Educational Objectives

„ Describe

The Phakomatoses
James G. Smirniotopoulos, M.D.
Uniformed Services University 4301 Jones Bridge Road Bethesda, MD 20814 Voice: 301301-295295-3145 FAX: 301301-295295-3893 Visit us on the WEB: http://rad.usuhs. edu http://rad.usuhs.edu

why NFNF-1 is truly “Neurofibromatosis” Neurofibromatosis” „ Describe three neoplasms caused by the chromosome 22 mutation in NFNF-2 „ Explain why Tuberous Sclerosis is a disorder of neuronal migration

Dorland’s Medical Dictionary

“Bummer of a birthmark, Hal”

Birthmarks

PHAKOMATOSES: Why Study Them?
„ They

Phakomatoses Mnemonic Tool
„ NFNF-1 „ NFNF-2

are COMMON diseases „ DIAGNOSED by Imaging „ GENETIC Implications „ SCREEN Relatives „ SURVEILLANCE of Affected

(von Reck's) (Bilateral VS Syndrome) SCLEROSIS

– TRUE Neurofibromatosis #17 – M.I.S.M.E. #22
„ TUBEROUS

– Pringle's "HAMARTOMA" Disease

1

TYPES „ 2nd Mutation ‘Hit’ Neurofibromatosis Type 1 (NF(NF-1) .)."True" Neurofibromatosis .1 Axillary (Intertriginous) Freckling .Chromosome 22q One copy of gene.2 or more "Distinctive Bone Lesions" 1st degree Relative with NFNF-1 NF-1: EYE MANIFESTATIONS „ Lisch Nodules LISCH Nodules (Iris Hamartomas) – – – – Penetrance > 90% Specificity > 90% Translucent/pigmented Small ( < 3mm. some protein No gene No protein Neurofibromatosis Type 1 von Recklinghausen Disease Chromosome 17 NIH Diagnostic Criteria: 2 from list „ CafeCafe-AuAu-Lait spots – 6 or more – 5 mm child.Minimal Skin Manifestations .Bilateral Acoustic Schwannoma . 15 mm adult „ „ „ „ „ „ „ Neurofibromas . or Embryo Tumor Suppressor Gene: “Two Hit” Hypothesis NEUROFIBROMATOSES . Tx? True Neoplasms.Prominent Cutaneous Signs .1 Optic Glioma Lisch Nodules (Iris) .von Recklinghausen Disease . Testis.1st Mutation ‘Hit’ Germ Line Mutation: Ovary."Central Neurofibromatosis" .Chromosome 17q Somatic Mutation „ Neurofibromatosis Type 2 (NF(NF-2) . spread along SAS up to 1/2 of Childhood ONG w/NFw/NF-1 2 . SlitSlit-Lamp Exam „ OPTIC GLIOMA – – – – – Up to 15% of patients Pilocytic Astrocytomas Benign ("Hamartoma("Hamartoma-like").2 or more Plexiform Neurofibroma .

M.Optic Nerve Glioma Optic Nerve Glioma Bilateral Optic Nerve Glioma – – – – – NEUROFIBROMATOSIS . Café-au-lait spot Axillary Freckle 3 .1 „ Cutaneous Manifestations CafeCafe-auau-Lait spots Intertriginous Freckling Neurofibromas (Skin and SubQ) Fibroma Molluscum (TNTC NFB) Elephantiasis Neuromatosa ƒ diffuse skin thickening/plexiform NFB ƒ -oror.D.focal gigantism Courtesy of Greg Petermann.

scoliosis) „ Pseudoarthrosis – especially congenital „ Genu Valgum/Varum „ Twisted "Ribbon Ribs" Sphenoid Dysplasia Sphenoid Dysplasia Courtesy of Greg Petermann.D. Courtesy of Greg Petermann. M.D. Later Hyperemic demineralization 4 . Progressive Pseudoarthrosis Pseudo-arthrosis Bowing Deformity 8 mo. M.1 Bone Dysplasia and Remodeling „ Macrocephaly „ Craniofacial dysplasia – especially sphenoid „ Vertebrae (scalloping.NEUROFIBROMATOSIS .

cranial and spinal nerves „ Neurofibroma – usually NFNF-1. if spinal or paraspinal – spindle or dumbdumb-bell lesion „ „ Plexiform Neurofibroma (usually NFNF-1) – diffuse or fusiform enlargement Malignant Peripheral Nerve Sheath Tumor – NFNF-1 or Sporadic Neurofibroma vs.Focal Gigantism „ NERVE SHEATH TUMORS Schwannoma (Sporadic >> NFNF-2 > NFNF-1) – focal mass – usually sensory root. Schwannoma „ Schwannoma Neurofibroma – – – – – Schwann cells Fibroblasts Acellular material Infiltrating Resect Parent Nerve „ Schwannoma – Schwann Cell Neoplasm – Secondary vascular changes – Mostly cellular – Encapsulated – Nerve Sparing Surgery Neurofibroma „ „ „ „ „ Distribution of Nerve Sheath Tumors IntraIntra-Cranial => Schwannoma – Sporadic >> NFNF-2 Spinal => Both Types (S >> N) Dumbbell => Both (N >> S) PNS => Both Cutaneous => Neurofibroma – Usually N in NFNF-1 5 . esp.

