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Home , Neurofibroma, Phakomatosis, Schwannoma, Tuberous sclerosis

06/04/19

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

- NEUROECTODERM: CNS, PNS, , eye - MESODERM: blood vessels, bone, cartilage

- ENDODERM: epithelial lining the GI tract NEURAL CREST Neurocutaneous syndromes (covers , , ...) Andrea Rossi, MD Neuroradiology Unit G. Gaslini Children’s Hospital - Genoa, Italy [email protected] Sarnat H J Child Neurol 2005

OTHER RARE PHAKOMATOSES Basal Cell Syndrome [fak′ōmətō′sis] pl. phakomatoses Organoid Nevus Syndrome Cowden-Lhermitte-Duclos (COLD) Epidermal nevus Syndrome Etymology: Gk, φακός phako: spot, lens, oma: tumor, osis: condition Encephalocraniocutaneous Lipomatosis Xeroderma pigmentosum This term was introduced by Jan van der Hoeve, a Dutch ophthalmologist, MELANO in 1920, to indicate the -like nodules of the eye in VASCULAR PHAKOMATOSES PHAKOMATOSES - (Recklinghausen's disease) PHACE Syndrome Hypomelanosis of Ito Ataxia Telangiectasia - (Bourneville's disease) Wyburn-Mason Waardenburg Syndrome Neurocutaneous Melanosis HHT Nevus of Ota - Encephalotrigeminal (Sturge-Weber syndrome) Blue Rubber Bleb Nevus Meningioangiomatosis McCune-Albright - Cerebroretinal angiomatosis (Von Hippel-Lindau disease) Nelson Syndrome MAIN RETINAL PHAKOMATOSES The original “Phakoma” of van der Hoeve in a TSC patient Neurofibromatosis 1 Neurofibromatosis 2 Tuberous Sclerosis C. Sturge-Weber s. Von Hippel Lindau d.

© Saunders D, GOSH

BUMMER OF A Tumor Suppressor : BIRTHMARK, “TWO HIT” HYPOTHESIS HAL.

1st “Hit” 2nd Mutation “Hit”

Germ Line Mutation: ovary, testis or Embryo Somatic Mutation

One copy of gene, No gene, Some No protein

EARLY ONSET AND HIGH FREQUENCY OF TUMORS © Smirniotopoulos J

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Neurofibromatosis Type 1 Diagnostic criteria for NF1 von Recklinghausen disease Two or more of the following: -peripheral – bad term NEUROFIBROMIN - autosomal dominant disease - Six or more café-au-lait spots - 17q11.2 - 1 in 3,000 live births - Two or more or 1 plexiform - Axillary or inguinal freckling Negative regulator of ras - Optic signal transduction pathway - Two or more Lisch nodules Lisch Nodules - A distinctive bony (sphenoid dysplasia) - A first-degree relative with NF1

Axillary freckling Cafè-au-lait spot Neurofibromas

Diagnostic criteria for NF1 Optic Pathway Glioma Two or more of the following: Pilocytic

- first two decades of life - Six or more café-au-lait spots - 30-70% of cases - peak incidence around 4-5 years - Two or more neurofibromas or 1 plexiform neurofibroma - one nerve: 40-50% - both optic : 20% - Axillary or inguinal freckling Possible extension - to the posterior optic pathways - Two or more Lisch nodules - A distinctive bony lesion (sphenoid dysplasia) - A first-degree relative with NF1

Optic Pathway Glioma BETTER PROGNOSIS Other CNS Tumors in NF1 THAN ISOLATED FORMS

HEMIS 7% 3V/BN 5%

OPT onset 66% Possible spontaneous regression BS Parazzini C et al, AJNR 1995; 16:1711-1718 17% CEREB 4%

Intracranial hypertension Focal neurological symptoms SC Headache 1% @ 1 yr

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Brainstem in NF1 DDx UBO’s and Extra-OPG Unidentified Bright Objects Glioma Diffuse Focal UBO’s +/- exophytic component +/- cystic component Mass effect NO C.E. YES

MRS COMPLEX EVOLUTION Jones ‘01 COMPLEX EVOLUTION PATTERN PATTERN 3-4 yrs appear Variable behaviour with 10-12 yrs disappear possible spontaneous regression

