Transcript What`s new in Neurofibromatosis? - GER-NF

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
Optic gliomas
Lisch nodules
Scoliosis
Spinal neurofibromas
Dural ectasia
Lateral meningocoeles
Brain tumours
Aqueduct stenosis
Moya Moya
Precocious/delayed puberty
T2Hyperintencities (UBOs)
Macrocephaly (often relaitive)
Learning and behaviour issues
(ADHD/ASD)
Skin fold freckling
Pectus
Excavatum/Carinatum
Pulmonary stenosis
Women with NF1 have
increased risk of Breast
cancer<50 yers
GISTs
Duodenal carcinoid
Renal artery stenosis
Phaeochromocytoma
Glomus tumours in
nailbeds
CAL patches
Skin and nerve neurofibromas
Plexiform neurofibromas
MPNSTs
Hyperextensible joints
Flat feet
Low vitamin D levels
May be 7-8 cms shorter than sibs
Osteoporosis
Pseudarthrosis
Limb overgrowth (usually with plexiform
neurofibromas
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
Cognitive Development
IQ - Intellectual Functioning
• 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
Cognitive Development
Language
•
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
Academic Skills
•
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
Cognitive Development
Visuospatial Functioning
•
One of the most robustly established areas of difficulty for children with NF1
–
•
Difficulties with judgements of lines
Visuomotor integration problems
–
Eliason, 1986
Motor Control/Co-ordination
•
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
Memory
•
Biggest problem is working memory
•
Visual memory tests seem to be more problematic than verbal memory
Cognitive Development
Executive Functioning and Attention
• 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)
Social Skills
Social Competence
• 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
Autism
• 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)
Behavioural Difficulties
Behaviour
•
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
Common Challenges
•
•
•
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
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
Why ASD and Neurofibromatosis Type 1? – perspective from ASD
Idiopathic ASD highly heritable but genetically heterogeneous – up to 1000 candidate
genes - identification of detailed neuropathology/neurophysiology has been challenging
Increasing 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
Cell
(Ras)
NFI
Autism
Synapse
Brain Structure
/ Function
Intermediate
Phenotypes
Autism
Phenotype
Figure 5
Genes affected by CNVs and SNVs in
autism converge on neural system
functional networks
Pinto et al., The American Journal of
Human Genetics (2014),
The American Journal of Human Genetics DOI: (10.1016/j.ajhg.2014.03.018)
Prodromal Development
Collaboration: Johnson, Birkbeck
BASIS
British Autism
Study of Infant
Siblings (n>200)
Discovery of early
intermediate phenotypes (IP)
Prodromal Intervention
iBASIS 9-14 months
8 months
Intervention as
developmental experiment
(Green and Dunn 2008)
Neural sensitivity
(ERP) to gaze
Attention disengagement
Parent-infant
interaction
14 months
Atypical behaviour
24 months
36 months
Autism
What I will cover…
• NF1 and learning/behaviour in childhood
• NF1 in adults new associationsglomus tumours, breast cancer
• NF1 and genetic testing
• Progress on treatment- NF2 and avastin, NF1
and MEK inhibitors
• Models of care for NF1
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
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: 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 featureshypertelorism, 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
9/29
12/24
Musculoskeletal features
- Joint hyperflexibility
- Muscular hypotonia
- Bone cysts
- Pes cavus
21/29
13/29
8/16
5/29 (only reported in Mautner series)
NF1 Microdeletions 2
Neurofibroma 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
• Screened a panel of 86
samples with CAL only,
7/86 had SPRED1
mutations
Figure from Denayer et al, J Med
Genet, 2008
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…)
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
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
Imaging
Right Ear
Pre Avastin
Volume (cm3)
3 Days Post Avastin
3 Months Post Avastin
Pre Avastin
3 Days Post
Avastin
3 Months Post
Avastin
6.5
6.4
5.6
a
b
c
d
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
UT Southwestern
Lu Le
Fox Chase Cancer Center
Johnathan Chernoff
Joe Testa
Dermal
Neuroibroma
Indiana University
Wade Clapp
Plexiform
Neurofibroma
CCHMC
Nancy Ratner
Tim Cripe
Mesothelioma
Mass. General Hospital
Andrea McClatchey
House Research Institute
Marco Giovannini
NFPC
MPNST
Harvard/BWH
Karen Cichowski
Meningioma
Schwannoma
Ohio State University
Brad Welling
Long-Sheng Chang
JMML &
MPN
UCSF: Kevin Shannon
Benjamin Braun
Optic
Glioma
Washington Univ.
David Gutmann
MEK inhibition: Widemann et al
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
‘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
Unusual cases
Regular updates re:
assessment protocol
Personal Health Record
rare/severe
new disease entities
complications
research developments
patients keen
to help with
NEUROSURGEON
PATIENTS KNOW BEST
CLINICAL
ONCOLOGIST
OPHTHALMOLOGIST
ORTHOPAEDIC
SURGEON
research
NEUROFIBROMATOSIS
CLINIC:SEVERE NF1 ALL
AGES; ALL AGED 16-25yrs
PSYCHOLOGIST
ENDOCRINOLOGIST
OTOLARYNGOLOGIST
GENETICIST
PLASTIC SURGEON
NEUROLOGIST
SCIENTIFIC COLLABORATORS
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
THE PROBLEM
Charities & Patient
Advocacy Groups
Employers
Researchers
Government &
Commissioning bodies
Primary care
services
Relatives
Patient
GP
Specialist services
Pharmacies
Secondary
care/Hospital
Community teams
Pharmacy
Mobile device and
app developers
TRADITIONAL PATIENT PORTALS – THE SOLUTION?
‘New’ ways to empower the patient gives them
access to lots of information in lots of places
Fundamentally flawed:
GP
•
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
Hospital services
= EVEN MORE FRAGMENTATION OF INFORMATION
Apps and devices
THE SOLUTION
Employers
Government &
Commissioning bodies
Researchers
Community
teams
Social services
Charities & Patient
Advocacy Groups
Relatives
GP
Pharmacies
Primary care
health services
Pharmaceuticals
Secondary
care/hospitals
Specialist services
Mobile device and
app developers
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
•
•
•
•
PALLIATIVE CARE WITH PKB
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
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