Revision of Diagnostic Criteria for

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: : • Gareth Evans • Nilton Rezende • Vanessa Merker • Robert Avery • Sue Huson • Catherine Cassiman • Eric Legius Clinical Genetics: Internal : : • 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: : • 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 and • Arthur Aylsworth • Gareth Evans : • 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 : • Theirry Frebourg Neurology: • David Gutmann • Bruce Poppe : • 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-: • 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 who recommendations at attend NF Conference ▪ July 5 – Europe the 2019 NF ▪ To non-NF physicians ▪ July 17- USA Conference through Continuing ▪ Present criteria 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 of any type or 1 plexiform

(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 can be silent or cause disease (and it is often difficult to know with certainty for a given patient) Genetics in Medicine 17(5):405-424, 2015 Schwannomatosis and NF2 Neurofibromatosis type 2 Current Manchester diagnostic criteria

Must meet one of the following criteria: 1. Bilateral vestibular (VS) 2. First-degree relative with NF2 AND unilateral VS 3. First-degree relative with NF2 OR unilateral VS AND two of: • meningioma, cataract, glioma, neurofibroma • , cerebral calcification 4. Multiple meningioma (2 or more) AND two of: • unilateral VS, cataract, glioma, neurofibroma, schwannoma, cerebral calcification

Evans et al Quart J Med 1992 Limitations of Manchester criteria in 2019

• Recent studies demonstrate significant overlap in features of NF2 and schwannomatosis. • 9% of patients with clinical diagnosis of schwannomatosis actually have NF2 upon genetic analysis • 1-2% of patients with clinical diagnosis of NF2 actually have schwannomatosis upon genetic analysis • Bilateral vestibular schwannomas in patients over age 50 can be related to NF2 or to chance • High grade glioma is not a feature of NF2 • Neurofibromas are not a feature of NF2

Evans et al J Med Genet 2015 Evans et al, Neurology 2017 King et al., Neurosurg, 2017 Evans et al., J Neurol Neurosurg Psych, 2018 Current diagnostic criteria for schwannomatosis Developed in 2011

Clinical diagnosis Molecular diagnosis • Two or more non-intradermal • Two or more pathologically schwannomas, one with pathological proved schwannomas or confirmation, including no bilateral vestibular schwannoma by high- meningiomas AND genetic quality MRI. studies of at least two tumors • One pathologically confirmed with LOH for chromosome 22 schwannoma or intracranial and two different NF2 meningioma AND affected first- mutations; if there is a degree relative common SMARCB1 mutation, • Consider as possible diagnosis if this defines SMARCB1- there are two or more non- associated schwannomatosis intradermal tumors but none has been pathologically proven to be a • One pathologically proved schwannoma; the occurrence of schwannoma or meningioma chronic pain in association with the AND germline SMARCB1 tumor(s) increase the likelihood of schwannomatosis pathogenic mutation

Plotkin et al, Am J Med Genet, 2011 Limitations of the 2011 schwannomatosis criteria • Significant overlap in features of schwannomatosis with mosaic NF2 patients • No mention of LZTR1 gene or other genetic features • Does not account for new form of nerve sheath tumor (hybrid nerve sheath tumor à WHO 2016 version)

• Conclusion à consider renaming NF2 and schwannomatosis

Plotkin et al, Am J Med Genet, 2011 Pros for grouping NF2/schwannomatosis together under a new name • Reduce misdiagnosis of NF2 and schwannomatosis patients as “neurofibromatosis” (which is assumed to be NF1) • Facilitate clinical care guidelines and direct clinical care more appropriately • Clinicians believe it is clinically and scientifically appropriate given that neurofibromas don’t occur in NF2 patients • Acknowledges the clinical overlap between NF2 and schwannomatosis • Emphasizes molecular diagnosis and allows for discovery of additional schwannoma genes • Industry already recognizes NF and schwannomatosis; this moves NF2 to the “correct” category • We successfully changed names before (in 1997): • von Recklinghausen/peripheral neurofibromatosis àNF1 • Central neurofibromatosis à NF2 Cons for grouping NF2/schwannomatosis together under a new name • Recognize it will be emotionally difficult for patients and families living with NF2 • Challenging for organizations with “NF” in their names • Possible negative impact on funding efforts • Requires education of consumers, providers, funding agencies, etc. • Splits NF2/schwannomatosis into even more rare categories • Diverts effort and energy from more important issues • Confuses the literature • Billing codes would lag DOD Funding for Research

• The Congressional Appropriations language for the NFRP has not in the past specifically defined Neurofibromatosis. • Research funded under the NFRP are determined based on recommendations of the experts in the field both at peer review and programmatic review. • The Programmatic Panel consists of clinicians, patient advocates and researchers from the NF community and on an annual basis they recommend a strategy for the program considering factors such as the current state of the science and gaps in research. • In absence of specific Congressional language, any change in the diagnostic criteria and or definition of NF, as long as it is accepted by the community will be reflected in the NFRP based on the recommendations of the Panel. • For example, when schwannomatosis, was called out from NF2, the NFRP also accepted this consensus. Naming options so far…..

