usuhs1 the phakomatoses james g. smirniotopoulos, m.d. uniformed services university of the health...

USUHS 1

THE PHAKOMATOSES

James G. Smirniotopoulos, M.D.

Uniformed Services University of the Health Sciences

4301 Jones Bridge RoadBethesda, MD 20814 Voice: 301-295-3145FAX: 301-295-3893

Visit us on the WEB: http://rad.usuhs.mil/rad

USUHS 2

DISCLAIMER:

The opinions expressed herein are those of the author(s), and are not necessarily representative of the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DOD); or the World Health Organization (WHO). Medicine is a constantly changing field, and medical information is subject to frequent correction and revision. Therefore the reader is entirely responsible for verifying the accuracy and relevance of the information contained herein. Portions herein copyright 1997-1999 James G. Smirniotopoulos, M.D.

USUHS 3

THE PHAKOMATOSES

Neuro ‑ Ectodermal ‑ or ‑

Nerves and Skin

USUHS 4

NEUROCUTANEOUS SYNDROMES

(Partial Listing)• AUTOSOMAL DOMINANT:

•Neurofibromatosis•Tuberous Sclerosis•von Hippel‑Lindau•Gorlin's •Hypomelanosis of Ito

USUHS 5

NEUROCUTANEOUS SYNDROMES

• AUTOSOMAL RECESSIVE:– Ataxia‑Telangiectasia – Xeroderma Pigmentosa– Cockayne's – Dysautonomia– Refsum's– Werner's– Progeria– Chediak‑Higashi– Sjogren‑Larsson– Other: – Sturge‑Weber, Klippel‑Trenaunay– Neurocutaneous Melanosis– Maffucci's– Klippel‑Trenaunay

USUHS 6

THE PHAKOMATOSESFive Most

Common/Important

– Neurofibromatosis Type 1•von Recklinghausen

– Neurofibromatosis Type 2• Wishart, Bilateral VS

– Encephalo‑Trigeminal Angiomatosis•Sturge-Weber

– Tuberous Sclerosis•Bourneville

– Cerebello‑Retinal Angiomatosis•von Hippel-Lindau

USUHS 7

PHAKOMATOSES

• Why Study Them?• They are COMMON diseases• DIAGNOSED by Imaging• GENETIC Implications• SCREEN Relatives• SURVEILLANCE of Affected

USUHS 8

Phakomatoses - Mnemonic

• NF‑1 (von Reck's) Truly Neurofibromatosis– HAS mult. NFBA/#17

• NF‑2 is M.I.S.M.E. (Bil. VIII) Syndrome/#22– Does not Really have Neurofibroma

• STURGE‑WEBER (Dimitri) Syndrome– Congenital Vascular Lesion, perhaps NOT

inherited • TUBEROUS SCLEROSIS

– Pringle's "HAMARTOMA" Disease• von HIPPEL‑LINDAU Syndrome

– Hemangioblastomas and Visceral Lesions– NO cutaneous lesions

USUHS 9

PHAKOMATOSES

• NEUROFIBROMATOSIS– Type 1, Chromosome 17q11– Type 2, Chromosome 22q12

• TUBEROUS SCLEROSIS– Chromosome 9q, 16p, 11?– STURGE‑WEBER (? not inherited)

• von HIPPEL‑LINDAU– Chromosome 3p25

USUHS 10

CNS NEOPLASMS

• Clonal Chromosome LOSS (LOH)• MENINGIOMA ‑ 22q (long arm)• SCHWANNOMA ‑ 22q• EPENDYMOMA ‑ 22• MEDULLOBLASTOMA ‑ 17p (short arm)• NEUROFIBROSARCOMA ‑ 17p• RETINOBLASTOMA ‑ 13q• PILOCYTIC ASTROCYTOMA ‑ NONE !• TUMOR SUPPRESSOR GENES

USUHS 11

NEUROFIBROMATOSIS

• 1768 MARK AKENSIDE (New York)• 1793 TILESIUS (Leipzig)• 1849 R.W. SMITH (England)• 1822 WISHART (Edinburg) NF‑2• 1882 von RECKLINGHAUSEN (Germany)

USUHS 12

NEUROFIBROMATOSIS

• NF‑1, von Recklinghausen ("peripheral")• NF‑2, Bilateral Acoustic ("central")• NF‑3, Overlap of 1 and 2• NF-4, ??• NF‑5, Segmental (e.g. a quadrant)• NF‑6, Cafe‑au‑lait, w/o CNS/PNS• NF‑7, Late Onset• NF‑8, Other

