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Control # 848
Title: “Polkadots and Moonbeams”
Neurocutaneous Syndromes Made Easy
eEdE# eEdE-197
Nothing To Disclose
“Polkadots and Moonbeams”
Neurocutaneous Syndrome Made Easy
1
Nucharin Supakul, MD
2
Chang Y Ho, MD
1 Ramathibodi Hospital, Mahidol University
Bangkok, Thailand
2 Riley Hospital for Children,
Indiana University School of Medicine
Indianapolis, Indiana, USA
Purpose
• To recognize characteristic imaging
findings for the most common
neurocutaneous syndromes
• To develop a search pattern for each
disease
• To understand and be able to suggest a
proper imaging technique for further
evaluation and follow-up.
Introduction
• Neurocutaneous syndrome
aka phakomatoses
Group of neuroectodermal disorders
• Central nervous system disorder
associated with lesions in the skin, eye
and other visceral organs
Case list
• Neurofibromatosis
type 1
• Neurofibromatosis
type 2
• Tuberous sclerosis
• Ataxia telangiectasia
• Sturge -Weber
syndrome
• Von Hipple-Lindau
syndrome
• Neurocutaneous
melanosis
• Basal nevous
syndrome
NEUROFIBROMATOSIS TYPE 1
Neurofibromatosis type 1
•
•
•
•
von Recklinghausen disease
Most common neurocutaneous disorder
1: 1,500 - 3,000
50% autosomal dominant, 50% spontaneous
mutation
• Chromosome 17 (17q11.2)
• NF1 gene  Neurofibromin protein
• Multisystemic manifestations (skin, CNS and
orthopedic)

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Neurofibromas
Café-au-lait spots
Axillary or inguinal freckles
Lisch nodule
Skeletal dysplasia
Malignant nervous system tumor
• Highly related to learning disability/autism
www.medicalobserver.com.au
http://emedicine.medscape.com/article/1177266-overview#showall
http://emedicine.medscape.com/article/1219222-overview
Neurofibromatosis type 1
• Diagnostic Criteria (≥ 2
findings for diagnosis)
 ≥ 6 café-au-lait spots
 > 2 axillary or inguinal
freckles
 ≥ 2 typical
neurofibromatosis or 1
plexiform neurofibroma
 Optic nerve glioma
 ≥ 2 Lisch nodules (Iris
harmartomas)
 Sphenoid dysplasia or
typical long bone
abnormalities
 1st degree relative with NF1
• Classic Radiographic
Findings
 Plexiform neurofibromas
(target appearance)
 Sphenoid wing dysplasia
 Optic nerve gliomas
 Deep gray and white matter
changes (myelin vacuolization
/ unidentified bright objects)
• Moya Moya pattern of
vasculopathy
• Imaging Recommendation
 MRI with contrast
Neurofibromatosis type 1
10-year-old boy with café-au-late spots
A-B: Axial and coronal T2 images
demonstrate extensive, ropy T2
hyperintense lesions with target
appearance consistent with plexiform
neurofibromas (orange arrows) along the
right side of the face extending to the
intra- and extraconal space of the right
orbit and along the right Meckel cave.
A
B
Noted is right sphenoid wing dysplasia
(blue star).
C: Coronal T1 post contrast image
demonstrates diffuse heterogeneous
enhancement of the plexiform
neurofibromas (orange arrows).
C
D
D: Axial T2 image of a different patient (2
year-old girl with NF1) shows multiple
bilateral foci of abnormal signal intensity
in the deep cerebellar white matter and
dentate nuclei consistent with NF related
dysplasia/myelin vacuolization (pink
arrows).
BACK to case list
NEUROFIBROMATOSIS TYPE 2
Neurofibromatosis type 2
• Manifestations (skin and
CNS)
 Café-au-lait spots (few or
absent)
 MISME (Multiple Inherited
Schwannomas Meningiomas
and Ependymomas)
• 1: 25,000 – 30, 000
• 50% autosomal dominant,
50% spontaneous mutation
• Chromosome 22 (22q12)
• NF2 gene  Merlin protein
http://flipper.diff.org/app/items/3683
• Late presentation and
diagnosis  less cutaneous
manifestations compared to
NF 1
• Clinical presentations:
Hearing loss/ vertigo
Neurofibromatosis type 2
• Diagnostic Criteria:
 Bilateral vestibular
schwannomas or
 1st degree relative with NF2
and 1 vestibular
schwannoma or
 1st degree relative with NF2
and 2 of the following
findings
 Neurofibroma
 Meningioma
 Glioma
 Schwannoma
 Posterior subcapsular
lenticular opacity
• Classic Radiographic
Findings: MISME
 Multiple Inherited
Schwannomas
 Meningiomas
 Ependymomas
• Carefully check other
cranial nerves in any new
diagnosis of schwannoma
or meningioma in a child or
young adult
• Imaging Recommendation
 MRI with contrast, high
resolution T1+C to evaluate
cranial nerves
Neurofibromatosis type 2
A
B
30-year-old female with history of
headache and dizziness.
