1 The Phakomatoses The Phakomatoses James G. Smirniotopoulos, M.D. James G. Smirniotopoulos, M.D. Uniformed Services University Uniformed Services University 4301 Jones Bridge Road 4301 Jones Bridge Road Bethesda, MD 20814 Bethesda, MD 20814 Voice: 301 Voice: 301-295 295-3145 3145 FAX: 301 FAX: 301-295 295-3893 3893 Visit us on the WEB: Visit us on the WEB: http:// http://rad.usuhs. rad.usuhs.edu edu Educational Objectives Educational Objectives Describe why NF Describe why NF- 1 is truly 1 is truly “Neurofibromatosis Neurofibromatosis” Describe three neoplasms caused by the Describe three neoplasms caused by the chromosome 22 mutation in NF chromosome 22 mutation in NF-2 Explain why Tuberous Sclerosis is a Explain why Tuberous Sclerosis is a disorder of neuronal migration disorder of neuronal migration Dorland Dorland’ s Medical Dictionary s Medical Dictionary Birthmarks Birthmarks “Bummer of a birthmark, Hal” PHAKOMATOSES: PHAKOMATOSES: Why Study Them? Why Study Them? They are COMMON diseases They are COMMON diseases DIAGNOSED by Imaging DIAGNOSED by Imaging GENETIC Implications GENETIC Implications SCREEN Relatives SCREEN Relatives SURVEILLANCE of Affected SURVEILLANCE of Affected Phakomatoses Mnemonic Tool Phakomatoses Mnemonic Tool NF NF- 1 (von Reck's) 1 (von Reck's) – TRUE Neurofibromatosis #17 TRUE Neurofibromatosis #17 NF NF- 2 (Bilateral VS Syndrome) 2 (Bilateral VS Syndrome) – M.I.S.M.E. #22 M.I.S.M.E. #22 TUBEROUS SCLEROSIS TUBEROUS SCLEROSIS – Pringle's "HAMARTOMA" Disease Pringle's "HAMARTOMA" Disease
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1
The PhakomatosesThe PhakomatosesJames G. Smirniotopoulos, M.D. James G. Smirniotopoulos, M.D.
Uniformed Services UniversityUniformed Services University4301 Jones Bridge Road4301 Jones Bridge Road
Visit us on the WEB:Visit us on the WEB:http://http://rad.usuhs.rad.usuhs.eduedu
Educational ObjectivesEducational Objectives
Describe why NFDescribe why NF--1 is truly 1 is truly ““NeurofibromatosisNeurofibromatosis””Describe three neoplasms caused by the Describe three neoplasms caused by the chromosome 22 mutation in NFchromosome 22 mutation in NF--22Explain why Tuberous Sclerosis is a Explain why Tuberous Sclerosis is a disorder of neuronal migrationdisorder of neuronal migration
DorlandDorland’’s Medical Dictionarys Medical DictionaryBirthmarksBirthmarks
“Bummer of a birthmark,
Hal”
PHAKOMATOSES:PHAKOMATOSES:Why Study Them?Why Study Them?
They are COMMON diseasesThey are COMMON diseasesDIAGNOSED by ImagingDIAGNOSED by ImagingGENETIC ImplicationsGENETIC ImplicationsSCREEN RelativesSCREEN RelativesSURVEILLANCE of AffectedSURVEILLANCE of Affected
OPTIC GLIOMAOPTIC GLIOMA–– Up to 15% of patientsUp to 15% of patients–– Pilocytic AstrocytomasPilocytic Astrocytomas–– Benign ("HamartomaBenign ("Hamartoma--like"), Tx?like"), Tx?–– True Neoplasms, spread along SASTrue Neoplasms, spread along SAS–– up to 1/2 of Childhood ONG w/NFup to 1/2 of Childhood ONG w/NF--11
NeurofibromaNeurofibroma–– usually NFusually NF--1, esp. if spinal or paraspinal1, esp. if spinal or paraspinal–– spindle or dumbspindle or dumb--bell lesionbell lesion
Plexiform Neurofibroma (usually NFPlexiform Neurofibroma (usually NF--1)1)–– diffuse or fusiform enlargementdiffuse or fusiform enlargement
Malignant Peripheral Nerve Sheath TumorMalignant Peripheral Nerve Sheath Tumor–– NFNF--1 or Sporadic1 or Sporadic
Neurofibroma vs. SchwannomaNeurofibroma vs. Schwannoma
changeschanges–– Mostly cellularMostly cellular–– EncapsulatedEncapsulated–– Nerve Sparing SurgeryNerve Sparing Surgery
SchwannomaSchwannoma
NeurofibromaNeurofibroma Distribution of Nerve Sheath Distribution of Nerve Sheath TumorsTumors
