version of criteria Milestones for revising the diagnostic criteria Creating third draft of revised criteria 2020 Future plans January 2020 Dissemination September 2019 of revised Submit/publish 12 criteria July 2019 11 manuscripts NF Conference ▪ To patients and Patient and family 10 ▪ Publish revised families with help of 9 engagement criteria in high profile NF foundations (Europe and US) ▪ Present FINAL journal ▪ To NF physicians who recommendations at attend NF Conference ▪ July 5 – Europe the 2019 NF ▪ To non-NF physicians ▪ July 17- USA Conference through Continuing ▪ Present criteria Medical Education developed by ▪ To the Department of international experts Defense, NIH, and to patients, families, other funding and foundations agencies ▪ Solicit feedback on ▪ Continued refinement changes and of diagnostic criteria implications of these changes Current NF1 Diagnostic criteria Developed in 1987 at NIH Café-au-lait Skin fold macule Freckling Two or more of the following manifestations: (1) ³ 6 CAL macules – > 5mm if prepubertal > 15mm if postpubertal (2) axillary or inguinal freckling (armpit or groin freckling) Optic pathway Osseous lesion glioma (3) ³ 2 neurofibromas of any type or 1 plexiform neurofibroma (4) optic glioma (5) ³ 2 Lisch nodules (6) distinctive osseous lesions such as sphenoid dysplasia or thinning of long bone cortex with/without pseudarthrosis Cutaneous NF Lisch nodules (7) affected first degree relative by 1-6 Recommended changes (in blue) NF1 criteria Two or more of the following manifestations: • Six or more café-au-lait spots • greater than 5 mm in prepubertal children • greater than 15 mm in postpubertal children. • Bilateral freckles in axilla or groin (clarification of existing criterion) • Two or more neurofibromas of any type or one plexiform neurofibroma • Two or more iris Lisch nodules or two or more choroidal abnormalities (CAs) (addition to existing criteria) • Optic pathway glioma • A distinctive osseous lesion such as: sphenoid wing dysplasia; anterolateral bowing of tibia (tibial dysplasia); or pseudarthrosis of a long bone (clarification of existing criterion) • A pathogenic NF1 variant (addition to existing criteria) • A parent with NF1 by the above criteria (clarification of existing criterion) Clarified criteria: bilateral freckles Unaffected Affected Unilateral freckling raises concern for mosaic NF1, a form of NF1 in which only some cells in the body are affected by the pathogenic NF1 variant Modified criteria: choroidal abnormalities (CA) • Two or more iris Lisch nodules or two or more CAs Viola et al., 2012 Choroid Retina Choroid Retina Additional Considerations: 1) If Lisch nodules are present, no advantage to obtaining optical coherence tomography (OCT) for choroidal abnormalities. 2) OCT assessment for CA’s should be limited to cases of diagnostic uncertainty and where OCT can be easily obtained in the outpatient clinic (i.e., without sedation/anesthesia) Clarified criteria: distinctive osseous lesions sphenoid wing dysplasia anterolateral bowing of tibia pseudarthrosis of a (tibial dysplasia) long bone Pathogenic NF1 heterozygous variant • Pathogenic variant = “mutation” • The term “mutation” is no longer accepted in genetics • Genetic analysis is used in some clinical practices for diagnosis. In the US, there is wide variation in insurance coverage for genetic analysis • 95% support among NF experts for adding genetic analysis to criteria • Genetic analysis is highly sensitive to identify pathogenic variants associated with NF1 (90%) • Note: Genetic analysis is not REQUIRED for diagnosis but will allow for an earlier diagnosis in many cases. • Note: Genetic analysis ALONE will not be sufficient to diagnose NF1 (diagnosis will also require a diagnostic feature of NF1) • DNA variants
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