Disclosure
Cerebellar involvement in
neurocutaneous disorders
• I have nothing to disclose
• No relevant financial relations interfering with
my presentation
Andrea Poretti, MD
Section of Pediatric Neuroradiology, Division of Pediatric Radiology,
Russell H Morgan Department of Radiology and Radiological Science,
The Johns Hopkins University School of Medicine, Baltimore, MD
13th Congress of the European Society Of Magnetic Resonance in
Neuropediatrics, Porto, May 13-16, 2015
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Overview
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Neurofibromatosis type 1
• Cerebellar involvement:
Neurofibromatosis type 1
Tuberous sclerosis complex
PHACE(S) syndrome
Gómez-López-Hernández syndrome
Oculocerebrocutaneous syndrome
1. Unidentified bright objects (UBOs)
2. Cerebellar tumors
3. Other morphological abnormalities
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1. Cerebellar UBOs
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1. Cerebellar UBOs
• Cerebellum = common
location
• T2/FLAIR hyperintense
• No mass effect
• No contrast enhancement
in the majority of cerebellar
UBOs
• Lower IQ
• Impaired visuospatial
function
• Impaired language
 Role of the cerebellum in
cognitive functions
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Piscitelli O et al, Dev Med Child Neurol, 2011
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3. Other morphological abnormalities
2. Cerebellar tumors
• Rare (<1%)
• Mostly low-grade gliomas
• High propensity for
malignant degeneration
n=5
Pascual-Castroviejo I et al, Childs Nerv Syst, 2010
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3. Other morphological abnormalities
3. Other morphological abnormalities
• Cerebellar hypoplasia = Enlarged interfolial spaces
mimicking cerebellar atrophy, stable over time
• Cerebellar dysmorphia = Anomaly related to size,
shape, and extension of a cerebellar hemisphere
n=2
n=3
Toelle S, Poretti A et al, Cerebellum, 2015
Toelle S, Poretti A et al, Cerebellum, 2015
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Tuberous sclerosis complex (TSC)
3. Other morphological abnormalities
1. Cerebellar tubers
• Nf1 inactivation during
early stages of cerebellar
development disrupts
neuronal lamination
• Mutants exhibited extra
foliation
• Pattern reminiscent of
cerebellar dysmorphia
2. Role of the cerebellum in autistic-like features in
TSC
Kim et al, eLife, 2014
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1. Cerebellar tubers
1. Cerebellar tubers
• In up to 33% of patients
• Triangular shape with
broad base towards the
cerebellar cortex
• Mild-moderate “zebra-like”
contrast enhancement in >
50% of patients
• Higher prevalence of SEGA
in patients with cerebellar
tubers (20% vs 11%)
Calcifications in 29-54% of patients
Ertan G et al, J Neuroradiol, 2010; Vaughn J et al, AJNR, 2013
Vaughn J et al, AJNR, 2013; Daghistani R et al, Childs Nerv Syst, 2015
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2. Cerebellum  autistic-like features
1. Cerebellar tubers
• Up to 20% of cerebellar
tubers  increase in
– Size
– Enhancement
– Calcifications
over time
• No reduction in size or
enhancement over time
• Changes occurred in the
first 8 years of life
Positive correlation between
number of cerebellar tubers  CARS score
(r = .82, p = .001)
Vaughn J et al, AJNR, 2013; Daghistani R et al, Childs Nerv Syst, 2015
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2. Cerebellum  autistic-like features
Weber AM et al, J Autism Dev Disord, 2000
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2. Cerebellum  autistic-like features
• Tsc1 mouse model
• Decrease in number of
Purkinjie cells compared
to control
• Most likely explanation
for smaller cerebellar
volume in TSC patients
compared to controls
• Smaller cerebellar volume in TSC patients compared to controls
• Volumetric changes stronger in patients with TSC2 mutations
Tsai PT et al, Nature, 2012
Weisenfeld NI et al, Pediatr Neurol, 2013
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2. Cerebellum  autistic-like features
PHACE(S)
• Heterozygotes and mutant mice:
• P = Posterior fossa anomalies
• H = Facial hemangioma
• A = Arterial (intra +
extracranial) anomalies
• C = Congenital cardiac defect
(aortic coarctation and others)
• E = Eye abnormalities
• (S) = Sternal clefting or
supraumbilical raphe
– Social approach: No preference for a
novel mouse over a novel object
– Social novelty: No preference for a
novel mouse compared to familiar
mouse
• Abnormal social behavior
remembering autistic-like features
• Social behavior improved with
mTOR inhibitor rapamycin
Tsai PT et al, Nature, 2012
Oza VS et al, AJNR, 2008; Metry D et al, Pediatrics, 2009
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Cerebellar involvement in PHACE(S)
Cerebellar involvement in PHACE(S)
Unilateral cerebellar hypoplasia in PHACE(S) =
most likely sequelae of prenatal ischemic stroke
• Unilateral cerebellar hypoplasia
= most common finding
• Consistent association with
ipsilateral arterial anomaly
Hess CP et al, AJNR, 2010
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Cerebellar involvement in PHACE(S)
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Gómez-López-Hernández syndrome (GLHS)
• Abnormal neurodevelopment in 69% of children
• Cerebral, but not cerebellar abnormalities = more
common in children with abnormal vs. normal
neurodevelopment (35% vs. 0%, p = .04)
Poretti A et al, Eur J Med Genet, 2008; Sukhudyan B, Poretti A et al, Eur J Pediatr, 2010
Tantiphaiboontana J et al, J Child Neurol, 2012
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Cerebellar involvement in GLHS
Cerebellar involvement in GLHS
Rhombencephalosynapsis (RES):
• Agenesis/hypogenesis of the
cerebellar vermis
• Continuity of the cerebellar
hemispheres over the midline
• Fusion of dentate nuclei +
superior cerebellar peduncles
 keyhole-shaped appearance
of the IV. ventricle
• Hydrocephalus associated
in 50% of patients
• Aqueductal stenosis +
collicular fusion
• Ishak et al: RES in 9% of
patients with aqueductal
stenosis
Ishak GE et al, Brain, 2012
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Oculocerebrocutaneous syndrome (OCCS)
1. Oculo: Congenital cystic eye or
micro-/anophthalmia with cyst
2. Cerebro: Tectal abnormality,
vermis agenesis, callosal
dysgenesis, malformation of
cortical development
3. Cutaneous: Striated muscle
hamartoma, skin tags, cutis
aplasia/hypoplasia
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Cerebellar involvement in OCCS
Giant tectum + absent vermis = pathognomonic
Moog U et al, J Med Genet, 2005; Hunter AG, Am J Med Genet, 2006
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Take-home message
• Cerebellum involved in several neurocutaneous
disorders
• Role of cerebellar involvement:
1. Needed for the diagnosis (e.g. GLHS, OCCS)
2. Explain cognitive + behavioral phenotype (e.g. NF1,
TSC)
3. Shed light onto the pathogenesis (e.g. PHACE(S))
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