A-B: Axial T1 postconstrast images
show bilateral enhancing masses in the
internal auditory canals, consistent with
vestibular schwannomas (orange
arrows). A large extra-axial mass with
homogeneous enhancement along the
posterior falx cerebri, consistent with a
meningioma (blue star).
C-D: Axial T1 (C) and sagittal T1 (D)
postcontrast images show a mixed
enhancing mass in the medulla with a
dorsal cyst, consistent with a
ependymoma (pink arrows).
A homogeneous intensely enhancing
mass is noted at the cranial cervical
junction, consistent with a cervical
meningioma (blue arrow).
C
D
BACK to case list
TUBEROUS SCLEROSIS
Tuberous Sclerosis
• 50% autosomal
dominant
• 50% sporadic
mutation
• 1 : 10,000
• Clinical triad
 Facial angiofibromas
(90%)
 Mental retardation
(50-80%)
 Seizure (80-90%)
A: Ash leaf macule
B: Adenoma sebaceum
C: Periungual fibroma
D: Shagreen patch
http://www.e-ijd.org/viewimage.asp?img=IndianJDermatol_2013_58_5_346_117297_f7.jpg
Tuberous Sclerosis
Diagnostic criteria: 2 major or 1 major+2 minor
• Major:

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•
Facial angiofibroma/forehead plaque
sub-/periungual fibroma
≥ 3 hypomelanotic macules
shagreen patch
multiple retinal nodular hamartomas
cortical tuber,
Subependymal nodule (SEN)
Subependymal giant cell astrocystoma (SEGA)
Cardiac rhabdomyoma
Lymphangioleiomyomatosis
Renal angiomyolipoma
Minor:

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



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
Dental enamel pits
Hamartomatous rectal polyps
Bone cysts
Cerebral WM radial migration lines (> 3 = major
sign)
Gingival fibromas
Nonrenal hamartoma
Retinal achromic patch
Confetti skin lesions
Multiple renal cysts
• Classic Radiographic
Findings:
 Cortical tuber
 Subependymal nodule
(<1.3 cm)
 Subepedymal giant cell
astrocytoma (> 1.3 cm)
• Imaging Recommendations:
 MRI brain with contrast
 FLAIR is the most
sensitive for white matter
abnormalities
Tuberous Sclerosis
5-year-old girl with seizure
A-B: Axial FLAIR images shows
multiple areas of FLAIR hyper
intensity involving bifrontoparietal
and occipital cortical and
juxtacortical white matter, consistent
with cortical tuber (orange arrows).
A
C
B
D
C: Axial post contrast T1 image
shows an enhancing lesion within
the right foramen of Monro,
measuring approximately 1.5 cm in
size, consistent with subependymal
giant cell astrocytoma (blue arrow).
D: Axial T2 image shows few T2
hypointense foci along the
ependymal lining of the left lateral
ventricle, consistent with
subependymal nodules (pink
arrows).
BACK to case list
ATAXIA TELANGIECTASIA
Ataxia telangiectasia
• Rare
• Autosomal recessive
• 1: 40,000 - 100,000
• Chromosome 11 (11q33-23)
• ATM gene mutation
• Complex multi systemic disorder
 Cerebellar ataxia (incoordination and lack
of balance)
 Mucocutaneous telangiectasia
 Immune deficiency  recurrent
bronchopulmonary and sinonasal infection
 Sensitive to ionizing radiation
• Increased risk of heart disease and
cancer (leukemia/lymphoma in children
and solid tumors in adult)
http://en.wikipedia.org/wiki/Ataxia_telangiectasia
http://dermatologyoasis.net/?s=ataxia+telangiectasia
• Most common cause of death: recurrent
sinopulmonary infection
Ataxia telangiectasia
• Classic Radiographic Findings:
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A
Progressive cerebellar volume loss
Compensatory enlargement of the 4th ventricle
Cerebral white matter dysmyelination/demyelination
Microhemorrhages/ telangiectasis
Decreased/ absent lymphoid tissue: adenoid gland,
thymus, mediastinal lymphoid tissue
• Imaging Recommendation:
 MRI due to no ionizing radiation and high tissue
contrast
B
7-year-old boy with history of autism and developmental
delay
A and B: Sagittal T1 (A) and coronal T2 (B) images
demonstrate severe atrophy of the cerebellar hemisphere
with widening of the cerebellar folia and CSF space (orange
arrows). Note the hypoplastic adenoid tissue for this age
(blue arrow).