MEDULLARY (68%), PONTINE (52%), MIDBRAIN (44%) 56% multiple localizations Di Paolo Radiology 1995, Griffiths 1999, Varella 1997

Diffuse Brainstem Gliomas in NF1 Focal Brainstem Gliomas in NF1 More indolent course than sporadic BS diffuse gliomas Apr ‘07 Aug ‘08SpontaneousApr ‘09 RegressionApr ‘10

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

12% extended to spinal cord 20% extended to MCP or vermis 2001 2002 2007 2010

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

Spinal Cord Tumors in NF1 Plexiform Neurofibromas “PLEXIFORM”: irregularly About 1-3% cylindrical enlargement of the affected nerve

Very rare! - WHO grade I (DD NF2) - tortuous cord of Schwann cells, , fibroblastic proliferation in unorganized Lee ‘96 intercellular matrix Thakkar ‘99 - aggressive, infiltrating FRONTO-TEMPORO- - tendency to anaplastic degeneration ORBITAL REGIONS

T1 isointense T2 inhomogeously Inhomogeneous to muscles hyperintense contrast enhancement

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Plexiform Neurofibromas Spinal Neurofibromas and Kyphoscoliosis TEMPORO-OCCIPITAL Kyphoscoliosis REGIONS

10% MPNST Malignant Peripheral Nerve Sheath Tumors

Dural sinus occlusion! Spindle or dumb-bell DORSAL REGIONS Neurogenic Pain - 50% of patients - cervical/thoracic - vertebral dysplasia - neurofibromas - intrinsic SC lesions Intraspinal and/or paravertebral neurofibromas or neurofibrosarcomas

Neurofibromatosis type 2 1. NON-CNS VASCULAR LESIONS +++ central neurofibromatosis with bilateral vestibular Renal artery stenosis, aortic stenosis ARTERIAL ECTASIA & MISME 2. CNS VASCULAR LESIONS ANEURYSMS (Multiple Inherited Schwannomas, , and ) - 10-fold less common than NF1 Incidence 1/25,000 Prevalence 1/210,000 - Autosomal Dominant Moesin-Ezrin-Radixin- - Tumor suppressor gene on 22q12.2 Like Protein - Symptoms develop in the 2nd decade (no skeletal dysplasias, minimal skin manifestations, no learning disabilities)

Most of NF2 arise from MOYAMOYA the CNS coverings! NF2-plaques

Diagnostic criteria for NF2 Intracranial Schwannomas

Coronal thin slice Bilateral Vestibular Schwannomas or relative with NF2 plus -Sat T1 C+ Ø Unilateral VS < 30 y or Ø Any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile

VIII CN 90-95% III CN

1/3 HEARING IMPAIRMENT 1/3 CN DEFICITS No neurorx difference with isolated forms LOOK CAREFULLY INTO THE IAC! Greater growth rate than isolated schwannomas

In a child, even unilateral schwannomas or single Schwannomas involve the superior vestibular, meningiomas are highly suspicious of NF2! V CN rather than the cochlear branch

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Intracranial Meningiomas Meningioangiomatosis Rare, benign, hamartomatous lesion of the leptomeninges

Fibroblast-like cells USUALLY MULTIPLE surrounding blood vessels ASYMPTOMATIC LESIONS IN NF2 Temporal & frontal lobes Enhancing, well-demarcated cortical lesion Microvasculature and spindle cells proliferation Perilesional edema Leptomeningeal enhancement

CALCIFICATIONS

MENINGIOMAS 45-58% Multiple transitional type DURAL SINUS NOT meningothelial INVASION! Childhood +++

Spinal manifestations in NF2 Tuberous Sclerosis Complex Bourneville-Pringle disease

MULTI-ORGAN HAMARTOMAS (skin, brain, , , kidneys)

Incidence 1/6,000 - 1/10,000 Autosomal Dominant

GENETIC HETEROGENEITY TSC1 - 9q34 – Hamartin TSC2 - 16p13 - Tuberin Adenoma Sebaceum SIMILAR PHENOTYPE

Hypomelanotic macules Schwannomas Meningiomas Ependymomas Original “VOGT TRIAD” Dental enamel pits Usually sensory root and 20% Cervical spine +++ Facial nevus (Adenoma Sebaceum) spinal nerves Intradural Slowly growing Focal mass extramedullary often asymptomatic Mental deficiency Shagreen patches