IntraIntra--Cranial => SchwannomaCranial => Schwannoma–– Sporadic >> NFSporadic >> NF--22Spinal => Both Types (S >> N)Spinal => Both Types (S >> N)Dumbbell => Both (N >> S)Dumbbell => Both (N >> S)PNS => BothPNS => BothCutaneous => NeurofibromaCutaneous => Neurofibroma–– Usually N in NFUsually N in NF--11
NEUROFIBROMATOSIS NEUROFIBROMATOSIS -- Type Type 22
Incidence: 1/50,000Incidence: 1/50,000Inheritance: Autosomal DominantInheritance: Autosomal DominantAge at Presentation: Birth to 40's (peak in 20Age at Presentation: Birth to 40's (peak in 20’’s)s)Sx at Presentation: Hearing loss from VSSx at Presentation: Hearing loss from VSDiagnostic Criteria: VIII massesDiagnostic Criteria: VIII massesChromosome Abnl.: 22Chromosome Abnl.: 22Cutaneous Findings: minimal (skin tags)Cutaneous Findings: minimal (skin tags)CNS Findings: Schwannoma, Meningioma, CNS Findings: Schwannoma, Meningioma, Ependymoma (intramedullary spinal cord)Ependymoma (intramedullary spinal cord)
CNS Neoplasms CNS Neoplasms -- Chromosome Loss Chromosome Loss of Heterozygosityof Heterozygosity
NFNF--2 ("CENTRAL"), 1 OR MORE2 ("CENTRAL"), 1 OR MORE
Bilateral VIIIth MassesBilateral VIIIth MassesRelative with NFRelative with NF--2 and either:2 and either:–– Unilateral VIIIth MassUnilateral VIIIth Mass
55--10% of All CNS Tumors10% of All CNS TumorsBenign, Slowly growingBenign, Slowly growingF > M (Intracranial), M > F (Spinal)F > M (Intracranial), M > F (Spinal)30's 30's -- 60's, w/NF60's, w/NF--2 10's 2 10's -- 30's30'sSensory Nerves (usually):Sensory Nerves (usually):–– CNN VIII (Sup.Vestibular), V, XCNN VIII (Sup.Vestibular), V, X–– Spine: Dorsal RootsSpine: Dorsal Roots
Majority (>90%) are SporadicMajority (>90%) are SporadicMultiple in NFMultiple in NF--2, Bilat.VIII Pathognomonic2, Bilat.VIII Pathognomonic
Minor Features: Minor Features: Multiple dental Multiple dental enamalenamal pits pits Hamartomatous rectal polyps Hamartomatous rectal polyps Bone cysts Bone cysts White matter migration lines White matter migration lines Gingival fibromas Gingival fibromas NonNon--renal hamartoma renal hamartoma Retinal achromic patch Retinal achromic patch "Confetti" skin lesions "Confetti" skin lesions Multiple renal cysts Multiple renal cysts
Hyman MH, Whittemore VH:"National Institutes of Health Consensus Conference:tuberous sclerosis Complex" Arch Neurol 2000; 57: 662-665.
Definite TS - (2 Major) or (1 Major + 2 Minor)
Probable TS - 1 Major + 1 Minor
Possible TS - (1 Major) or (2 Minor)
Adenoma Sebaceum Adenoma Sebaceum
AKA PRINGLE'S DISEASEAKA PRINGLE'S DISEASENOT present at birthNOT present at birthdevelop before pubertydevelop before pubertynasolabial fold nasolabial fold -->bi>bi--malarmalarpapules of angiofibromapapules of angiofibroma
HETEROTOPIAS AND HAMARTOMASHETEROTOPIAS AND HAMARTOMAS–– in white and gray matterin white and gray matter
CORTICAL TUBERSCORTICAL TUBERS–– "HAMARTOMAS""HAMARTOMAS"–– but with abnormal "N" cellsbut with abnormal "N" cells–– neither Astrocyte nor Neuronneither Astrocyte nor Neuron–– Decreased MyelinationDecreased Myelination–– No laminar architectureNo laminar architecture
10% w/enough FAT for plain film10% w/enough FAT for plain film1/6 of Solitary AML Pts. Have TS1/6 of Solitary AML Pts. Have TS1/31/3--1/2 of solitary AML Pts. Have other 1/2 of solitary AML Pts. Have other stigmata of TSstigmata of TS5050--80% of Pts. W/TS will have AML80% of Pts. W/TS will have AML3/4 Multiple3/4 Multiple1/3 1/3 -- 1/2 Bilateral (probably more)1/2 Bilateral (probably more)variable amts. of variable amts. of FATFAT, Smooth mm., and , Smooth mm., and vesselsvessels