1. THE PHAKOMATOSES James G. Smirniotopoulos, M.D.
Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, MD 20814
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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 James G. Smirniotopoulos, M.D.
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3. THE PHAKOMATOSES Neuro ‑ Ectodermal ‑ or ‑ Nerves and Skin
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4. NEUROCUTANEOUS SYNDROMES
(Partial Listing)
AUTOSOMAL DOMINANT:
Neurofibromatosis
Tuberous Sclerosis
von Hippel‑Lindau
Gorlin's
Hypomelanosis of Ito
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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
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6. THE PHAKOMATOSES Five 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
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7. PHAKOMATOSES Why Study Them? They are COMMON diseases
DIAGNOSED by Imaging
GENETIC Implications
SCREEN Relatives
SURVEILLANCE of Affected
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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
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9. PHAKOMATOSES NEUROFIBROMATOSIS Type 1, Chromosome 17q11
TUBEROUS SCLEROSIS
Chromosome 9q, 16p, 11?
STURGE‑WEBER (? not inherited)
von HIPPEL‑LINDAU
Chromosome 3p25
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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
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11. NEUROFIBROMATOSIS 1768 MARK AKENSIDE (New York)
1793 TILESIUS (Leipzig)
1849 R.W. SMITH (England)
1822 WISHART (Edinburg) NF‑2
1882 von RECKLINGHAUSEN (Germany)
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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
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13. NEUROFIBROMATOSES ‑ TYPES
NEUROFIBROMATOSIS TYPE 1 (NF‑1)
‑von Recklinghausen Disease
‑"Peripheral" Neurofibromatosis
‑Prominent cutaneous signs
‑Multiple Neurofibromas
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14. NEUROFIBROMATOSIS TYPE 2 (NF‑2)
‑Bilateral Acoustic Schwannoma
‑"Central Neurofibromatosis"
‑Minimal Skin Manifestations
‑Multiple Schwannomas, Meningiomas, Ependymomas
HENCE the nickname “MISME”
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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
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16. NEUROFIBROMATOSIS - 1
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17. NEUROFIBROMATOSIS
Species Affected
MAN
GOLDFISH
TURKEYS
CATTLE
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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
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19. NF‑1 (VRD or "PERIPHERAL")
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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
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21. NEUROFIBROMATOSIS ‑ 1 Clinical
Chromosome Abnl.: 17
Ocular: Myelinated retina
Cutaneous: cafe‑au‑lait, neurofibroma
CNS: Optic N. Glioma, Hamartoma, Heterotopia, Macrocephaly, Mentation
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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
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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)
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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)
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25. NEUROFIBROMATOSIS ‑ 1 Bony Dysplasia
Macrocephaly
Craniofacial (esp. Sphenoid)
Vertebral (scalloping, scoliosis)
Pseudoarthrosis (esp. CONGENITAL)
Genu Valgum/Varum
"Ribbon Ribs"
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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
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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)
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28. NERVE SHEATH TUMORS
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29. Pathology
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30. SCHWANNOMA vs. NEUROFIBROMA
Encapsulated vs. Infiltrating
Focal Involvement vs. Diffuse, Reticular
Schwann Cells vs. S.C. and Fibroblasts
“Angiomatous” Vessels vs.Acellular Matrix
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31. INTRASPINAL NEOPLASMS
68 Pts. (w/86 Nerve Sheath neoplasms)
SPORADIC - 42 pts. (65%)
42 Schwannoma/2 NFBA
NF Pts. (18%)
All Neurofibroma
NF Pts. (11%)
18 Schwannoma/1 “mixed” tumor
UNKNOWN - 5Pts.
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32. INTRASPINAL NEOPLASMS
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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)
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34. NEUROFIBROMATOSIS: Spine
Scoliosis (NF‑1, only?)
‑Simple ("idiopathic")
‑Acute Cervical Kyphosis
Dural Ectasia (NF‑1, only?)
‑Vertebral Scalloping
‑Arachnoid "cysts"
‑Lateral meningocele
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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
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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
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37. NEUROFIBROMATOSIS‑1: Spine
Scoliosis (Acute Cx Kyphoscoliosis)
Vertebral Scalloping
Enlarged Neural Foramina
Lateral Thoracic Meningocele
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38. LATERAL THORACIC MENINGOCELE
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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.
