what’s new in neurofibromatosis? dr sue huson, clinical lead, complex nf1 centre, manchester...

What’s new in Neurofibromatosis?

Dr Sue Huson, Clinical lead, Complex NF1 centre, Manchester Centre for

Genomic Medicine

What I will cover…

• NF1 and learning/behaviour in childhood• NF1 in adults new associations- glomus

tumours, breast cancer• NF1 and genetic testing• Progress on treatment- NF2 and avastin, NF1

and MEK inhibitors• Models of care for NF1

NF1: Natural History

MAJOR CAL CAL spots CAL spots

DEFINING spots (± freckles) (± freckles)

FEATURES only + + Lisch nodules

Lisch Nodules

+

Dermal NFs

BIRTH …. 5 years …. 15 years…. Adults

Brain tumoursAqueduct stenosisMoya MoyaPrecocious/delayed pubertyT2Hyperintencities (UBOs)Macrocephaly (often relaitive)Learning and behaviour issues (ADHD/ASD)

Optic gliomasLisch nodules

Women with NF1 have increased risk of Breast cancer<50 yers

Pectus Excavatum/CarinatumPulmonary stenosis

Glomus tumours in nailbeds

Low vitamin D levelsMay be 7-8 cms shorter than sibsOsteoporosisPseudarthrosisLimb overgrowth (usually with plexiform neurofibromas

Hyperextensible jointsFlat feet

Renal artery stenosisPhaeochromocytoma

ScoliosisSpinal neurofibromasDural ectasiaLateral meningocoeles

GISTsDuodenal carcinoid

Skin fold freckling

CAL patchesSkin and nerve neurofibromasPlexiform neurofibromasMPNSTs


• NF1 and learning/behaviour in childhood

• NF1 in adults new associations- glomus tumours, breast cancer

• NF1 and genetic testing• Progress on treatment- NF2 and avastin, NF1


Cognitive Development

• Majority of children with NF1 within the average range, but roughly 10 points lower•Between 6 and 7% of children with NF1 have IQ below 70 compared with 2% of general population

NB The vast majority of children with NF1 will NOT have global learning disabilities and IQ is not always a particularly meaningful measure for individuals

IQ - Intellectual Functioning

• Some evidence of lower scores on measures of expressive and receptive language– Mixed picture

• Speech production difficulties– Commonly reported in clinic, but not well researched

– Some studies indicate significantly higher involvement of SLTs than the general population

• Up to 65% children with NF1 impaired (>2 years behind chronological age) in at least one area of academic functioning (North et al, 1995)

• Difficulties in methodology lead to wide variations in frequency, but anecdotally one of the most commonly reported areas of concern for parents


Language

Academic Skills

• One of the most robustly established areas of difficulty for children with NF1 – Difficulties with judgements of lines

• Visuomotor integration problems– Eliason, 1986

• Not well researched, but frequently observed/reported clinically

• Related to visuo-spatial functioning

• Difficulties with gross and fine motor skills

• Difficulties with handwriting, clumsiness and poor co-ordination• Levine et al, 2006

• Biggest problem is working memory

• Visual memory tests seem to be more problematic than verbal memory


Visuospatial Functioning

Motor Control/Co-ordination

Memory

• Includes working memory, planning, organization, inhibitory processes, categorization, flexibility, rule deduction, and divided and sustained attention

• Difficulties even after accounting for IQ

• Well recognised area of difficulty for children with NF1

• High levels of ADHD – approx. half of NF population compared to 3-5% of general population (Garg et al, 2013)– Predominantly inattentive type

– Increasing evidence base relating to low doses of methylphenidate for children with NF1 and attention problems

• Difficulties with sustained and divided attention

• Anecdotal evidence that difficulties are not always identified because of the lack of hyperactivity (children being quiet in the back of the class but not attending)


Executive Functioning and Attention

• Children with NF1 have poorer social competence than typically developing children (Noll et al, 2007)

• Perceived by both teachers and peers as more sensitive and isolated, less well liked, having fewer reciprocal friendships, displaying less leadership behaviour – But not self report - children with NF1 did not

have lower self-ratings than children without NF1• IQ does not appear to account for these difficulties