Option 1a: Option 2: • Neurofibromatosis • Neurofibromatosis syndrome • Schwannoma predisposition (NF) syndromes (SPS) • syndrome (MER) • Merlin-SPS • Schwannomatosis syndrome • SMARCB1-SPS (SWN) • LZTR1-SPS • SMARCB1-SWN • 22q-SPS • LZTR1-SPS-SWN • SPS-NOS • 22q-SWN

Option 1b: Option 1 • Neurofibromatosis • Emphasizes clinical overlap • Schwannoma predisposition between NF2 and SWN syndromes (SPS Option 2 • NF2-SPS • Retains separation between • SMARCB1-SPS NF2 and SWN to allow for • LZTR1-SPS unique names • 22q-SPS • SPS-NOS Schwannoma Predisposition Syndromes (SPS) • Proposed umbrella term for both NF2 and schwannomatosis since they share a genetic predisposition for schwannoma formation • Molecular analysis is clinically indicated for all patients suspected to have SPS (except for those with bilateral vestibular schwannoma). • Classify type of SPS according to pathogenic gene variant (e.g., NF2, SMARCB1, LZTR1, not found) Recommended changes (in blue) NF2 criteria (now called MERLIN-SPS or Merlin syndrome) A diagnosis of SPS-MERLIN (previously termed neurofibromatosis 2/NF2) can be made when a patient has one of the following: 1. Bilateral vestibular schwannoma (VS) 2. An identical NF2 pathogenic variant in at least two anatomically distinct NF2 related tumors (schwannoma, meningioma and/or ependymoma). (addition)

OR when either two Major OR one Major and two Minor criteria as follows: (clarification)

Major criteria: • Unilateral VS • First degree relative other than sibling with SPS-MERLIN (clarification) • 2 or more meningiomas. Note: single meningioma qualifies as minor criteria. • NF2 pathogenic variant# in an unaffected tissue such as blood (when the variant is present at significantly less than 50% this confirms mosaicism) (addition)

Minor criteria: can count more than one of a type (e.g. two schwannomas) • Ependymoma; Schwannoma (require at least one dermal if major criterion is unilateral VS) (clarification – removed neurofibroma, glioma) can count only once • Juvenile subcapsular or cortical cataract; Retinal hamartoma; Epiretinal membrane aged less than 40 years (clarification), meningioma #if a likely pathogenic variant is identified tumor analysis may aid upward classification Additional criteria: NF2 heterozygous pathogenic variant

• Genetic analysis is sensitive: able to identify pathogenic NF2 variants in blood in 66%-90% of individuals • Note: Genetic analysis is not REQUIRED for diagnosis. It will be possible to diagnose NF2 based on clinical criteria without genetic analysis • Note: Genetic analysis ALONE will not be sufficient to diagnose NF2 (diagnosis will also require a diagnostic feature of NF2 or a family history of NF2) Clarified criteria: removing sibling from family history

• Remove sibling with no affected parent from qualification as first-degree relative. • RATIONALE: By removing “sibling”, we will avoid over- diagnosing somebody with a sporadic (non-NF2) tumor. Clarified criteria: cataracts

• : “Cataract” will be refined to “juvenile cortical wedge cataract” or “presenile posterior lenticular opacity.” • RATIONALE: Age-related cataracts (over age 40) are not associated with NF2. By modifying this language, we can minimize confusion surrounding the presence of cataracts in the diagnosis. Additional criteria: retinal hamartoma

• The presence of retinal hamartoma should be included as a criterion for diagnosis of NF2. Macula • RATIONALE: Diagnosis of children with NF2 remains a challenge. Children with NF2 are less likely to present with symptoms referable to a vestibular schwannoma and more likely to present with ophthalmologic findings. Clarified criteria: Replace glioma with ependymoma

• The term “glioma” will be updated to specify “ependymoma” • RATIONALE: Ependymomas are relatively common in NF2 patients. In contrast, other types of glioma are rare or unreported (including especially high-grade glioma). Clarified criteria: remove neurofibroma from criteria