BACK to case list
STURGE-WEBER SYNDROME
Sturge-Weber Syndrome
• Synonym: encephalotrigeminal
angiomatosis
• Rare
• Sporadic
• 1: 20,000 - 50,000
• Clinical presentation
• Port wine stain (CN V1 98%)
• Seizure (75-90%)
• Hemiparesis (30-66%)
• Pathophysiology: failure to develop of
fetal cortical vein plus persistent
primordial vessels venous stasis 
hypoperfused cortex
Sturge-Weber Syndrome
• Classic Radiographic
Findings:
 Ipsilateral to port wine stain
 Gyral/subcortical white
matter calcifications (tramtrack calcification)
 hemispheric brain atrophy
 Serpentine leptomeningeal
enhancement
 Engorged/enlarged
enhancing choroid plexi
• Location:
 Occipital > parietal >
fronto/temporal > midbrain >
cerebellum
• 90% of infants with facial
port wine stains do not
have intracranial lesions
and are expected to
develop normally.
• Imaging
Recommendation:
 MRI with contrast 
leptomeningeal angiomatosis
 GRE/SWI sequence 
gyral/subcortical calcification
Sturge-Weber Syndrome
3-year-old girl with history of facial hemangioma
and seizure
A: Non contrast CT image of the brain shows severe
atrophy of the right cerebral hemisphere with extensive
cortical/subcortical calcifications (orange arrows) in the
right cerebral hemisphere and left parieto-occipital
lobe.
A
B
B: GRE image shows hypointensity without blooming
involving the right cerebral hemisphere and left
occipital cortical/subcortical white matter, consistent
with calcifications (orange arrows) seen on the prior
CT.
C: Axial FLAIR image shows severe atrophy of the
right cerebral hemisphere. Bilateral choroidal cysts are
noted (blue arrows).
D: Post contrast T1 image demonstrates extensive
leptomeningeal enhancement involving right cerebral
cortical sulci and left parieto-occipital sulci (pink
arrows) as well as avid enhancement of the choroid
plexi bilaterally (yellow arrows).
C
D
Relative lack of cortical veins of the atrophied right
cerebral hemisphere compared to the contralateral
normal brain parenchyma and increased pial
enhancement of the left parietal occipital lobe.
BACK to case list
VON HIPPLE-LINDAU SYNDROME
Von Hipple-Lindau Syndrome
•
•
80% Autosomal dominant (Variable
expression and high penetrance; 97% •
by age of 65)
•
20% sporadic mutation
•
Chromosome 3 (3p25-26)
•
VHL gene  VHL protein
•
1 : 36,000
Multi Systemic manifestations:
 Less than 5% with skin manifestration
(Capillary malformation)
 Hemangioblastomas (Cerebellar 40-70%,
retinal 40-60% and spinal cord 10-60%)
 Pancreatic lesion (cyst 50-90%,
neuroendocrine tumor/ serous cystadenoma
5-15%)
 Renal lesion (cyst 60%, renal cell carcinoma
20-45%)
 Pheochromocytoma (0-60%)
 15% of VHL patients develop endolymphatic
sac tumor; 30% bilateral
Clinical presentation:
 Hemangioblastoma symptoms  headache,
dizziness, double vision, weakness
 Pheochromocytoma symptoms  high
blood pressure, sweating, rapid/irregular
heart rate, tremor, weight loss
http://emedicine.medscape.com/article/1084479-treatment#showall
http://www.umd.be/VHL/W_VHL/clinic.shtml1
Von Hipple-Lindau Syndrome
• Diagnostic Criteria
 ≥ 1 hemangioblastomas in the
CNS (brain and spinal cord) or
retina or
 A hemangioblastoma in the CNS
or retina plus a visceral
manifestation or
 Positive family history plus any of
above manifestations
• Classic Radiographic
Findings:
 Mixed cystic lesion with peripheral
nodular enhancement
 Near pial surface
• Imaging Recommendation:
MRI brain and spine with
contrast
• NIH recommendation for
screening:
 MRI brain and spine with contrast
from age of 11 then every 2 years
 US abdomen from age of 11, then
every year
 CT abdomen from age of 20, then
every year
 MRI temporal bone if hearing
loss/ tinnitus/ vertigo
Von Hipple-Lindau Syndrome
20-year-old male with history of headache
and back pain
A: Non contrast CT image shows a cystic lesion
(orange asterisk) in the left cerebellar
hemisphere with surrounding vasogenic edema.
