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