USUHS 13

NEUROFIBROMATOSES ‑ TYPES

• NEUROFIBROMATOSIS TYPE 1 (NF‑1) ‑von Recklinghausen Disease ‑"Peripheral" Neurofibromatosis ‑Prominent cutaneous signs ‑Multiple Neurofibromas

USUHS 14

NEUROFIBROMATOSIS TYPE 2 (NF‑2)

‑Bilateral Acoustic Schwannoma ‑"Central Neurofibromatosis" ‑Minimal Skin Manifestations ‑Multiple Schwannomas, Meningiomas,

Ependymomas

HENCE the nickname “MISME”

USUHS 15

NEUROFIBROMATOSIS ‑ TYPES

• Neurofibromatosis Type 1 (NF‑1) ‑ von Recklinghausen's Disease ‑ "True" Neurofibromatosis ‑ Prominent Cutaneous Signs ‑ Chromosome 17q

• Neurofibromatosis Type 2 (NF‑2) ‑ Bilateral Acoustic Schwannoma ‑ "Central Neurofibromatosis" ‑ Minimal Skin Manifestations ‑ Chromosome 22q

USUHS 16

NEUROFIBROMATOSIS - 1

USUHS 17

NEUROFIBROMATOSIS

• Species Affected– MAN– GOLDFISH– TURKEYS– CATTLE

USUHS 18

NEUROFIBROMATOSIS ‑ 1

• Clinical• Incidence: 1/2,500 births• Inheritance: Autosomal Dominant• Age at Presentation: Birth to Death• Sx at Presentation: Spots, NFB• Diagnostic Criteria: Cutaneous, PNS• Chromosome Abnl.: 17• Ocular Findings: Myelinated retina• Cutaneous Findings: cafe‑au‑lait, neurofibroma• CNS Findings: Optic N. Glioma, Hamartoma,

Heterotopia, macrocephaly, mentation problems

USUHS 19

NF‑1 (VRD or "PERIPHERAL")

USUHS 20

NF-1 NIH Diagnostic Criteria

• Cafe‑Au‑Lait spots• ‑ 6 or more• ‑ 5 mm child, 15 mm adult• Neurofibromas ‑ 2 or more• Plexiform Neurofibroma ‑ 1• Axillary (Intertriginous) Freckling• Optic Glioma• Lisch Nodules (Iris) ‑ 2 or more• "Distinctive Bone Lesions"• Relative with NF‑1

USUHS 21

NEUROFIBROMATOSIS ‑ 1 Clinical

• Chromosome Abnl.: 17• Ocular: Myelinated retina• Cutaneous: cafe‑au‑lait, neurofibroma• CNS: Optic N. Glioma, Hamartoma,

Heterotopia, Macrocephaly, Mentation

USUHS 22

NF‑1: EYE MANIFESTATIONS

• LISCH Nodules (Iris Hamartomas)– Penetrance > 90%– Specificity > 90%– Translucent/pigmented– Small ( < 3mm.), Slit‑Lamp Exam

• OPTIC GLIOMA– Pilocytic Astrocytomas– Benign ("Hamartoma‑like"), Tx?– True Neoplasms, spread along SAS– up to 1/2 of Childhood ONG w/NF‑1

USUHS 23

Neurofibromatoses:Orbit MANIFESTATIONS

• NF-1 – LISCH Nodules (Iris Hamartomas)– OPTIC GLIOMA– Sphenoid Dysplasia– Non-optic tumors (neurofibroma)

• NF-2– Optic Sheath Meningioma– Non-optic tumor (schwannoma)

USUHS 24

NEUROFIBROMATOSIS ‑ 1 Cutaneous

• Cafe‑au‑Lait spots• Intertriginous Freckling• Neurofibromas (Skin and SubQ)• Fibroma Molluscum (TNTC NFB)• Elephantiasis Neuromatosa (diffuse skin

thickening/plexiform NFB ‑or‑ focal gigantism)

USUHS 25

NEUROFIBROMATOSIS ‑ 1 Bony Dysplasia

• Macrocephaly• Craniofacial (esp. Sphenoid)• Vertebral (scalloping, scoliosis)• Pseudoarthrosis (esp. CONGENITAL)• Genu Valgum/Varum• "Ribbon Ribs"

