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

Dorlands 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

1st Mutation Hit

Germ Line Mutation: Ovary, Testis, or Embryo

Tumor Suppressor Gene: Two Hit Hypothesis

NEUROFIBROMATOSES - TYPES

2nd Mutation Hit

Neurofibromatosis Type 1 (NF(NF-1)

- von Recklinghausen Disease - "True" Neurofibromatosis - Prominent Cutaneous Signs - Chromosome 17q

Somatic Mutation

Neurofibromatosis Type 2 (NF(NF-2)

- Bilateral Acoustic Schwannoma - "Central Neurofibromatosis" - Minimal Skin Manifestations - Chromosome 22q

One copy of gene, 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, 15 mm adult

Neurofibromas - 2 or more Plexiform Neurofibroma - 1 Axillary (Intertriginous) Freckling - 1 Optic Glioma Lisch Nodules (Iris) - 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.), SlitSlit-Lamp Exam

OPTIC GLIOMA
Up to 15% of patients Pilocytic Astrocytomas Benign ("Hamartoma("Hamartoma-like"), Tx? True Neoplasms, spread along SAS up to 1/2 of Childhood ONG w/NFw/NF-1

Optic Nerve Glioma

Optic Nerve Glioma

Bilateral Optic Nerve Glioma

NEUROFIBROMATOSIS - 1
Cutaneous

Manifestations

CafeCafe-auau-Lait spots Intertriginous Freckling Neurofibromas (Skin and SubQ) Fibroma Molluscum (TNTC NFB) Elephantiasis Neuromatosa
diffuse skin thickening/plexiform NFB -oror- focal gigantism

Courtesy of Greg Petermann, M.D.

Caf-au-lait spot

Axillary Freckle

NEUROFIBROMATOSIS - 1
Bone Dysplasia and Remodeling Macrocephaly Craniofacial dysplasia
especially sphenoid
Vertebrae

(scalloping, scoliosis) Pseudoarthrosis

especially congenital
Genu

Valgum/Varum Twisted "Ribbon Ribs"

Sphenoid Dysplasia

Sphenoid Dysplasia

Courtesy of Greg Petermann, M.D.

Courtesy of Greg Petermann, M.D.

Progressive Pseudoarthrosis

Pseudo-arthrosis

Bowing Deformity

8 mo. Later

Hyperemic demineralization

Focal Gigantism

NERVE SHEATH TUMORS

Schwannoma (Sporadic >> NFNF-2 > NFNF-1)
focal mass usually sensory root, cranial and spinal nerves

Neurofibroma
usually NFNF-1, esp. 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. 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

Neurofibromatosis : Spine
Scoliosis

Acute Cervical Kyphoscoliosis

(NF(NF-1, 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, only?)

Idiopathic Parathyroid Adenoma
Schwannoma

Neurofibromatosis: Enlarged Neural Foramen

Nerve Sheath Tumor

Neurofibroma
NFNF-1 >> sporadic "dumbbell "dumbbell shape

Schwannoma
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. Schwannoma

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, M.D.

NEUROFIBROMATOSIS - 1: DBOs 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, don't enhance Cerebellar peduncles, Pons, midbrain globus pallidus, thalamus, optic radiations

May become Neoplasms (uncommon)

Courtesy of Greg Petermann, M.D.

Ectopic Schwann cells, Melanocytes ?? Intramyelin Vacuoles Dysmyelination ?? Intracellular proteinaceous fluid ?

DBO DBOs of NFNF-1: Cerebellar peduncle

Early ----- Later

Neurofibromatosis Type 1
vs.

James Brown or James S.?

