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Neurocutaneous Syndromes (Covers Schwannoma, Hemangioblastoma, ...) Andrea Rossi, MD Neuroradiology Unit G

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Neurocutaneous Syndromes (Covers Schwannoma, Hemangioblastoma, ...) Andrea Rossi, MD Neuroradiology Unit G 06/04/19 The Neurocutaneous Syndromes, also called Phakomatoses, are a heterogeneous group of congenital disorders involving structures primarily derived from: - NEUROECTODERM: CNS, PNS, skin, eye - MESODERM: blood vessels, bone, cartilage - ENDODERM: epithelial lining the GI tract NEURAL CREST Neurocutaneous syndromes (covers schwannoma, hemangioblastoma, ...) 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 Nevus Syndrome phakomatosis [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 benign tumor-like nodules of the eye in VASCULAR PHAKOMATOSES PHAKOMATOSES - Neurofibromatosis (Recklinghausen's disease) PHACE Syndrome Hypomelanosis of Ito Ataxia Telangiectasia Incontinentia Pigmenti - Tuberous sclerosis (Bourneville's disease) Wyburn-Mason Waardenburg Syndrome Neurocutaneous Melanosis HHT Nevus of Ota - Encephalotrigeminal angiomatosis (Sturge-Weber syndrome) Blue Rubber Bleb Nevus Meningioangiomatosis McCune-Albright - Cerebroretinal angiomatosis (Von Hippel-Lindau disease) Nelson Syndrome MAIN RETINAL HAMARTOMAS 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 Gene: BIRTHMARK, “TWO HIT” HYPOTHESIS HAL. 1st Mutation “Hit” 2nd Mutation “Hit” Germ Line Mutation: ovary, testis or Embryo Somatic Mutation One copy of gene, No gene, Some protein No protein EARLY ONSET AND HIGH FREQUENCY OF TUMORS © Smirniotopoulos J 1 06/04/19 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 - tumor suppressor gene 17q11.2 - 1 in 3,000 live births - Two or more neurofibromas or 1 plexiform neurofibroma - Axillary or inguinal freckling Negative regulator of ras - Optic nerve glioma signal transduction pathway - Two or more Lisch nodules Lisch Nodules - A distinctive bony lesion (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 Astrocytoma - 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 nerves: 20% - Axillary or inguinal freckling Possible extension - Optic nerve glioma 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 2 06/04/19 Brainstem Gliomas 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 Astrocytomas (DD NF2) - tortuous cord of Schwann cells, neurons, 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 3 06/04/19 Plexiform Neurofibromas Spinal Neurofibromas and Kyphoscoliosis TEMPORO-OCCIPITAL Kyphoscoliosis REGIONS 10% MPNST Malignant Peripheral Nerve Sheath Tumors Dural sinus occlusion! Spindle or dumb-bell lesions 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 schwannomas Renal artery stenosis, aortic stenosis ARTERIAL ECTASIA & MISME 2. CNS VASCULAR LESIONS ANEURYSMS (Multiple Inherited Schwannomas, Meningiomas, and Ependymomas) - 10-fold less common than NF1 MERLIN 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 neoplasms 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 Fat-Sat T1 C+ Ø Unilateral VS < 30 y or Ø Any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cataract 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 4 06/04/19 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, lungs, heart, 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 Seizures 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 myelin 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 5 06/04/19 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 neoplasm (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 angiomyolipomas, angiofibromas, involving the trigeminal territory lymphangioleiomyomatosis, epilepsy) 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 +/- glaucoma Hamartomas TYPE II: Facial only +/- glaucoma Port-wine stain TYPE III: Leptomeningeal only PROTEIN SYNTHESIS & CELL GROWTH SHRINKAGE REGROWTH 6 06/04/19 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
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