USUHS 26

NEUROFIBROMATOSIS‑I

Skull and Spine Dysplasia

• Sphenoid Bone ("absent orbit")• Lambdoid Suture at Temporal Bone• Optic and Auditory Canals (enlarged)• Scoliosis (Simple or Acute Cx Kyphosis)• Vertebral Scalloping (usu. Lumbar)• Enlarged Spinal Foramina

USUHS 27

NERVE SHEATH TUMORS

• Schwannoma (Sporadic >> NF‑2 >> NF‑1)– focal mass, usually sensory root‑

cranial and spinal nerves• Neurofibroma (Commonly NF‑1 esp if

mult.)– esp. if spinal or paraspinal– elongated focal mass or dumb‑bell lesion

• Plexiform Neurofibroma (usually NF‑1)• ‑ diffuse or fusiform enlargement• Malignant P.N.S. Tumor (NF‑1 or Sporadic)

USUHS 28

NERVE SHEATH TUMORS

USUHS 29

Pathology

USUHS 30

SCHWANNOMA vs. NEUROFIBROMA

Encapsulated vs. Infiltrating

Focal Involvement vs. Diffuse, Reticular

Schwann Cells vs. S.C. and Fibroblasts

“Angiomatous” Vessels vs.Acellular Matrix

USUHS 31

INTRASPINAL NEOPLASMS

68 Pts. (w/86 Nerve Sheath neoplasms)• SPORADIC - 42 pts. (65%)

– 42 Schwannoma/2 NFBA

• NF-1- 12 Pts. (18%)– All Neurofibroma

• NF-2- 7 Pts. (11%)– 18 Schwannoma/1 “mixed” tumor

• UNKNOWN - 5Pts.

USUHS 32

INTRASPINAL NEOPLASMS

USUHS 33

DISTRIBUTION of Nerve Sheath Tumors

• Cranial ‑ Schwannoma (Sporadic >> NF‑2)

• Spinal ‑ Both Types (Sporadic S >> N)

• Dumbell ‑ Both (N >> S)

• PNS ‑ Both

• Cutaneous ‑ Neurofibroma (usu. NF‑1)

USUHS 34

NEUROFIBROMATOSIS: Spine

• Scoliosis (NF‑1, only?)• ‑Simple ("idiopathic")• ‑Acute Cervical Kyphosis• Dural Ectasia (NF‑1, only?)• ‑Vertebral Scalloping• ‑Arachnoid "cysts"• ‑Lateral meningocele

USUHS 35

NEUROFIBROMATOSIS: Spine

• Neoplasm (BOTH NF‑1 and NF‑2)• ‑ Neurofibroma (NF‑1)• ‑ Schwannoma (NF‑2)• ‑ Ependymoma (NF‑2)• Osteoporosis (NF‑1, only?) • ‑ Idiopathic• ‑ Parathyroid Adenoma

USUHS 36

NEUROFIBROMATOSIS: Enlarged Neural Foramen

• Nerve Sheath Tumor ("dumbbell")• ‑ Neurofibroma (NF‑1 >> sporadic)• ‑ Schwannoma (sporadic >> NF‑2)• Mesodermal Defect (NF‑1, only?)• ‑ Dural weakness• ‑ Bone weakness

USUHS 37

NEUROFIBROMATOSIS‑1: Spine

• Scoliosis (Acute Cx Kyphoscoliosis)• Vertebral Scalloping• Enlarged Neural Foramina• Lateral Thoracic Meningocele

USUHS 38

LATERAL THORACIC MENINGOCELE

USUHS 39

NEUROFIBROMATOSIS‑1

• Posterior Meningocele (sporadic) – dorsal dysraphism, closure of tube

• Anterior Meningocele (sporadic)– neurenteric canal/cyst – anterior vertebral cleft

• Lateral Thoracic Meningocele (NF‑1)– "pulsion diverticulum" of SAS– negative intrathoracic pressure– no overlying paravertebral MM.

USUHS 40

NEUROFIBROMATOSIS ‑ 1:MR Signal Abnormalities

• T1W Bright Foci: globus pallidus

• T2W Bright Foci w/o mass, don't enhance:– Cerebellar peduncles, Pons, globus

pallidus– midbrain, thalamus, optic radiations

• What in the heck are they??– (intracellular proteinaceous fluid?)

