06/04/19. phakomatosis [fak ōmətō sis] pl. phakomatoses. Tumor Suppressor Gene: TWO HIT HYPOTHESIS

(1)

Neurocutaneous syndromes (covers

schwannoma, hemangioblastoma, ...)

Andrea Rossi, MD

Neuroradiology Unit

G. Gaslini Children’s Hospital - Genoa, Italy

The Neurocutaneous Syndromes, also called Phakomatoses, are a heterogeneous group of congenital disorders involving structures

primarily derived from:

NEURAL CREST

-

NEUROECTODERM

: CNS, PNS, skin, eye

-

MESODERM

: blood vessels, bone, cartilage

-ENDODERM: epithelial lining the GI tract

Sarnat H J Child Neurol 2005

This term was introduced by Jan van der Hoeve, a Dutch ophthalmologist, in 1920, to indicate the benign tumor-like nodules of the eye in - Neurofibromatosis (Recklinghausen's disease)

- Tuberous sclerosis (Bourneville's disease)

- Encephalotrigeminal angiomatosis (Sturge-Weber syndrome) - Cerebroretinal angiomatosis (Von Hippel-Lindau disease)

RETINAL HAMARTOMAS

The original “Phakoma” of van der Hoeve in a TSC patient

phakomatosis

[fak′ōmətō′sis] pl. phakomatoses Etymology: Gk, φακόςphako: spot, lens,oma:tumor,osis:condition

MAIN PHAKOMATOSES Neurofibromatosis 1 Neurofibromatosis 2 Tuberous Sclerosis C. Sturge-Weber s. Von Hippel Lindau d.

VASCULAR PHAKOMATOSES PHACE Syndrome Ataxia Telangiectasia Wyburn-Mason HHT Blue Rubber Bleb Nevus

Meningioangiomatosis MELANO PHAKOMATOSES Hypomelanosis of Ito Incontinentia Pigmenti Waardenburg Syndrome Neurocutaneous Melanosis Nevus of Ota McCune-Albright Nelson Syndrome OTHER RARE PHAKOMATOSES

Basal Cell Nevus Syndrome Organoid Nevus Syndrome Cowden-Lhermitte-Duclos (COLD)

Epidermal nevus Syndrome Encephalocraniocutaneous

Lipomatosis Xeroderma pigmentosum

EARLY ONSET AND HIGH FREQUENCY OF TUMORS

Tumor Suppressor Gene:

“TWO HIT” HYPOTHESIS

1st_{Mutation “Hit”} ₂nd_{Mutation “Hit”}

Germ Line Mutation: ovary,

testis or Embryo _Somatic

Mutation

One copy of gene,

Some protein No proteinNo gene,

BUMMER OF A

BIRTHMARK,

(2)

- peripheral – bad term

- autosomal dominant disease

- tumor suppressor gene

17q11.2

- 1 in 3,000 live births

Negative regulator of ras signal transduction pathway

NEUROFIBROMIN

Neurofibromatosis Type 1

von Recklinghausen disease

Lisch Nodules

Axillary freckling

Cafè-au-lait spot Neurofibromas

Diagnostic criteria for NF1

Two or more of the following:

- Six or more café-au-lait spots

- Two or more neurofibromas

or 1 plexiform neurofibroma

- Axillary or inguinal freckling

- Optic nerve glioma

- Two or more Lisch nodules

- A distinctive bony lesion (sphenoid dysplasia)

- A first-degree relative with NF1

Diagnostic criteria for NF1

Two or more of the following:

- Six or more café-au-lait spots

- Two or more

neurofibromas

or 1

plexiform neurofibroma

- Axillary or inguinal freckling

-

Optic nerve glioma

- Two or more Lisch nodules

- A distinctive

bony lesion

(sphenoid dysplasia)

- A first-degree relative with NF1

Optic Pathway Glioma

Possible extension to the posterior

optic pathways

Pilocytic Astrocytoma - first two decades of life - 30-70% of cases

- peak incidence around 4-5 years - one nerve: 40-50%

- both optic nerves: 20%

Possible spontaneous regression

Parazzini C et al, AJNR 1995; 16:1711-1718

onset

@ 1 yr BETTER PROGNOSIS THAN ISOLATED FORMS

Optic Pathway Glioma

OPT 66% SC 1% BS 17% CEREB 4% HEMIS 7% 3V/BN 5%

Other CNS Tumors in NF1

Intracranial hypertension Focal neurological symptoms

(3)

Diffuse

+/- exophytic component +/- cystic component

Focal

MEDULLARY

(68%)

, PONTINE

(52%)

, MIDBRAIN

(44%) 56% multiple localizations

Brainstem Gliomas in NF1

Unidentified Bright Objects

UBO’s

Glioma

Mass effect

C.E.