Brain lesions in TSC Cerebral Cortical Tubers

Developmental disorder of cell proliferation, migration, and CALCIFICATIONS Cortical/subcortical 50% differentiation F>P>O>T>C Variable signal relative to maturation CORTICAL TUBERS Firm cortical masses (tubers) SUBEPENDYMAL NODULES with dimpling (“potato eye”)

WM ABNORMALITIES CORTICAL DYSPLASIA WITH SEGA BALLOON CELLS AND ECTOPIC NEURONS Not all these lesions are necessarily present in Balloon Cells Dysmorphic each patient Neurons

© Osborn A

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WM Abnormalities Subependymal nodules

• “Candle gutterings” appearance • Main axis perpendicular to ventricular wall • After 1 year, calcifications • Variable CE with no prognostic value

+C

Straight or curvilinear bands HETEROTOPIC NEURONAL AND GLIAL ELEMENTS Along lines of neuronal migration

Sub-Ependymal Giant-cell Astrocytoma Subependymal Giant Cell Astrocytoma

SEGA is a benign (WHO grade 1) CT 2-26% of cases of TSC -Isodense -calcifications Size > 10 mm FORAMEN OF MONRO, sometimes bilateral MRI -T1 Hypo-iso -T2-FLAIR Hyper -CE marked

3 years after…

Hydrocephalus!

Rapa Nui Rapamycin and TSC Sturge-Weber Syndrome mTOR Encephalotrigeminal Angiomatosis mammalian Target Of Rapamycin - Rare, sporadic disease - Seizures in 1st year of life (dev. delay) - Progressive hemiparesis 30%, hemianopsia 2% RAPAMYCIN NORMALIZES THE DYSREGULATED mTOR PATHWAY 1) FACIAL CAPILLARY VASCULAR MALFORMATION Efficacy in various TSC manifestations (port-wine stain or nevus flammeus) (renal , , involving the trigeminal territory , ) 2) LEPTOMENINGEAL ANGIOMATOSIS 3) ANGIOMATOSIS OF THE CHOROID

Rapamycin of the ipsilateral eye BASELINE 3mths TRT 3mths STOP TRT

ROACH SCALE

TYPE I: Leptomeningeal plus facial +/- Hamartomas TYPE II: Facial only +/- glaucoma Port-wine stain TYPE III: Leptomeningeal only PROTEIN SYNTHESIS & SHRINKAGE REGROWTH

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Absence of normal cortical venous drainage Pial Angiomatosis causing venous stasis with flow redirection to the deep vascular system -Multiple thin, tortuous venous channels involving leptomeninges with possible cortical extension -Enhancement of cortical surface ENLARGEMENT OF MEDULLARY AND BASAL VEINS

UNILATERAL 80% O>P>F/T>BS>C T1 Gd+

Ca++ BILATERAL 20% gyral/subcortical WM FLAIR Gd+ Bilat multi-lobar

Other lesions in SWS Von Hippel-Lindau disease of the choroid and Hypertrophic Cerebroretinal angiomatosis sclera - 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

(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

Hemangioblastoma Cerebellar Hemangioblastoma

T1: T2: hypo hyper

High Strongly enhancing, rCBV pial-based mural • Highly vascular nodule that abuts the pial surface • Diffusion from vascular elements within the nodule accounts for fluid Nonenhancing • The cyst wall is composed of compressed brain or reactive cyst wall neuroglial cells, and is not considered part of the neoplasm PWI

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Cerebellar Hemangioblastoma D Dx

Mural nodule not pial-based

(Partly) enhancing cyst Hemangioblastoma wall

Pilocytic astrocytoma

Other intracranial Spinal hemangioblastoma

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VHL related hemangioblastoma: multicentricity VHL related hemangioblastoma: multicentricity

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Neurocutaneous syndromes: relationships with specific oncotypes

NF1 Pilocytic astrocytoma Neurofibroma

NF2 Schwannoma Thank you!

Tuberous sclerosis Subependymal giant cell astrocytoma

Sturge-Weber syndrome None

Von Hippel-Lindau disease Hemangioblastoma [email protected]

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