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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?)
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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
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42. NEUROFIBROMATOSIS Malignant Peripheral Nerve Sheath Tumor
(neurofibrosarcoma, malignant ...)
Embryonal Malignancies:
Wilms, Rhabdomyosarcoma
Leukemia (CML)
Melanoma, Medullary Thyroid Ca.
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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)
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44. NF ‑ 2 Autosomal Dominant 1 in 50,000 VIII‑TH Nerve Tumors
Other CNS Tumors (Meningioma, Ependymoma)
Chromosome 22
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45. CNS NEOPLASMS - Chromosome LOH
MENINGIOMA ‑ 22q (long arm)
SCHWANNOMA ‑ 22q
EPENDYMOMA ‑ 22
MEDULLOBLASTOMA ‑ 17p (short arm)
NEUROFIBROSARCOMA ‑ 17p
RETINOBLASTOMA ‑ 13q
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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
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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"
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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
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49. Neurofibromatosis ‑ 2
Meningiomas: multiple transitional type (NOT meningothelial)
Meningioangiomatosis: cortical (intracortical)
vascular tissue (resembles a malformation)
meningothelial and fibroblast‑like cells
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50. NEUROFIBROMATOSIS‑2 Meningiomas
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%
SPORADIC in 90%
SPORADIC in ??
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51. NEUROFIBROMATOSIS ‑ 2: MR Imaging
Vestibular Schwannoma (Multiple)
T1W: hypo‑ to isointense
T2W: brighter
Meningioma (Multiple)
T2W: iso‑ to brighter
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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
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53. NEUROFIBROMATOSIS TYPE‑2 => MISME
M ultiple
I nherited
S chwannomas
M eningiomas
E pendymomas
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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
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55. NEUROFIBROMATOSES NEUROFIBROMATOSIS 1
Lesions of Astrocytic/Neuronal Origin‑glioma, neurofibroma‑hamartoma, heterotopia
NEUROFIBROMATOSIS 2
Lesions of Covering/Lining‑meningioma, schwannoma‑ependymoma
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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)
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57. THE PHAKOMATOSES von Recklinghausen Disease MISME Syndrome
Sturge‑Weber‑Dimitri Syndrome
Bourneville Disease
von Hippel‑Lindau Syndrome
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58. STURGE-WEBER SYNDROME: Classic Triad
Facial Neveus Flammeus
Port-Wine Stain
Seizures
Mental Deficiency
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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
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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.
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61. STURGE-WEBER: Manifestations
Seizures, Mental Decline
Facial Angioma
Angiomatous Overgrowth
Leptomeningeal Angioma
Cortical Atrophy w/Ca++
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62. STURGE-WEBER: Variants
Facial and Intracranial w/o Eye
Intracranial and Eye w/o Face
Intracranial Alone
(Cerebral and Leptomeningeal)
Klippel-Trenaunay (?)
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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
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64. Association of PWS with SWS
All 3 >> 1+2 >> 1 or 2 alone >> other locations
medial aspect of eyelid (V1 or V2)
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65. STURGE-WEBER: Orbit/Eye
BUPHTHALMOS
-congenital glaucoma
-enlarged globe
CHOROIDAL ANGIOMA
EPISCLERAL TELANGIECTASIA
ANGIOMATOUS OVERGROWTH EOM’s
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66. STURGE-WEBER: Vascular
Absence of cortical veins
Poor filling of sagittal sinus
Persistent Primitive Plexus (SAS)
Recruitment of Medullary Veins
Prominent Choroid Plexus
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67. STURGE-WEBER: Pathology
Facial Nevus Flammeus
- dilated tortuous vv.
- from Ectoderm originally overlying the affected brain
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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
- Enlarged choroidal vessels
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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
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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
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71. STURGE-WEBER Gadolinium Enhancement Abnormal BBB in Cortex
(Chronic ischemia)
"Epi-Cortical" enhancement
(slow flow in superficial veins)
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72. STURGE-WEBER: Treatment
Symptomatic (anticonvulsants)
Cosmetic Tattooing
Laser Treatment of Skin
Hemispherectomy
Aspirin ?