DDx

UBO’s and

Extra-OPG

MRS

Jones ‘01 COMPLEX EVOLUTION PATTERN 3-4 yrs appear 10-12 yrs disappear

Di Paolo Radiology 1995, Griffiths 1999, Varella 1997

COMPLEX EVOLUTION PATTERN

Variable behaviour with possible spontaneous

regression

NO

YES

More indolent course

than sporadic BS diffuse gliomas

SLOW PROGRESSION(30-50% - puberty Pollack 96)

2001

2002

2007

2010

Diffuse Brainstem Gliomas in NF1

12% extended to spinal cord

20% extended to MCP or vermis

Molloy 95, Bilaniuk 97, Pascual-Castroviejo 07, Ulrich 07

Spontaneous Regression

Apr ‘07 Aug ‘08 Apr ‘09 Apr ‘10

Focal Brainstem Gliomas in NF1

About 1-3%

Very rare!

Astrocytomas

(DD NF2)

Lee ‘96 Thakkar ‘99

Spinal Cord Tumors in NF1

-

WHO grade I

- tortuous cord of Schwann cells, neurons, fibroblastic proliferation in unorganized intercellular matrix

- aggressive, infiltrating

- tendency to anaplastic degeneration

Plexiform Neurofibromas

FRONTO-TEMPORO-ORBITAL REGIONS

“PLEXIFORM”: irregularly cylindrical enlargement of the affected nerve

T1 isointense

(4)

Plexiform Neurofibromas

Dural sinus occlusion!

Neurogenic Pain TEMPORO-OCCIPITAL REGIONS DORSAL REGIONS 10% MPNST MalignantPeripheral Nerve SheathTumors

Spinal Neurofibromas and Kyphoscoliosis

Intraspinal and/or paravertebral neurofibromas or neurofibrosarcomas Spindle or dumb-bell lesions - 50% of patients - cervical/thoracic - vertebral dysplasia - neurofibromas - intrinsic SC lesions Kyphoscoliosis

1. NON-CNS VASCULAR LESIONS

+++

Renal artery stenosis, aortic stenosis

2. CNS VASCULAR LESIONS

MOYAMOYA ARTERIAL ECTASIA & ANEURYSMS

Neurofibromatosis type 2

central neurofibromatosis with bilateral vestibular schwannomas

MISME

(Multiple Inherited Schwannomas, Meningiomas, and Ependymomas)

NF2-plaques

- 10-fold less common than NF1

- Autosomal Dominant

- Tumor suppressor gene on

22q12.2

- Symptoms develop in the 2

nd

_decade

Incidence 1/25,000 Prevalence 1/210,000

(no skeletal dysplasias, minimal skin manifestations, no learning disabilities)

Most of NF2 neoplasms arise from the CNS coverings!

MERLIN

Moesin-Ezrin-Radixin-Like Protein

Bilateral Vestibular Schwannomas

or

relative with NF2

plus

ØUnilateral VS < 30 y or

ØAny 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cataract

Diagnostic criteria for NF2

In a child, even unilateral schwannomas or single meningiomas are highly suspicious of NF2!

LOOK CAREFULLY INTO THE IAC!

Intracranial Schwannomas

Greater growth rate than isolated schwannomas Schwannomas involve the superior vestibular,

rather than the cochlear branch No neurorx difference with isolated forms

1/3 HEARING IMPAIRMENT 1/3 CN DEFICITS

Coronal thin slice Fat-Sat T1 C+

VIII CN

90-95% III CN

(5)

Intracranial Meningiomas

45-58%

MENINGIOMAS

Multiple transitional type NOT meningothelial Childhood +++

DURAL SINUS INVASION!

Meningioangiomatosis

Rare, benign, hamartomatous lesion of the leptomeninges

USUALLY MULTIPLE ASYMPTOMATIC LESIONS IN NF2

Temporal & frontal lobes Enhancing, well-demarcated cortical lesion Perilesional edema Leptomeningeal enhancement CALCIFICATIONS Fibroblast-like cells surrounding blood vessels

Microvasculature and spindle cells proliferation

Spinal manifestations in NF2

Cervical spine +++ Slowly growing often asymptomatic Ependymomas Schwannomas

Usually sensory root and spinal nerves Focal mass Meningiomas 20% Intradural extramedullary Incidence 1/6,000 - 1/10,000 Autosomal Dominant

Tuberous Sclerosis Complex

Bourneville-Pringle disease

MULTI-ORGAN HAMARTOMAS

(skin, brain, lungs, heart, kidneys)

Original “VOGT TRIAD”