only?) – Idiopathic – Parathyroid Adenoma „ Schwannoma Neurofibromatosis: Enlarged Neural Foramen „ Nerve Sheath Tumor – Neurofibroma ƒ NFNF-1 >> sporadic ƒ "dumbbell“ "dumbbell“ shape – Schwannoma ƒ sporadic >> NFNF-2 (NF(NF-2) „ Meningioma (NF(NF-2 „ Ependymoma (NF(NF-2) „ Mesodermal Defect – NFNF-1 only? – Dural weakness – Bone weakness NF-2 Multiple Dumbbell Lesions Neurofibroma vs. only?) – Simple ("idiopathic") – Acute Cervical Kyphosis „ Dural Ectasia (NF(NF-1. only?) – – – Vertebral Scalloping Arachnoid "cysts" Lateral Thoracic meningocele Neurofibromatosis : Spine „ Neurofibroma (NF(NF-1) „ Osteoporosis (NF(NF-1. Schwannoma 6 .Neurofibromatosis : Spine „ Scoliosis Acute Cervical Kyphoscoliosis (NF(NF-1.

thalamus.Rib Notching •Aortic Coarctation –Older than 5-6 years –3-9 possible –Ribs 5-8 most often –1-2 arise from subclavian artery –Usually Bilateral –Unilateral on the Right –if Coarctation involves Left Subclavian origin •A-V Fistulae •Nerve Sheath tumors Plexiform NF Multiple Neurofibromas Tumors of the Nerve Sheaths Courtesy of Greg Petermann. Ectopic Schwann cells. Melanocytes ?? Intramyelin Vacuoles Dysmyelination ?? Intracellular proteinaceous fluid ? 7 .D. optic radiations „ May become Neoplasms (uncommon) Courtesy of Greg Petermann. don't enhance Cerebellar peduncles. M. midbrain globus pallidus. Pons. NEUROFIBROMATOSIS .1: DBO’s MR Signal Abnormalities „ „ T1W Bright Foci T2W Bright Foci – – – – globus pallidus High signal in Brain on T2 Resolve over age 10 „ What in the heck are they?? – – – – w/o mass.D. M.

DBO’ DBO’s of NFNF-1: Cerebellar peduncle Early ----."Central Neurofibromatosis" .Chromosome 17q „ Neurofibromatosis Type 2 (NF(NF-2) .? Little man behind the Curtin Hugh Curtin of the Mass Eye and Ear Neurofibromatosis Type 2 Neurofibromatosis Type 2 or Wishart Disease Chromosome 22 NEUROFIBROMATOSES .TYPES „ Neurofibromatosis Type 1 (NF(NF-1) ."True" Neurofibromatosis .Minimal Skin Manifestations . James Brown or James S.von Recklinghausen Disease .Chromosome 22q 8 .Later Neurofibromatosis Type 1 vs.Bilateral Acoustic Schwannoma .Prominent Cutaneous Signs .

Vestibular). V. w/NFw/NF-2 10's .: 22 Cutaneous Findings: minimal (skin tags) CNS Findings: Schwannoma.22 NOT Neurofibroma NOT Astrocytoma NOT Optic Glioma NF-2 NF-1 NF-2 ("CENTRAL").Type 2 „ „ „ „ „ „ „ „ Incidence: 1/50. Glioma.60's.22q (long arm) „ Ependymoma . Schwannoma.000 Inheritance: Autosomal Dominant Age at Presentation: Birth to 40's (peak in 20’ 20’s) Sx at Presentation: Hearing loss from VS Diagnostic Criteria: VIII masses Chromosome Abnl. (Congenital) Lens Opacity Bilateral Vestibular T1W axial Schwannoma „ „ „ „ „ SCHWANNOMA 5-10% of All CNS Tumors Benign. X – Spine: Dorsal Roots „ „ Majority (>90%) are Sporadic Multiple in NFNF-2.30's Sensory Nerves (usually): – CNN VIII (Sup. 1 OR MORE Bilateral VIIIth Masses „ Relative with NFNF-2 and either: „ Intracanalicular Schwannoma – Unilateral VIIIth Mass – Any Two: ƒ "Neurofibroma". Ependymoma (intramedullary spinal cord) CNS Neoplasms . Slowly growing F > M (Intracranial).NEUROFIBROMATOSIS .22q . Meningioma. DNI 9 .Chromosome Loss of Heterozygosity „ Schwannoma „ Meningioma .VIII Pathognomonic From Laszlo Mechtler. Meningioma. Bilat. M > F (Spinal) 30's .

Meningiomas.Bilateral Vestibular Schwannoma Bilateral Vestibular Schwannoma Bilateral vestibular and one Trigeminal Schwannoma Multiple Meningiomas 5th 8th 8th T1-contrast axial From Laszlo Mechtler. DNI 8th 8th Multiple Schwannomas and Meningiomas Multiple Schwannomas. and Ependymomas 10 .