Social Skills

Social Competence

Social Skills

• Autism Spectrum Disorder (ASD)– Triad of impairment

• Language and Communication

• Social and Emotional

• Flexibility of Thought – Imagination

– Population estimate of 25% of children with NF1 meet diagnostic criteria for ASD (Garg et al, 2013)

Autism

• Behaviour in part related to high rates of ADHD• Little research in some areas

– Sleep and feeding problems frequently reported clinically but little research• Children with NF1 generally under-report difficulties and over-estimate own abilities• Behavioural problems very frequently reported in clinic

• Not one thing you can put your finger on– She’s struggling but not the worst in the class– Combination of a number of complex needs (learning, behaviour, health, psychological

difficulties) but may be at sub threshold levels• What’s about the NF and what is about the social circumstances or other factors?

– Impossible to ever separate this out on individual basis!– A combination of factors – systemic assessment important

• It’s just the NF1– Dismissing concerns as just being about the NF1– Not assessing for ADHD or ASD etc

Behavioural Difficulties

Behaviour

Common Challenges

References

Eliason MJ. (1986) Neurofibromatosis: implications for learning and behavior. Journal of Developmental and Behavioral Pediatrics. 7: 175–9

Garg, S. Green, J. Leadmitter, K. Emsley, R. Lehtonen, A. Evans, DG. Huson, S. (2013) Neurofibromatosis Type 1 and Autism Spectrum Disorder. Pediatrics DOI:10.1542/peds.2013-1868

Hyman SL, Shores A, North KN. (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology; 65: 1037–44

Lehtonen A, Howie, E, Trump D, Huson, S (2012) Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence. Developmental Medicine and Child Neurology DOI: 10.1111/j.1469-8749.2012.04399.x

Levine TM, Materek A, Abel J, O’Donnell M, Cutting LE (2006) Cognitive profile of neurofibromatosis type 1. Seminars in Pediatric Neurology 2006; 13: 8–20

NICE (2006) NICE technology appraisal guidance 102: Parent-Training/Education Programmes in the Management of Children With Conduct Disorders. www.nice.org.uk

North K, Joy P, Yuille D, Cocks N, Hutchins P. (1995) Cognitive function and academic performance in children with neurofibromatosis type 1. Dev Med Child Neurol. 37: 427–36

Webster-Stratton, C. (2006) The Incredible Years: A trouble Shooting Guide for Parents of Children Aged 2-8. Seattle, WA; Incredible Years

Cell Synapse Brain Structure Intermediate Autism(Ras) / Function Phenotypes Phenotype

NFI

Autism

Idiopathic ASD highly heritable but genetically heterogeneous – up to 1000 candidate genes - identification of detailed neuropathology/neurophysiology has been challengingIncreasing interest in the study of known single gene models of ASD NF1 has well understood cell/neural system pathogenesis - and a potential associated intervention strategy Evidence linking RasMAPKinase intracellular signaling pathway with ASD generally (eg Parker 2012)

• Common genes associated with autism and Ras activity• Cortical Ras expression in ASD• Associated pathways in Frax/TSC/SLO

Why ASD and Neurofibromatosis Type 1? – perspective from ASD

Figure 5

The American Journal of Human Genetics DOI: (10.1016/j.ajhg.2014.03.018)

Genes affected by CNVs and SNVs in autism converge on neural system functional networks

Pinto et al., The American Journal of Human Genetics (2014),

8 months

Autism

Neural sensitivity (ERP) to gaze

Parent-infant interaction

Prodromal DevelopmentCollaboration: Johnson, Birkbeck

14 months

24 months

36 months

BASISBritish Autism Study of Infant Siblings (n>200)

Discovery of early intermediate phenotypes (IP)

Attention disengagement

Atypical behaviour

Prodromal InterventioniBASIS 9-14 months

Intervention as developmental experiment (Green and Dunn 2008)


• NF1 and learning/behaviour in childhood

• NF1 in adults new associations- glomus tumours, breast cancer



Glomus tumours

NF1 and breast cancer

• Women with NF1 have an increased risk of breast cancer compared with general population