USUHS 41

NEUROFIBROMATOSIS‑1

• VISCERAL ‑FOCAL OVERGROWTH, HYPERTROPHY

• GI/GU NEUROFIBROMAS (MURAL MASS)• RENAL ARTERIES

– PROXIMAL STENOSIS– TAPERED– HYPERTENSION (R/O PHEO IN ADULT)

• AORTIC COARCTATION• INTRACRANIAL VASCULAR STENOSIS

USUHS 42

NEUROFIBROMATOSIS

• Malignant Peripheral Nerve Sheath Tumor– (neurofibrosarcoma, malignant ...)

• Embryonal Malignancies:– Wilms, Rhabdomyosarcoma

• Leukemia (CML)• Melanoma, Medullary Thyroid Ca.

USUHS 43

NEUROFIBROMATOSIS ‑ Type 2

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

Ependymoma (spinal cord)

USUHS 44

NF ‑ 2

• Autosomal Dominant• 1 in 50,000• VIII‑TH Nerve Tumors• Other CNS Tumors (Meningioma,

Ependymoma)• Chromosome 22

USUHS 45

CNS NEOPLASMS - Chromosome LOH

• MENINGIOMA ‑ 22q (long arm)• SCHWANNOMA ‑ 22q• EPENDYMOMA ‑ 22• MEDULLOBLASTOMA ‑ 17p (short arm)• NEUROFIBROSARCOMA ‑ 17p• RETINOBLASTOMA ‑ 13q

USUHS 46

NF‑2 ("CENTRAL"), 1 OR MORE

• Bilateral VIIIth Masses• Relative with NF‑2 and either:

– Unilateral VIIIth Mass– Any Two "Neurofibroma",

Meningioma, Glioma, Schwannoma, (Congenital) Lens Opacity

USUHS 47

NEUROFIBROMATOSIS ‑ Type 2

• NEJM 319:278-83, 1988 (Gulf of Mexico)• 23 Pts. (15M/8F), Kindred of 137• 0.95 Penetrance• 18 Acoustic Schwannoma (17 bil.)• 8 Meningioma (3 mult.)• 4 Ependymoma• 2 Spinal "Neurofibroma"

USUHS 48

SCHWANNOMA

• 5‑10% of All CNS Tumors• Benign, Slowly growing• F > M (Intracranial), M > F (Spinal)• 30's ‑ 60's, w/NF‑2 10's ‑ 30's• Sensory Nerves (usually):

– CNN VIII (Sup.Vestibular), V, X– Spine: Dorsal Roots

• Majority (>90%) are Sporadic• Multiple in NF‑2, Bilat.VIII Pathognomonic

USUHS 49

Neurofibromatosis ‑ 2

• Meningiomas: multiple transitional type (NOT meningothelial)

• Meningioangiomatosis: cortical (intracortical)– vascular tissue (resembles a

malformation)– meningothelial and fibroblast‑like cells

USUHS 50

NEUROFIBROMATOSIS‑2Meningiomas

• Multiple Meningiomas– (up to 45% of Pts w/NF-2)

• Intraventricular Meningiomas• Childhood Meningiomas

• Multiple Meningiomas (1‑10% of all MENIN.)– SPORADIC in 80‑90%

• Intraventricular Meningiomas– SPORADIC in 90%

• Childhood Meningiomas– SPORADIC in ??

USUHS 51

NEUROFIBROMATOSIS ‑ 2:MR Imaging

• Vestibular Schwannoma (Multiple)– T1W: hypo‑ to isointense– T2W: brighter

• Meningioma (Multiple)– T1W: hypo‑ to isointense– T2W: iso‑ to brighter

USUHS 52

NEUROFIBROMATOSIS ‑2

• 80% of Gliomas in NF2 are SPINAL– (intramedullary or cauda equina)

• 10% of Gliomas are in medulla– (Cerebral, Cerebellar, Pontine are rare)

• 65‑75% of ALL gliomas in NF2 are EPENDYMOMAS and most pts. will have multiple ependymomas

• Diffuse, pilocytic and optic nerve gliomas are NOT characteristic of NF2, but are NF1

USUHS 53

NEUROFIBROMATOSIS TYPE‑2 => MISME

M ultiple I nherited S chwannomas M eningiomas E pendymomas

USUHS 54

NEUROFIBROMATOSIS ‑ TYPES

• Neurofibromatosis Type 1 (NF‑1)– ‑ von Recklinghausen's Disease– ‑ "True" Neurofibromatosis– ‑ Prominent Cutaneous Signs– ‑ Chromosome 17q