• The feature “neurofibroma” will be removed from the diagnostic criteria. • RATIONALE: True neurofibromas are rare in the setting of NF2. Thus, use of this tumor type in diagnosis may lead to more confusion among clinicians. There are still many pathologists who report ‘neurofibroma’ when it is a schwannoma Updated criteria for SMARCB1-SPS

• Previously classified as “schwannomatosis with SMARCB1 mutation” • A diagnosis of SMARCB1-SPS can be made when a patient meets one of the following criteria: • At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND a SMARCB1 pathogenic variant in an unaffected tissue such as blood. • A common SMARCB1 pathogenic variant in two schwannomas or hybrid nerve sheath tumors. E2 E3 SMARCB1-associated schwannomatosis

SMARCB1 SMARCB1

E1 Somatic; NF2 – Tumor 1 Mut A Inactivation both NF2 Deletion A copies 22q

SMARCB1

E2 E3

Somatic: Tumor 2

Germline SMARCB1 SMARCB1 or Somatic (mosaic SCH) NF2 – Mut B Inactivation both NF2 Deletion B copies 22q

Courtesy of Ludwine Messiaen, PhD Molecular signature of SMARCB1-SPS

Tumor 1 Tumor 2 Comment SMARCB1 Allele 1 Mut1 Mut1 Common SMARCB1 pathogenic variant Allele 2 LOH LOH Tumor-specific partial loss of 22q in trans position NF2 Allele 1 Mut2 Mut3 Tumor-specific pathogenic NF2 variant in cis to pathogenic SMARCB1 variant Allele 2 LOH LOH Tumor-specific partial loss of 22q in trans position

Abbreviations: Mut 1 = mutation 1; Mut2 = mutation 2; Mut3 = mutation 3; LOH = loss of heterozygosity (commonly an event encompassing LZTR1-SMARCB1- NF2) Updated criteria for LZTR1-SPS

• Previously classified as “schwannomatosis with LZTR1 mutation” • A diagnosis of SPS-LZTR1 can be made when a patient meets one of the following criteria: • At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND an LZTR1 pathogenic variant in an unaffected tissue such as blood. • A common LZTR1 pathogenic variant in two anatomically distinct tumors . E2 E3 LZTR1-associated schwannomatosis

LZTR1 LZTR1

E1 Somatic; NF2 – Tumor 1 Mut A Inactivation both NF2 Deletion A copies 22q

LZTR1

E2 E3

Somatic: Tumor 2

Germline LZTR1 LZTR1 or Somatic (mosaic SCH) NF2 – Mut B Inactivation both NF2 Deletion B copies 22q

Courtesy of Ludwine Messiaen, PhD Molecular signature of LZTR1-SPS

Tumor 1 Tumor 2 Comment LZTR1 Allele 1 Mut1 Mut1 Common LZTR1 pathogenic variant Allele 2 LOH LOH Tumor-specific partial loss of 22q in trans position NF2 Allele 1 Mut2 Mut3 Tumor-specific NF2 pathogenic variant in cis to LZTR1 pathogenic variant Allele 2 LOH LOH Tumor-specific partial loss of 22q in trans position

Abbreviations: Mut 1 = mutation 1; Mut2 = mutation 2; Mut3 = mutation 3; LOH = loss of heterozygosity (commonly deletion spanning region encompassing LZTR1-SMARCB1-NF2) Updated criteria for 22q-SPS

• Previously classified as “schwannomatosis without identified mutation in blood” • A diagnosis of SPS-22q can be made when a patient does not meet criteria for MERLIN-SPS, SMARCB1-SPS or LTZR1-SPS and has both molecular features: • LOH of the same chromosome 22q markers in two anatomically distinct schwannomas or hybrid nerve sheath tumors AND • A different NF2 pathogenic variant in each tumor which cannot be detected in unaffected tissue. E2 E3 22q-associated schwannomatosis

?? ??

E1 Somatic; NF2 – Tumor 1 Mut A Inactivation both NF2 Deletion A copies 22q

?? E2 E3

Somatic: Tumor 2

Germline ?? ?? or Somatic (mosaic SCH) NF2 – Mut B Inactivation both NF2 Deletion B copies 22q

Courtesy of Ludwine Messiaen, PhD Molecular signature for 22q-SPS

Tumor 1 Tumor 2 Comment SMARCB1/ LZTR1 Allele 1 none none No common pathogenic LZTR1 or SMARCB1 found found variant Allele 2 LOH LOH Tumor-specific partial loss of the same chromosome 22q NF2 Allele 1 Mut1 Mut2 tumor-specific pathogenic NF2 variant trans to the 22q del Allele 2 LOH LOH Tumor-specific partial loss of the same chromosome 22q , a single somatic event results in LOH of LZTR1-SMARCB1-NF2