Prevent thrombosis in telangiectasias
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73. TUBEROUS SCLEROSIS Original “VOGT TRIAD”
FACIAL NEVUS (ADENOMA SEBACEUM)
SEIZURES
MENTAL DEFICIENCY
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74. TUBEROUS SCLEROSIS AUTOSOMAL DOMINANT No Racial/Sexual
High Spontaneous Mutation
High Penetrance
"SPORADIC" over‑reported
Multiple Genes
TSC1 ‑ 9q
TSC2 ‑ 16p
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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
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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
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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%
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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
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79. Tuberous Sclerosis “Hamartomas” - CNS (Cortical Ventricular)
- Retina (Phakoma)
- Kidney (Angio Myo Lipoma - Aml)
Angiofibromas
Face (“Adenoma Sebaceum”)
Nail Bed (“Fibromas”)
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80. Tuberous Sclerosis: Rhabdomyomas - Heart “Hamartomas”
Angiomyomatosis - Lung
smooth muscle proliferation
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81. Tuberous Sclerosis: Cutaneous
"Adenoma Sebaceum"
Peau D'orange
Ash‑Leaf Macule
Ungual Angiofibromas
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82. Adenoma Sebaceum aka PRINGLE'S DISEASE NOT present at birth
develop before puberty
nasolabial fold ‑>bi‑malar
papules of angiofibroma
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83. Depigmentation: Ash‑Leaf Spots (Lance‑ Ovate Shape)
Confetti‑ Like Hypopigmentation
(Inverse Freckle)
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84. Other Cutaneous Manifestations
Subepidermal Fibrosis:
Dorsal Surfaces
"Shagreen Patch"
"Peau D'orange"
"Pigskin"
"Elephant Hide"
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85. TUBEROUS SCLEROSIS: Ocular
PHAKOMA
- benign astrocytic hamartoma
LEUKOKORIA
White light reflex
Calcification Common
Especially over Optic Nerve
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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
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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
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88. TUBEROUS SCLEROSIS Renal Angiomyolipoma Multiple Simple Cysts
Another cause of PCKD
RCC Reported
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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
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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
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91. TUBEROUS SCLEROSIS ADENOMA SEBACEUM 90% SEIZURES 90%
RETARDATION % %
RETINAL 50%
PHAKOMA 50%
INTRACRANIAL Ca++ 17% XR, 60% CT
UNGUAL FIBROMATA 15%
GIANT CELL ASTROCYTOMA 15%
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92. Phakomatoses Encephalo‑Trigeminal Angiomatosis
Neurofibromatosis Type 1
Neurofibromatosis Type 2
Tuberous Sclerosis
Cerebello‑Retinal Angiomatosis
Ataxia ‑ Telangiectasia
Neurocutaneous Melanosis
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93. CEREBELLO‑RETINAL HEMANGIOMATOSIS (von HIPPEL-LINDAU SYNDROME/VHL)
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94. NEUROCUTANEOUS ANGIOMATOSES:
STURGE‑WEBER‑DIMITRI
KLIPPEL‑TRENAUNEY‑WEBER
OSLER‑WEBER‑RENDU
von HIPPEL‑LINDAU
LOUIS‑BAR
FABRY'S DISEASE
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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
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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
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97. von HIPPEL ‑ LINDAU 1. CNS and Retinal hemangioblastoma
2. Hemangioblastoma and one:
a. renal, pancreatic, hepatic, epididymal cyst
b. pheochromocytoma
c. renal cancer
3. Family history and one:
a. hemangioblastoma
b. viscera
c. pheochromocytoma
d. renal cancer
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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
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99. von HIPPEL‑LINDAU Hemangioblastoma Cerebellum Retina Medulla, Cord
Cysts/Tumor
Kidney
Liver
Pancreas
Epididymis and Endolymphatic Cystadenoma
Pheochromocytoma -Adrenal (Certain Families -Type II)
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100. Von HIPPEL-LINDAU: Six Classic Lesions
Hemangioblastoma
Retinal Angioma
Pancreatic Cyst
Renal Cysts and Ca
Pheochromocytoma
Epididymal Cystadenoma
USUHS

101. von HIPPEL‑LINDAU Manifestations (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 ‑63%
ANGIOMAS %
ADENOMAS %
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
USUHS