• Neurofibromatosis Type 2 (NF‑2)– ‑ Bilateral Acoustic Schwannoma– ‑ "Central Neurofibromatosis"– ‑ Minimal Skin Manifestations– ‑ Chromosome 22q

USUHS 55

NEUROFIBROMATOSES

• NEUROFIBROMATOSIS 1– Lesions of Astrocytic/Neuronal

Origin‑glioma, neurofibroma‑hamartoma, heterotopia

• NEUROFIBROMATOSIS 2– Lesions of

Covering/Lining‑meningioma, schwannoma‑ependymoma

USUHS 56

Neurofibromatoses:Orbit MANIFESTATIONS

• NF-1 – LISCH Nodules (Iris Hamartomas)– OPTIC GLIOMA– Sphenoid Dysplasia– Non-optic tumors (neurofibroma)

• NF-2– Optic Sheath Meningioma– Non-optic tumor (schwannoma)

USUHS 57

THE PHAKOMATOSES

• von Recklinghausen Disease

• MISME Syndrome

• Sturge‑Weber‑Dimitri Syndrome

• Bourneville Disease

• von Hippel‑Lindau Syndrome

USUHS 58

STURGE-WEBER SYNDROME: Classic Triad

• Facial Neveus Flammeus

– Port-Wine Stain

• Seizures

• Mental Deficiency

USUHS 59

STURGE-WEBER SYNDROME: History

– 1879 STURGE, Clinical description– 1897 Kalischer, Vascular nature– 1922 Weber, published

radiography– 1923 Dimitri, "tram-track" Ca++– 1934 krabbe, Ca++ in cortex– 1937 van der Hoeve,

Phakomatosis

USUHS 60

STURGE-WEBER: Definition:

A telangiectatic venous angioma of the leptomeninges, face, and choroid of the eye.

Dilated small vascular spaces, without shunting, without arterial enlargement.

USUHS 61

STURGE-WEBER: Manifestations

• Seizures, Mental Decline• Facial Angioma• Angiomatous Overgrowth• Leptomeningeal Angioma• Cortical Atrophy w/Ca++

USUHS 62

STURGE-WEBER: Variants

• Facial and Intracranial w/o Eye• Intracranial and Eye w/o Face• Intracranial Alone

– (Cerebral and Leptomeningeal)• Klippel-Trenaunay (?)

USUHS 63

STURGE-WEBER SYNDROME: Port Wine Stain (PWS)

• Facial Neveus Flammeus• Blanches w/ pressure• Trigeminal Dermatome

– V1 - Ophthalmic– V2 - Maxillary– V3 - Mandibular

• Most typically involves medial eyelid (canthus)

• More extensive ==> More likely to have SWS

USUHS 64

Association of PWS with SWS

• All 3 >> 1+2 >> 1 or 2 alone >> other locations

• medial aspect of eyelid (V1 or V2)

USUHS 65

STURGE-WEBER: Orbit/Eye

• BUPHTHALMOS-congenital glaucoma-enlarged globe

• CHOROIDAL ANGIOMA• EPISCLERAL TELANGIECTASIA• ANGIOMATOUS OVERGROWTH EOM’s

USUHS 66

STURGE-WEBER: Vascular

• Absence of cortical veins• Poor filling of sagittal sinus• Persistent Primitive Plexus (SAS)• Recruitment of Medullary Veins• Prominent Choroid Plexus

USUHS 67

STURGE-WEBER: Pathology

• Facial Nevus Flammeus- dilated tortuous vv.- from Ectoderm originally overlying the

affected brain

USUHS 68

STURGE-WEBER: Etiology

• Persistence of Primitive Plexus• Abnormal Development of Capillaries

- Poor cortical venous drainage- Absent cortical veins- Prominent veins in SAS- Prominent deep (medullary) veins- Prominent deep (medullary) veins- Enlarged choroidal vessels

USUHS 69

STURGE-WEBER: Calcification

• Abnormal (sluggish) circulation• Chronic Cerebral Ischemia• Progressive Cell Loss (Atrophy)• Progressive Cerebral calcification• early - subcortical WM (?)• Later - middle layers of cortex

USUHS 70

DYKE, DAVIDOFF, MASSON:

• Cerebral Hemiatrophy with• Homolateral Hypertrophy • of the Skull and Sinuses

• Heterogeneous group of patients who all shared cerebral hemiatrophy

• Surgery Gynecology, & Obstetrics 1933 pp. 589-600

USUHS 71

STURGE-WEBER

• Gadolinium Enhancement• Abnormal BBB in Cortex

• (Chronic ischemia)• "Epi-Cortical"

enhancement• (slow flow in superficial veins)

USUHS 72

STURGE-WEBER: Treatment

• Symptomatic (anticonvulsants)• Cosmetic Tattooing• Laser Treatment of Skin• Hemispherectomy• Aspirin ?

– Prevent thrombosis in telangiectasias

USUHS 73

TUBEROUS SCLEROSIS

Original “VOGT TRIAD”• FACIAL NEVUS (ADENOMA SEBACEUM)• SEIZURES• MENTAL DEFICIENCY

USUHS 74

TUBEROUS SCLEROSIS

• AUTOSOMAL DOMINANT• No Racial/Sexual• High Spontaneous Mutation• High Penetrance• "SPORADIC" over‑reported• Multiple Genes• TSC1 ‑ 9q• TSC2 ‑ 16p

USUHS 75

TUBEROUS SCLEROSIS

• Definitive (need 1)(1) facial angiofibroma(2) ungual fibroma(3) retinal hamartoma(4) cortical tubers(5) subependymal nodules(6) multiple renal AML

USUHS 76

TUBEROUS SCLEROSIS

• Presumptive (need 2)(1) hypomelanotic nodules(2) shagreen patch(3) single renal AML(4) multicystic kidney(5) cardiac rhabdomyoma(6) pulmonary lymphangiomyomatosis(7) radiographic "honeycomb" lung(8) first degree relative with TS

USUHS 77

Tuberous Sclerosis: Adenoma Sebaceum 90%

• Seizures 90%• Retardation 40‑60%• Retinal Phakoma 50%• Xr: Intracranial Ca++ 50%• Ungual Fibromata 17%• Giant Cell Astrocytoma 15%

USUHS 78

INCIDENCE Of Tuberous Sclerosis:

• CLASSIC TRIAD ‑ VARIABLE• 1 In 10K‑ 500K• 1 In 150K In HONG KONG• MAYO Clinic Criteria• 1 IN 10,000 AT MAYO CLINIC• Local Population Olmsted Cty• FORME FRUSTE ‑ FIVE TIMES MORE

COMMON THAN CLASSIC

USUHS 79

Tuberous Sclerosis

• “Hamartomas” - CNS (Cortical Ventricular)- Retina (Phakoma)- Kidney (Angio Myo Lipoma - Aml)

• Angiofibromas– Face (“Adenoma Sebaceum”)– Nail Bed (“Fibromas”)

USUHS 80

Tuberous Sclerosis:

• Rhabdomyomas - Heart– “Hamartomas”

• Angiomyomatosis - Lung– smooth muscle proliferation

USUHS 81

Tuberous Sclerosis: Cutaneous

• "Adenoma Sebaceum"• Peau D'orange• Ash‑Leaf Macule• Ungual Angiofibromas

USUHS 82

Adenoma Sebaceum

• aka PRINGLE'S DISEASE• NOT present at birth• develop before puberty• nasolabial fold ‑>bi‑malar• papules of angiofibroma

USUHS 83

Depigmentation:

• Ash‑Leaf Spots– (Lance‑ Ovate Shape)

• Confetti‑ Like Hypopigmentation– (Inverse Freckle)

USUHS 84

Other Cutaneous Manifestations

• Subepidermal Fibrosis:• Dorsal Surfaces• "Shagreen Patch"• "Peau D'orange"• "Pigskin"• "Elephant Hide"

USUHS 85

TUBEROUS SCLEROSIS: Ocular

• PHAKOMA• - benign astrocytic hamartoma• LEUKOKORIA

– White light reflex• Calcification Common

• Especially over Optic Nerve

USUHS 86

TUBEROUS SCLEROSIS ‑ BRAIN:

• HETEROTOPIAS AND HAMARTOMAS– in white and gray matter

• CORTICAL TUBERS– "HAMARTOMAS"– but with abnormal "N" cells– neither Astrocyte nor Neuron– Decreased Myelination– No laminar architecture