Abbreviations: NF = not found; Mut1 = mutation 1; Mut2 = mutation 2; LOH = loss of heterozygosity Recommended criteria for SPS-Not Otherwise Specified (NOS)

• Previously classified as “schwannomatosis” • If genetic testing was not performed, is not available, or did not reveal a pathogenic variant, a diagnosis of SPS-NOS can be made if the following criteria are met: • Presence of two or more lesions on appropriate imaging consistent with non-intradermal schwannomas • At least one schwannoma is pathologically confirmed Genetic analysis for SPS

• Background: Genes involved with schwannomatosis not fully understood. • Important difference: Genetic analysis is REQUIRED for diagnosis of specific type of SPS (except for SPS-Merlin). It will NOT be possible to diagnose type of SPS based on clinical criteria alone. • Important reminder: Genetic analysis ALONE will not be sufficient to diagnose SPS (diagnosis will also require a clinical feature of SPS like schwannoma) Dropped criteria for schwannomatosis • “Possible diagnosis” category in the current criteria in favor of a Not Otherwise Specified (NOS) category in the new criteria. • “Fulfill diagnostic criteria for NF2” from a list of exclusion criteria for schwannomatosis. This decision reflects the considerable overlap between NF2 and Schwannomatosis. • “Intracranial meningioma” from the old criteria: “One pathologically confirmed schwannoma or intracranial meningioma AND affected first-degree relative.” The goal is to avoid overdiagnosis of older family members who may have an incidental meningioma. Additional criteria for schwannomatosis

• Add the requirement of “clinical evidence of a schwannoma” for individuals with evidence of a pathogenic variant in SMARCB1 or LZTR1 in unaffected tissue. Alteration of existing criteria

• Agreed to use of hybrid nerve sheath tumor for diagnosis of schwannomatosis in the setting of compatible molecular findings. Mosaicism

• Important for counseling of transmission and recurrence risk • General definition: individual composed of ≥2 genetically different cell populations/ lineages derived from the same zygote • gonadal, somatic, gonadosomal

• NF1: 5-10%; NF2: ~30%; SMARCB1/LZTR1: unknown • Significant phenotypic overlap (mosaic) NF2 and schwannomatosis

Referred by B. Korf Mosaicism: Awareness must increase and mosaicism should be discussed in the text accompanying the diagnostic criteria

• Mosaicism confirmed by either of following: • Significantly lower than 50% pathogenic variant in clinically unaffected tissue (e.g. NGS <35% variant allele frequency, VAF, in blood) à mosaicism • Pathogenic variant not detected in clinically unaffected tissue but common pathogenic variant in ≥2 anatomically unrelated affected lesions = mosaic disorder

* Lab must define and report criteria for orthologous confirmation of heterozygous versus “mosaicism” Next steps

• September 2019: Solicit feedback from community • October 2019: Writing committee generate draft manuscript • January 2020: Target date to submit manuscripts • 2020: dissemination plan to clinicians and patients Acknowledgements

• Children’s Tumor Foundation • Patrice Pancza • Participants of Delphi and other colleagues Questions? Confronting the NEJM image challenge: Improving patient care by reducing misdiagnosis

NEJM Image Challenge October 4, 2018 Why so much confusion between NF1 and NF2? A brief history • First probable case report of neurofibromatosis type 2 by Wishart in 1820 • Multiple intracranial tumours with no reported skin features • Different from patients reported by von Recklinghausen in 1882 • 1910-1920: authors reported cases of NF1 with intracranial tumours and NF2 with cutaneous features • Two conditions became lumped together and referred to as von Recklinghausen disease, or multiple neurofibromatosis • 1930: Gardner and Frazier suggested that bilateral acoustic neuromas represented a separate central form of von Recklinghausen neurofibromatosis • Subsequent reports did not follow this suggested subclassification • 5% of patients with what they called multiple neurofibromatosis had acoustic neuromas. In retrospect it is clear these patients had neurofibromatosis type 2 Why do doctors and patients confuse NF1 and NF2? A brief history • 1971: follow-up study again concluded that the disorder was distinct from that described by von Recklinghausen, and suggested that it should be called central neurofibromatosis • Acceptance of the two types of neurofibromatosis • 1987: name change based on NIH Consensus Conference • Neurofibromatosis type 1 rather than peripheral or von Recklinghausen neurofibromatosis • Neurofibromatosis type 2 rather than central or bilateral acoustic neurofibromatosis