Mass effect on the 4th ventricle (red arrow),
causes obstructive hydrocephalus (blue arrows).
A
B
B: Axial T1 post contrast image shows cystic
lesions with mural nodular enhancement (pink
arrows) in the left cerebellum and right-sided
pons. Also noted are few nodular enhancing foci
in the right cerebellar hemisphere (pink arrows).
C: Sagittal T1 post contrast image of the
thoracic spine demonstrates several enhancing
lesions in the spinal cord (yellow arrows).
C
D
D: Coronal contrasted CT image of the abdomen
shows multiple heterogeneous enhancing lesions
scattered through both kidneys (green arrows),
pathologically proven renal cell carcinoma.
BACK to case list
NEUROCUTANEOUS MELANOSIS
Neurocutaneous melanosis
•
Diagnostic Criteria:
 Melanocytic deposition within the CNS
and skin lesions
 Important to establish that cutaneous
lesions are benign or malignant to rule out
metastasis of cutaneous melanoma
•
Rare genetic disorder
•
100+ case reports
•
Mutation of NRAS gene
•
Clinical presentation:
melanocytic deposition within
 Skin  Giant or multiple
melanocytic nevi
 CNS
http://pediatricneuro.com/alfonso/pg303.htm
•
5-15% lifetime risk of malignant
transformation
•
Can have poor prognosis with median
survival of 6.5 months after symptom
onset
•
Classic Radiographic Findings:
 T1 shortening with susceptibility artifact
on GRE or SWI
 No contrast enhancement
 Locations: amygdala, cerebellum,
brainstem, inferior frontal lobes and
thalami
•
Imaging Recommendation:
 MRI with contrast of the brain and spine
 GRE/ SWI sequences
Neurocutaneous melanosis
13-day-old term infant with
multiple congenital nevi
A
B
A-B: Axial T1 noncontrast images
demonstrate a wedge-shaped T1
hyperintensity in the right caudal
thalamic groove and foci of T1
hyperintensity in the right medial
temporal lobe/ amygdala (orange
arrows).
C-D: Post contrast T1 image
demonstrates no contrast
enhancement within these lesions.
C
D
BACK to case list
BASAL CELL NEVUS SYNDROME
Basal cell nevus syndrome
•
•
•
•
•
•
Synonym: Gorlin syndrome
2/3 Autosomal dominant with
complete penetrance and variable
expressivity
1/3 sporadic mutation
1 : 31,000
Chromosome 9 (9q22.1-q31)
PICH1 gene  patched-1 protein
http://www.nlm.nih.gov/medlineplus/ency/imagepages/3190.htm
Basal cell nevus syndrome
Diagnostic criteria (2 majors, or 1 major + 2 minor)
•
Major criteria
 Early development of multiple basal cell
carcinomas
 Greater than 10 basal cell nevi
 Odontogenic keratocysts, commonly in the
mandible
 Palmar and plantar pitting
 Ectopic intracranial calcification, most often
along falx cerebri
 Family history
•
Minor criteria
 Craniofacial anomalies (macrocephaly,
frontal bossing, hypertelorism)
 Bifid ribs
 Early onset desmoplastic medulloblastoma
 Cardiac or ovarian fibroma, often bilateral
 Lymphomesenteric cysts
 Congenital malformation (cleft lip/palate,
polydactyly, eye abnormalties- colobomas,
cataract, glaucoma
•
•
Classic Radiographic Findings:
 Multiple odontogenic keratocysts
 Early dural calcifications
 Basal cell nevi and carcinomas
•
Odontogenic keratocyst (keratocytic
odontogenic tumor: KOT) in Gorlin
syndrome usually develop earlier
than non-syndromic KOT
•
Most patients with basal cell nevus
syndrome have KOT; however, only
5% of patients with KOT have basal
cell nevus syndrome.
•
Associated with desmoplastic
medulloblastoma
•
Imaging Recommendation:
 MRI to screen for medulloblastoma,
cystic jaw lesion
 CT of face for oral surgery planning
Basal cell nevus syndrome
A
C
B
15-year-old girl with abnormal panoramic radiograph
A-B: Coronal and axial CT images through the mandible shows an
expansile lucent lesion (orange arrow) in the right angle of the mandible
associated with an unerupted molar without cortical breakthrough.
C: Axial CT image of the skull near the vertex of the head demonstrates
prominent dural calcification along a reflection of the superior sagittal sinus
(blue arrows).