USUHS 87

TUBEROUS SCLEROSIS - BRAIN:

• SUBEPENDYMAL NODULES (almost 100%)– "hamartomas" vs. neoplasia– Caudothalamic groove– Polypoid "Candle Gutterings"

• DILATED VENTRICLES– variable– obstructive, atrophic vs. "idiopathic"

• TUMORS 15%• Sub‑ependymal Giant Cell Astrocytoma

– True neoplasm, Benign WHO Grade I

USUHS 88

TUBEROUS SCLEROSIS

• Renal– Angiomyolipoma– Multiple Simple Cysts– Another cause of PCKD– RCC Reported

USUHS 89

ANGIOMYOLIPOMA:

• 10% w/enough FAT for plain film• 1/6 OF Solitary AML Pts. Have TS• 1/3-12 OF solitary AML Pts. Have other

stigmata of TS• 50-80% 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

USUHS 90

ANGIOMYOMATOSIS vs. LYMPHANGIOMYOMATOSIS

• "sporadic" cases, all are female– 50% chylothorax– Perilymphatic smooth mm.– May have abdominal LN involvement

• In TS, males can be affected – chylothorax is rare– Smooth mm around pulmonary aa

USUHS 91

TUBEROUS SCLEROSIS

• ADENOMA SEBACEUM 90%• SEIZURES 90% • RETARDATION 40-60% %• RETINAL 50%• PHAKOMA 50%• INTRACRANIAL Ca++ 17% XR, 60% CT• UNGUAL FIBROMATA 15% • GIANT CELL ASTROCYTOMA 15%

USUHS 92

Phakomatoses

• Encephalo‑Trigeminal Angiomatosis• Neurofibromatosis Type 1• Neurofibromatosis Type 2• Tuberous Sclerosis• Cerebello‑Retinal Angiomatosis• Ataxia ‑ Telangiectasia• Neurocutaneous Melanosis

USUHS 93

CEREBELLO‑RETINAL HEMANGIOMATOSIS (von

HIPPEL-LINDAU SYNDROME/VHL)

USUHS 94

NEUROCUTANEOUS ANGIOMATOSES:

• STURGE‑WEBER‑DIMITRI• KLIPPEL‑TRENAUNEY‑WEBER• OSLER‑WEBER‑RENDU• von HIPPEL‑LINDAU• LOUIS‑BAR• FABRY'S DISEASE

USUHS 95

von HIPPEL‑LINDAU:

• Incidence of 1/35K ‑ 40K• 6‑7K pts in USA• AUTOSOMAL DOMINANT• NO RACIAL/SEXUAL PREDILECTION• VARIABLE PENETRANCE/

EXPRESSIVITY• Chromosome 3p25‑26

USUHS 96

von HIPPEL‑LINDAU SYNDROME: History

• 1864 scattered reports of angiomatous lesions of both retina and cerebellum

• 1894 Collins (England)– two sibs with retinal angioma

• 1904 von Hippel (Germany)– familial retinal hemangioblastoma

• 1926 Lindau (Sweden)– familial retinal and cerebellar

hemangioblastomas• 1964 Melmon and Rosen

USUHS 97

von HIPPEL ‑ LINDAU

1. CNS and Retinal hemangioblastoma2. Hemangioblastoma and one:

a. renal, pancreatic, hepatic, epididymal cystb. pheochromocytoma c. renal cancer

3. Family history and one: a. hemangioblastoma b. viscerac. pheochromocytomad. renal cancer

USUHS 98

von HIPPEL‑LINDAU SYNDROME: NIH

Classification

• Type I ‑ VHL w/o Pheo– Renal/Pancreatic cysts, RCC– most common type

• Type II ‑ VHL with Pheo– IIA Islet cell tumors (no cysts)– IIB Renal/Pancreatic Disease

• least common type

USUHS 99

von HIPPEL‑LINDAU

• Hemangioblastoma– Cerebellum– Retina– Medulla, Cord

• Cysts/Tumor– Kidney– Liver– Pancreas

• Epididymis and Endolymphatic Cystadenoma• Pheochromocytoma -Adrenal (Certain Families -

Type II)

USUHS 100

Von HIPPEL-LINDAU:Six Classic Lesions

• Hemangioblastoma• Retinal Angioma• Pancreatic Cyst• Renal Cysts and Ca• Pheochromocytoma• Epididymal Cystadenoma

USUHS 101

von HIPPEL‑LINDAUManifestations (Freiburg

6/93)

• Retinal Angioma 52%• Hemangioblastoma 43%• Pheochromocytoma 35%• Pancreatic Cyst 18%• Renal Cysts/Ca 25‑45%• Cystadenoma (testis) 3%

USUHS 102

von HIPPEL‑LINDAU:Risk for VHL (unselected

pts.)