• BUT only to age 50 years• NF1: 8% vs 1.5%• Encourage people to be ‘breast aware’• Annual mammograms 40-50 years



tumours, breast cancer



NF1: the role of Genetic Testing 1• Large gene with no mutation ‘hotspot’• DNA based techniques detect approx 85% cases;

improved to 95% using RNA based techniques• We now test all sporadic cases at presentation for

NF1 +/- SPRED1• As diagnosis obvious in many cases testing has not

been routine BUT should it be???• UKGTN advise testing organised through Clinical

Genetics • If gene test ‘normal’ and child has ≥6 CAL seek

specialist NF1 clinic opinion

NF1: genotypes and phenotypes

NF1 whole gene deletions - introduction

• 5% of unselected patients with NF1 (Cnossen 1997, Rasmussen 1998)

• Distinct phenotype – facial dysmorphism, learning difficulties, large number of dermal neurofibromas (Kayes 1994, Cnossen 1997)

• Usually a 1.5 Mb deletion between flanking NF1-REPS (type one); less commonly 1.3 Mb deletion (type two)

NF1 microdeletions

NF1 Microdeletions – Clinical features

Feature Frequency/comment

Dysmorphic facial features- hypertelorism, downslanting palpebral fissures, broad fleshy nose, ‘coarse’ face becoming more marked with age

26/29

Overgrowth with tall stature and large hands and feet

13/28)

Other dysmorphic features-- pectus excavatum - broad neck - excess soft tissue in hands and

feet

9/29 9/2912/24

Musculoskeletal features- Joint hyperflexibility - Muscular hypotonia - Bone cysts - Pes cavus

21/29 13/298/165/29 (only reported in Mautner series)

NF1 Microdeletions 2Neurofibroma burden -Dermal neurofibromas consistently

reported to occur at an earlier age and in increased numbers -Mautner et al report increased frequency of all types of neurofibroma compared with general NF1 population INCLUDING spinal neurofibromas

MPNST 6/29 ;de Raedt et al (2003) estimate double lifetime risk of general NF1 population

Learning and development -Significant delay in cognitive development 14/29 with IQ< 70 in 8/21(18)-Learning difficulties 13/29-Mean IQ lower than general NF1 population by 12.5 points (76 in microdeletions compared with 88.5; (Descheemaeker et al 2004)

Other features which may occur in excess

-Congenital heart disease-Scoliosis

NF1 SPINAL PHENOTYPE(Messiaen et al ASHG 2007)• Often <6CAL• No freckling• No dermal NFs• Few if any learning

problems• Excess splice and missense

mutations

Different kinds of neurofibromas associated

with prognosis

‘CAL only’ phenotypes

• In terms of clinical practice 95% of children with ≥ 6 CAL spots go on to develop NF1

• BUT some families reported with only CAL spots+/- skinfold freckling

• One family in literature linked to NF1 locus, two not

Exon 17 deletion and mild NF1 phenotype

• Identified through three large families with CAL only phenotype

• One large Manchester family initially shown to link to NF1 locus and two others (from Drs Haan and Turnpenny) all had same exon 17 p.990delM mutation

• Distinguishing features: no cutaneous neurofibromas, ‘bred true’, very few other disease complications

• Review of previously tested patients in Cardiff and contact with other NF1 labs identified 8 further families and 7 sporadic cases with same GT/PT

Mutations at p.Arg1908Cys also protect from neurofibromas

• Messiaen et al, European NF conference 2014

• 90 probands and 24 relatives with one of four missense mutations in p.Arg1908Cys

• No neurofibromas• Do have learning problems, Noonan

features

AD CAL spots only: another locus

• Brems et al (2007) identified SPRED1 mutations as another cause of AD CAL only- ‘NF1-like phenotype’

• Within Belgium’s largest NF clinic identified five families with CAL spots, axillary freckling,macrocephaly and Noonan-like facies in some individuals