BACK to case list
Summary
Cutaneous
manifestations
CNS
manifestations
Other organ
manifestations
Key images
NF1
• Neurofibroma
• Café-au-lait spots
• Axillary or inguinal
freckles
• Plexiform
neurofibroma
• Optic nerve glioma
• myelin vacuolization
• Sphenoid wing
dysplasia
• Lisch nodule
• Skeletal dysplasia
• MRI with
contrast
• T2  target
lesion 
plexiform
neurofibroma
NF2
• Few café-au-lait spot
• MISME
-
• MRI brain and
spine with
contrast
• High resolution
cranial nerve
•
•
•
•
• Cortical tuber
• Subependymal
nodules
• SEGA
• Cardiac rhabdomyoma
• Lymphangiomyomatosis
• Renal AML
• MRI brain with
contrast
• FLAIR to detect
cortical tuber
Tuberous
sclerosis
Ash leaf macule
Adenoma sebaceum
Periungual fibroma
Shagreen patch
Ataxia
telangiectasia
• Mucocutaneous
telangiectasia
• Progressive
cerebellar volume
loss
• Atrophy of lymphoid
tissue, thymus, adenoid
gland
• MRI brain to
avoid ionizing
radiation
Sturge-Weber
Syndrome
• Port wine stain along
trigeminal nerve
• Gyral/ subcortical
calcification
• Hemispheric atrophy
• Sepentine
leptomeningeal
enhancement
• Engored/ enlarged
choroid plexus
-
• MRI brain with
contrast 
leptomeningeal
angiomatosis
• SWI/GRE for
gyral calcification
Summary
Cutaneous
manifestations
Von HippleLindau Syndrome
Neurocutaneous
melanosis
Basal nervous
syndrome
CNS
manifestations
Other organ
manifestations
Key images
• Capillary
malformation (less
than 5% of patients)
• Hemangioblatoma
(retina, cerebellum,
spine)
• Pancreas (cyst,
neuroendocrine tumor,
serous cystadenoma)
• Renal (cyst, RCC)
• phreochromocytoma
• Endolymphatic sac
tumor
• MRI brain and
spine with
contrast
• screening
- US and CT
abdomen
- MRI temporal
bone
• Giant or multiple
melanocytic nevi
• Melanocytic
deposition within the
CNS with no contrast
enhancement
-
• MRI brain and
spine with
contrast
• GRE/SWI
sequence
• Basal cell nevi
• Early dural
calficification
• Odontogenic
keratosis
• Desmoplastic
medulloblastoma
• Bifid ribs
• Cardiac or ovarian
firbromas
• Lymphomesenteric
cyst
• Cleft lip/palate
• Polydactyly
• Eye abnormalities
(colobomas, cataract,
glaucoma)
• MRI /CT to
demonstrate
odontogenic cyst
and dural
calcification
Conclusion
• Neurocutaneous syndromes are a heterogeneous
group of disorders that primarily affect the central
nervous system with cutaneous manifestations.
• Cross-sectional imaging, especially MRI, can be
tailored to help the diagnosis and guide further
evaluation and treatment.
• Radiologists should be familiar with the
characteristic imaging findings of specific
neurocutaneous syndromes and develop a search
pattern for potential associated lesions once a
diagnosis is favored.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
www.medicalobserver.com.au
http://emedicine.medscape.com/article/1177266-overview#showall
http://emedicine.medscape.com/article/1219222-overview
http://flipper.diff.org/app/items/3683
http://www.e-ijd.org/viewimage.asp?img=IndianJDermatol_2013_58_5_346_117297_f7.jpg
http://en.wikipedia.org/wiki/Ataxia_telangiectasia
http://dermatologyoasis.net/?s=ataxia+telangiectasia
http://emedicine.medscape.com/article/1084479-treatment#showall
http://www.umd.be/VHL/W_VHL/clinic.shtml
http://pediatricneuro.com/alfonso/pg303.htm
http://www.nlm.nih.gov/medlineplus/ency/imagepages/3190.htm
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Am J Neuroradiol. 1992 Jul-Aug;13(4):1078-82.
Tortori-Donati, Paolo, et al. "Phakomatoses." Pediatric Neuroradiology. Springer Berlin Heidelberg,
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Pont MS, and Elster AD. Lesions of skin and brain: modern imaging of the neurocutaneous
syndromes. American Journal of Roentgenology 1992 158:6 , 1193-1203
Coats, David K., Evelyn A. Paysse, and Moise L. Levy. "PHACE: a neurocutaneous syndrome with
important ophthalmologic implications: case report and literature review." Ophthalmology 106.9 (1999):
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Roach, E. S. "Neurocutaneous syndromes." Pediatric Clinics of North America 39.4 (1992): 591-620.