• Retinal Angiomatosis => 85%• Hemangioblastoma => 19%• Pheochromocytoma =>18%• Renal Cell Carcinoma ??

– Risk for 3p is 100%

USUHS 103

Endolymphatic Sac Tumors

• Posterior fossa/CPA mass• Arises from Endolymphatic Sac

(intradural)– at end of vestibular aqueduct

• Histology is cystadenoma– Like testicular epididymal cystadenoma

• Local bone destruction• Enhance +/‑ necrosis• Bright on T1W MR

– blood?, protein?

USUHS 104

von HIPPEL‑LINDAU:Renal Manifestations

• CYSTS 25‑63%• ANGIOMAS 7%• ADENOMAS 14%• CLEAR CELL CA 15‑50%

– increases with age to >50% above age 50

USUHS 105

von Hippel‑LINDAU: Pancreas

• Pancreatic cysts 18‑72%• Pancreatic adenoma 7%

– microcystic ("glycogen rich")• Pancreatic Ca reported in single family• ISLET CELL TUMORS

USUHS 106

HEMANGIOBLASTOMA:

• TRUE NEOPLASM Endothelial Origin• HYPERVASCULAR

• capillary to sinusoidal• dilated feeding artery• dilated draining vein• slow flow

• STROMAL Cells• foamy, lipid‑laden

USUHS 107

von HIPPEL‑LINDAU: HEMANGIOBLASTOMA

• Cerebellum 66%• Retina ("angiomas") 58%• Spinal Cord/Roots 28%• Medulla 14%

USUHS 108

HEMANGIOBLASTOMA AND VHL:

• 1/6‑1/5 of solitary cerebellar hemangioblastomas are associated w/ VHL

• up to 1/2 of medullary occur in VHL• "ALL" MULTIPLE HBL are VHL

– there was one family w/o “known” VHL

USUHS 109

ERYTHROPOIETIN

• in cyst fluid• Elevated ESR• Elevated Hct• Recurrent or metachronous tumor may

cause elevation of Hct

USUHS 110

von HIPPEL-LINDAU:VISCERAL DISEASE

• Renal Cell Carcinoma– Multiple– Bilateral– Conservative Surgery

USUHS 111

Pancreatic Adenoma In Vhl

• Microcystic (Not Macrocystic)• Serous (Not Mucin Producing)• Not Pre-Malignant• Glycogen Rich• Stellate Scar

– which may be visible, have Ca++

USUHS 112

PHEOCHROMOCYTOMA AND VHL

• 20% of ALL Pheochromocytoma are VHL• Typically in Adrenal• Present YOUNGER w/VHL• Multiple with VHL• Mortality (5% of VHL DIE from

catecholamines)• Workup: MR and MIBG (95% sensitive)

– 24hr NOREPINEPHRINE– VMA (53% sensitive)– US (40% sensitive)

USUHS 113

Papillary Cystadenoma

• Epididymis 10‑26% of VHL men– 2‑3 cm– if BILATERAL ‑> VHL– Obstructive azoospermia– Infertility

• Broad Ligament (in Women)– Embryologic analogue of epididymis

USUHS 114

Von Hippel-Lindau:

• Hemangioblastoma– Cerebellum– Retina– Medulla, Cord

• Cysts/Neoplasms– Kidney– Liver– Pancreas– Epididymis

• Pheochromocytoma -Adrenal

USUHS 115

Phakomatoses - Mnemonic

• NF‑1 (von Reck's) Truly Neurofibromatosis– HAS mult. NFBA/#17

• NF‑2 is M.I.S.M.E. (Bil. VIII) Syndrome/#22– Does not Really have Neurofibroma

• STURGE‑WEBER (Dimitri) Syndrome– Congenital Vascular Lesion, perhaps NOT

inherited • TUBEROUS SCLEROSIS

– Pringle's "HAMARTOMA" Disease• von HIPPEL‑LINDAU Syndrome

– Hemangioblastomas and Visceral Lesions– NO cutaneous lesions