Facial nevus(Adenoma Sebaceum) Seizures Mental deficiency

GENETIC HETEROGENEITY

TSC1 - 9q34 –Hamartin TSC2- 16p13 -Tuberin

SIMILAR PHENOTYPE Adenoma Sebaceum

Shagreen patches Hypomelanotic macules

Dental enamel pits

Not all these lesions are necessarily present in each patient CORTICAL TUBERS SUBEPENDYMAL NODULES WM ABNORMALITIES SEGA

Brain lesions in TSC

Developmental disorder of cell proliferation, migration, and

differentiation

Cerebral Cortical Tubers

Cortical/subcortical F>P>O>T>C Variable signal relative to

myelin maturation Firm cortical masses (tubers)

with dimpling (“potato eye”)

Dysmorphic Neurons Balloon Cells

CORTICAL DYSPLASIA WITH BALLOON CELLS AND ECTOPIC

NEURONS

(6)

Straight or curvilinear bands

Along lines of neuronal migration

WM Abnormalities

HETEROTOPIC NEURONAL AND GLIAL ELEMENTS

• “Candle gutterings” appearance • Main axis perpendicular to

ventricular wall • After 1 year, calcifications • Variable CE with no prognostic

value

+C

Subependymal nodules

Sub-Ependymal Giant-cell Astrocytoma

SEGA

is a benign neoplasm

(WHO grade 1)

2-26% of cases of TSC

Size > 10 mm

FORAMEN OF MONRO

, sometimes bilateral

3 years

after…

Hydrocephalus! CT -Isodense -calcifications MRI -T1 Hypo-iso -T2-FLAIR Hyper -CE marked

Subependymal Giant Cell Astrocytoma

Rapamycin and TSC

Hamartomas

mTOR

mammalian Target Of Rapamycin

Rapamycin

PROTEIN SYNTHESIS & CELL GROWTH

Efficacy in various TSC manifestations

(renal angiomyolipomas, angiofibromas, lymphangioleiomyomatosis, epilepsy)

BASELINE 3mths TRT 3mths STOP TRT

REGROWTH SHRINKAGE

RAPAMYCIN NORMALIZES THE DYSREGULATED mTOR PATHWAY

Rapa Nui

- Rare, sporadic disease

- Seizures in 1st_{year of life (dev. delay)}

- Progressive hemiparesis 30%, hemianopsia 2%

Sturge-Weber Syndrome

Encephalotrigeminal Angiomatosis

1)

FACIAL CAPILLARY VASCULAR MALFORMATION

( port-wine stain or nevus flammeus ) involving the trigeminal territory

2)

LEPTOMENINGEAL ANGIOMATOSIS

3)

ANGIOMATOSIS OF THE CHOROID

of the ipsilateral eye

ROACH SCALE

TYPE I: Leptomeningeal plus facial +/- glaucoma

TYPE II: Facial only +/- glaucoma

TYPE III: Leptomeningeal only

(7)

Absence of normal cortical venous drainage causing venous stasis with flow redirection to the deep vascular system

ENLARGEMENT OF MEDULLARY AND BASAL VEINS FLAIR Gd+ T1 Gd+ -Enhancement of cortical surface

Pial Angiomatosis

-Multiple thin, tortuous venous channels involving leptomeninges with possible cortical extension

Ca++ gyral/subcortical WM UNILATERAL 80% O>P>F/T>BS>C BILATERAL 20% Bilat multi-lobar

Other lesions in SWS

Angiomas of the choroid and

sclera Hypertrophic choroid plexus

- VHL is a rare, autosomal dominant

multisystem disorder

- 20% of cases are familiar

- Development of a variety of benign and

malignant tumors (about 40 different lesions in 14 different organs have been described)

- Inactivation of a tumor suppression gene

located on chromosome 3p25-26

- Symptoms often begin in the second to

third decades of life

Von Hippel-Lindau disease

Cerebroretinal angiomatosis

(a) more than one CNS hemangioblastoma

(b) one CNS hemangioblastoma and visceral manifestations of VHL disease

(c) any manifestation and a known family history of VHL disease

• Highly vascular nodule that abuts the pial surface

• Diffusion from vascular elements within the nodule accounts for cyst fluid

• The cyst wall is composed of compressed brain or reactive

neuroglial cells, and is not considered part of the neoplasm

Hemangioblastoma

Cerebellar Hemangioblastoma

(8)

Cerebellar Hemangioblastoma

D Dx

Pilocytic

astrocytoma

Mural nodule not pial-based (Partly) enhancing cyst

wall Pilocytic astrocytoma Hemangioblastoma

Other intracranial hemangioblastomas

*

Spinal hemangioblastoma

VHL related hemangioblastoma: multicentricity

1

2

1

2

(9)

NF1 Pilocytic astrocytoma Neurofibroma

NF2 Schwannoma

Meningioma Ependymoma

Tuberous sclerosis Subependymal giant cell astrocytoma

Sturge-Weber syndrome None

Von Hippel-Lindau disease Hemangioblastoma