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)

- von Recklinghausen Disease - "True" Neurofibromatosis - Prominent Cutaneous Signs - Chromosome 17q

Neurofibromatosis Type 2 (NF(NF-2)

- Bilateral Acoustic Schwannoma - "Central Neurofibromatosis" - Minimal Skin Manifestations - Chromosome 22q

NEUROFIBROMATOSIS - Type 2

Incidence: 1/50,000 Inheritance: Autosomal Dominant Age at Presentation: Birth to 40's (peak in 20 20s) Sx at Presentation: Hearing loss from VS Diagnostic Criteria: VIII masses Chromosome Abnl.: 22 Cutaneous Findings: minimal (skin tags) CNS Findings: Schwannoma, Meningioma, Ependymoma (intramedullary spinal cord)

CNS Neoplasms - Chromosome Loss of Heterozygosity

Schwannoma Meningioma

- 22q - 22q (long arm) Ependymoma - 22 NOT Neurofibroma NOT Astrocytoma NOT Optic Glioma

NF-2

NF-1

NF-2 ("CENTRAL"), 1 OR MORE

Bilateral VIIIth Masses Relative with NFNF-2 and either:

Intracanalicular Schwannoma

Unilateral VIIIth Mass Any Two:

"Neurofibroma", Meningioma, Glioma, Schwannoma, (Congenital) Lens Opacity

Bilateral Vestibular T1W axial Schwannoma

SCHWANNOMA
5-10% of All CNS Tumors Benign, Slowly growing F > M (Intracranial), M > F (Spinal) 30's - 60's, w/NFw/NF-2 10's - 30's Sensory Nerves (usually):
CNN VIII (Sup.Vestibular), V, X Spine: Dorsal Roots

Majority (>90%) are Sporadic Multiple in NFNF-2, Bilat.VIII Pathognomonic

From Laszlo Mechtler, DNI

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, Meningiomas, and Ependymomas

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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 - 16p

Hyman MH, Whittemore VH:"National Institutes of Health Consensus Conference:tuberous sclerosis Complex" Arch Neurol 2000; 57: 662-665.

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 - (2 Major) or (1 Major + 2 Minor) Probable TS - 1 Major + 1 Minor Possible TS - (1 Major) or (2 Minor)

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Pringles Disease

Pringles Disease

Pringles Disease

Subungual/Periungual Fibroma

Pringle Pringles 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)

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Ash Leaf Macule

Astrocytic Hamartoma

Lance Ovate Shape

Astrocytic Hamartoma

Tuberous Sclerosis - 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. neoplasia Caudothalamic groove Polypoid "Candle Gutterings"

DILATED VENTRICLES
variable obstructive, atrophic vs. "idiopathic"

TUMORS 15% SubSub-ependymal Giant Cell Astrocytoma

True neoplasm, Benign WHO Grade I

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Cortical Tubers

Periventricular Ca++

Subependymal Nodules

Subependymal Nodules

TS in newborn

Subependymal Nodules

Courtesy Mauricio Castillo, M.D. UNC

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Germinal Matrix

Subependymal nodule

Cortical tuber

Hypervascular Neuroblast Factory Post-mitotic neuroblasts migrate out along radial glia

medpix20791.jpg

Subependymal Giant Cell Astrocytoma

Tubers, Nodules, and Tumors

Angiomyolipoma

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Angiomyolipoma
10% 1/6

ANGIOMYOLIPOMA:
w/enough FAT for plain film of Solitary AML Pts. Have TS 1/31/3-1/2 of solitary AML Pts. Have other stigmata of TS 5050-80% of Pts. W/TS will have AML 3/4 Multiple 1/3 - 1/2 Bilateral (probably more) variable amts. of FAT, Smooth mm., and vessels

Renal Cysts

Cardiac Rhabdomyoma

Phakomatoses Mnemonic Tool

NFNF-1 NFNF-2

(von Reck's) (Bil . VIII Syndrome) (Bil.

TRUE Neurofibromatosis #17

Summary

M.I.S.M.E. #22

TUBEROUS SCLEROSIS
Pringle's "HAMARTOMA" Disease

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Neurfibromatosis Type 1: Skin, Nerves, Optic Astrocytoma, Brain DBOs, Spine and Bone

Neurofibromatosis Type 2
No specific skin findings M.I.S.M.E.

Courtesy of Greg Petermann, M.D.

Courtesy of Greg Petermann, M.D.

Hamartomas and Pringles

Tuberous Sclerosis

Thank You!
EUXAPIT ! Mahalo ! Gracias! Obregado Merci Beaucoup Danke Shoen

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