(2 Major) or (1 Major + 2 Minor) Probable TS .1 Major + 1 Minor Possible TS .16p Hyman MH. Whittemore VH:"National Institutes of Health Consensus Conference:tuberous sclerosis Complex" Arch Neurol 2000. 57: 662-665.M I S M E Syndrome „M ultiple „ I nherited „ S chwannoma „ M eningioma „ E ependymoma Tuberous Sclerosis or Bourneville Disease Chromosomes 9 and 16 TUBEROUS SCLEROSIS Original “VOGT TRIAD” TRIAD” „ FACIAL NEVUS (ADENOMA SEBACEUM) „ SEIZURES „ MENTAL DEFICIENCY „ TUBEROUS SCLEROSIS AUTOSOMAL DOMINANT „ No Racial/Sexual „ High Spontaneous Mutation „ High Penetrance – "SPORADIC" overover-reported „ Multiple Genes – TSC1 .9q – TSC2 .(1 Major) or (2 Minor) 11 . „ Tuberous Sclerosis. NIH Consensus Conference Major Features: „ Minor Features: Facial angiofibroma or forehead plaque Ungual or Periungual fibroma >3 Hypomelanotic macules Shagreen patch Multiple retinal nodular hamartomas Cortical Tuber Subependymal Nodule Subependymal Giant Cell Astrocytoma Cardiac rhabdomyoma Lymphangiomyomatosis Renal angiomyolipoma Adenoma Sebaceum „ „ „ „ „ Multiple dental enamal pits Hamartomatous rectal polyps Bone cysts White matter migration lines Gingival fibromas NonNon-renal hamartoma Retinal achromic patch "Confetti" skin lesions Multiple renal cysts AKA PRINGLE'S DISEASE NOT present at birth develop before puberty nasolabial fold ->bi>bi-malar papules of angiofibroma Definite TS .

Pringle’s Disease Pringle’s Disease Pringle’s Disease „ Subungual/Periungual Fibroma „ „ „ „ Pringle’ Pringle’s Name – Entire Disease – Facial lesion only Mild Mental Retardation Seizures Hard Potatoes Tubular Can – ‘Tuberous’ Tuberous’ Confetti Hypopigmentation „ AshAsh-Leaf „ ConfettiConfetti- Depigmentation: Spots Like Hypopigmentation – (Lance(Lance.Ovate Shape) – (Inverse Freckle) 12 .

atrophic vs. Benign WHO Grade I 13 .Brain: „ HETEROTOPIAS „ CORTICAL AND HAMARTOMAS – in white and gray matter TUBERS – "HAMARTOMAS" – but with abnormal "N" cells – neither Astrocyte nor Neuron – Decreased Myelination – No laminar architecture Tuberous Sclerosis .Brain: „ Cortical Tubers SUBEPENDYMAL NODULES (almost 100%) – "hamartomas" vs.Ash Leaf Macule Astrocytic Hamartoma Lance Ovate Shape Astrocytic Hamartoma Tuberous Sclerosis . neoplasia – Caudothalamic groove – Polypoid "Candle Gutterings" „ DILATED VENTRICLES – variable – obstructive. "idiopathic" „ „ TUMORS 15% SubSub-ependymal Giant Cell Astrocytoma – True neoplasm.

UNC 14 .D. M.Cortical Tubers Periventricular Ca++ Subependymal Nodules Subependymal Nodules TS in newborn Subependymal Nodules Courtesy Mauricio Castillo.

jpg Subependymal Giant Cell Astrocytoma Tubers.Germinal Matrix Subependymal nodule Cortical tuber Hypervascular Neuroblast Factory Post-mitotic neuroblasts migrate out along radial glia medpix20791. Nodules. and Tumors Angiomyolipoma 15 .

. and vessels Renal Cysts Cardiac Rhabdomyoma Phakomatoses Mnemonic Tool „ NFNF-1 „ NFNF-2 (von Reck's) (Bil . Have other stigmata of TS „ 5050-80% of Pts.1/2 Bilateral (probably more) „ variable amts. VIII Syndrome) (Bil. of FAT.E.I. Smooth mm. – TRUE Neurofibromatosis #17 Summary – M. Have TS „ 1/31/3-1/2 of solitary AML Pts.S.M.Angiomyolipoma „ 10% „ 1/6 ANGIOMYOLIPOMA: w/enough FAT for plain film of Solitary AML Pts. W/TS will have AML „ 3/4 Multiple „ 1/3 . #22 „ TUBEROUS SCLEROSIS – Pringle's "HAMARTOMA" Disease 16 .

Courtesy of Greg Petermann.D. Brain DBO’s. Nerves.E. Hamartomas and Pringles Tuberous Sclerosis Thank You! EUXAPIΣTΩ ! Mahalo ! Gracias! Obregado Merci Beaucoup Danke Shoen 17 . Courtesy of Greg Petermann.M.S.Neurfibromatosis Type 1: Skin. M.I.D. M. Optic Astrocytoma. Spine and Bone Neurofibromatosis Type 2 No specific skin findings M.

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