• No NF1 mutations • Two largest families mapped to

12.25 Mb region on 15q

Neuro-cardio-facial-cutaneous syndromes and the RAS-MAPK pathway

Figure from Denayer et al, J Med Genet, 2008

• Screened a panel of 86 samples with CAL only,

7/86 had SPRED1 mutations

Recognising Legius syndrome

• NO Lisch nodules or neurofibromas• Older family members need testing even if only have

one or two CAL• Most CAL typical • ?Freckling may be unilateral even in adults-French

series 13/18 freckling and unilateral in axilla+/- groins in 7/13

• Although macrocephaly featured in original paper only 2/30 in UK/French series

• Dysmorphic facies unusual

Recognising Legius syndrome 2

• Learning and behavioural problems similar but less frequent than in NF1

• BUT neurocognitive impairments in SPRED1-/- and +/- mice mimic those in NF1 +/- mice (Denayer et al, J Neurosci, 2008)

• No other typical NF1 complications BUT need to record prospectively: one patient with Wilms, one with Acute monoblastic leukaemia

• 1% of children and no FH with CAL only will have Legius and approx 20% of those with FH

NF1 and at risk children

• Traditional approach for children at 50% risk: Paediatrician aware at birth, although VERY unusual

to see CAL at birth unless Asian/black family; complications at birth also extremely rare

Offer review at 3 months, 1 year, 2 years and 5 years and eye checks

• NOW: Check mutation in affected parent Test cord blood at birth

NF1 and genetic counselling

• Risk to children 50:50• Risk of severe NF1 one in twelve BUT no tests

to predict• Many couples opt to ‘take the risk’• Preimplantation genetic diagnosis• In Pregnancy: chorionic villous sample at 11

weeks OR looking at baby’s DNA in Mother’s blood (the future…)



tumours, breast cancer• NF1 and genetic testing

• Progress on treatment- NF2 and avastin, NF1 and MEK inhibitors

• Models of care for NF1

Avastin- English approach

• Drug company had no interest in trial• Commissioners and service agreed a national

protocol with strict treatment criteria and standardised follow-up

• Patients treated 2011 onwards

ImagingRight Ear

Pre Avastin 3 Days Post Avastin 3 Months Post Avastin

Pre Avastin 3 Days Post Avastin

3 Months Post Avastin

Volume (cm3) 6.5 6.4 5.6

a

dc

b

Avastin summary 2015

• 61 patients • 90% had growth stabilisation,

39% volume response• Hearing was maintained or

improved in 86% of patients with some hearing at the start of treatment

• BUT tumours regrow when stopped

• Improved patient reported QOL

NFPC

Dermal Neuroibroma Plexiform

Neurofibroma

MPNST

JMML & MPN

Meningioma

Mesothelioma

Optic Glioma

Schwannoma

Ohio State University Brad Welling Long-Sheng Chang

Indiana University Wade Clapp

CCHMC Nancy RatnerTim Cripe

UCSF: Kevin ShannonBenjamin Braun

Harvard/BWHKaren Cichowski

Mass. General HospitalAndrea McClatchey

UT Southwestern Lu Le

Fox Chase Cancer Center Johnathan Chernoff

Joe Testa

House Research Institute Marco Giovannini

Washington Univ.David Gutmann

MEK inhibition: Widemann et al



tumours, breast cancer• NF1 and genetic testing• Progress on treatment- NF2 and avastin, NF1

and MEK inhibitors

• Models of care for NF1

‘Most diseases will unfold in a certain way – slower or faster. With NF1, because the symptoms are so unpredictable and variable, you don’t know whether there will be symptoms, what they might be, or if they will be serious. You never get your balance or equilibrium how to deal with them. After one thing appears and you deal with it, here comes another. It is not just that there are big and little fires, there is always the worrying sign up that says ‘Danger of Fire’. The psychological burden is always there, regardless of the extent of the physical problems…..’

Ablon (1992)

LOCAL CLINIC:CHILDREN WITH NF1

GP:ADULTS WITH NF1

REGULAR DISEASE MONITORING, LOCAL REFERRAL FOR FREQUENT COMPLICATIONS

NEUROFIBROMATOSIS CLINIC:SEVERE NF1 ALL

AGES; ALL AGED 16-25yrs

SCIENTIFIC COLLABORATORS

Unusual cases

rare/severe

complications

patients keen

to help with

research

CLINICAL

PSYCHOLOGIST

ENDOCRIN-

OLOGIST

GENETICIST

NEUROLOGIST

Regular updates re:

assessment protocol

new disease entities

research developments

NEUROSURGEON

ONCOLOGIST

OPHTHALMOLOGIST

ORTHOPAEDIC

SURGEON

OTOLARYNGOLOGIST

PLASTIC SURGEON

Personal Health Record

PATIENTS KNOW BEST

What skills do NFologists have?

• Through a thorough knowledge of natural history able to REASSURE appropriately

• Able to interpret symptoms in NF1 according to age of patient

• Act as coordinator of care and sign post patients to relevant specialists

• Recognise atypical variants

Complex NF1 service- MDT out patient review

• Funded for diagnosis and management advice• Multidisciplinary team • Named Adult/Paediatric Neurologist and

Neurosurgeon, Plastic surgeons, Sarcoma oncology, Ophthalmology

• Clinical Nurse specialists, Psychologists and play therapy

• Northern service does regional clinics at Alderhey (Dr Bassi), Leeds (Dr Dobbie), Sheffield (Mr Carrol) and Newcastle (Dr Splitt)

Complex NF1 – referral indicators

• Possible/previous MPNST• Optic Nerve Glioma• NF1 major neurological complications• Multiple spinal root neurofibromas• Complex plexiforms• Pseudarthrosis• Atypical phenotype• Segmental NF1 counselling

Pharmacy

Pharmacies

Secondary care/Hospital Community teams

Employers

Relatives

GP

Charities & Patient Advocacy Groups

Government & Commissioning bodies

Researchers

Social services

Mobile device and app developers

Patient

Primary care services

Specialist services

THE PROBLEM

Hospital services

GP

‘New’ ways to empower the patient gives them access to lots of information in lots of places

Fundamentally flawed:

• The patient doesn’t own the data

• Often read-only

• Tied to an organisation or a software provider

• Multiple sites, multiple logins

• Patient can’t share information with anyone else

TRADITIONAL PATIENT PORTALS – THE SOLUTION?

Apps and devices

= EVEN MORE FRAGMENTATION OF INFORMATION

Pharmaceuticals

Pharmacies

Secondary care/hospitals

Primary care health services

Employers

Relatives

GP

Charities & Patient Advocacy Groups

Government & Commissioning bodies

Researchers

Mobile device and app developers

Community teams

Specialist services

Social services

THE SOLUTION

ABOUT PATIENTS KNOW BEST

WHAT YOU CAN DO WITH A PATIENT-CONTROLLED RECORD

• Send messages, letters, appointments and reports • Contact and message the patient or other

professionals• Web video consultations and remote appointments or

follow-ups

• Lab results all in one place• Track symptoms and be alerted• See measurements from a variety of sources,

including wearables and other devices

• Care plans for self-management

• Surveys completed remotely• Medications• Calendar of upcoming

appointments• Images, genetics and

diagnoses

1) Irish Hospice Foundation

2) Community setting in Ireland led by primary care (Dr Brendan O’Shea) in Kildare

3) Hospital setting in Ireland at St James Hospital, Dublin, and the Mercer’s Institute for Successful Ageing

4) EPaCCS templates available, working with UK hospices

Helping prevent unplanned admissions, unnecessary transportation and appointments

PALLIATIVE CARE WITH PKB

With many thanks to…

• Prof Gareth Evans (national NF2 lead)• Prof Ros Ferner (national complex NF1 lead)• Complex NF1 and NF2 teams in Manchester• PKB- especially Lloyd Humphries and

Mohammad Al-Ubaydli

what’s new in neurofibromatosis? dr sue huson, clinical lead, complex nf1 centre, manchester...

Documents

nf1 difficulties

attention children

children noll et

complex nf1 centre

self report children

lack of hyperactivity

asd garg et

general population garg