THE PHAKOMATOSES James G. Smirniotopoulos, M.D. Uniformed Services University of the Health Sciences 4301 Jones Bridge Road Bethesda, MD 20814 Voice: 301-295-3145 FAX: 301-295-3893 Visit us on the WEB: http://rad.usuhs.mil/rad USUHS

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

THE PHAKOMATOSES Neuro ‑ Ectodermal ‑ or ‑ Nerves and Skin USUHS

NEUROCUTANEOUS SYNDROMES (Partial Listing) AUTOSOMAL DOMINANT: Neurofibromatosis Tuberous Sclerosis von Hippel‑Lindau Gorlin's Hypomelanosis of Ito USUHS

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

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 USUHS

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

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

PHAKOMATOSES NEUROFIBROMATOSIS Type 1, Chromosome 17q11 TUBEROUS SCLEROSIS Chromosome 9q, 16p, 11? STURGE‑WEBER (? not inherited) von HIPPEL‑LINDAU Chromosome 3p25 USUHS

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

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

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

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

NEUROFIBROMATOSIS TYPE 2 (NF‑2) ‑Bilateral Acoustic Schwannoma ‑"Central Neurofibromatosis" ‑Minimal Skin Manifestations ‑Multiple Schwannomas, Meningiomas, Ependymomas HENCE the nickname “MISME” USUHS

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

NEUROFIBROMATOSIS - 1 USUHS

NEUROFIBROMATOSIS Species Affected MAN GOLDFISH TURKEYS CATTLE USUHS

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

NF‑1 (VRD or "PERIPHERAL") USUHS

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

NEUROFIBROMATOSIS ‑ 1 Clinical Chromosome Abnl.: 17 Ocular: Myelinated retina Cutaneous: cafe‑au‑lait, neurofibroma CNS: Optic N. Glioma, Hamartoma, Heterotopia, Macrocephaly, Mentation USUHS

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

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

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

NEUROFIBROMATOSIS ‑ 1 Bony Dysplasia Macrocephaly Craniofacial (esp. Sphenoid) Vertebral (scalloping, scoliosis) Pseudoarthrosis (esp. CONGENITAL) Genu Valgum/Varum "Ribbon Ribs" USUHS

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

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

NERVE SHEATH TUMORS USUHS

Pathology USUHS

SCHWANNOMA vs. NEUROFIBROMA Encapsulated vs. Infiltrating Focal Involvement vs. Diffuse, Reticular Schwann Cells vs. S.C. and Fibroblasts “Angiomatous” Vessels vs.Acellular Matrix USUHS

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

INTRASPINAL NEOPLASMS USUHS

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

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

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

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

NEUROFIBROMATOSIS‑1: Spine Scoliosis (Acute Cx Kyphoscoliosis) Vertebral Scalloping Enlarged Neural Foramina Lateral Thoracic Meningocele USUHS

LATERAL THORACIC MENINGOCELE USUHS

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

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

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

NEUROFIBROMATOSIS Malignant Peripheral Nerve Sheath Tumor (neurofibrosarcoma, malignant ...) Embryonal Malignancies: Wilms, Rhabdomyosarcoma Leukemia (CML) Melanoma, Medullary Thyroid Ca. USUHS

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

NF ‑ 2 Autosomal Dominant 1 in 50,000 VIII‑TH Nerve Tumors Other CNS Tumors (Meningioma, Ependymoma) Chromosome 22 USUHS

CNS NEOPLASMS - Chromosome LOH MENINGIOMA ‑ 22q (long arm) SCHWANNOMA ‑ 22q EPENDYMOMA ‑ 22 MEDULLOBLASTOMA ‑ 17p (short arm) NEUROFIBROSARCOMA ‑ 17p RETINOBLASTOMA ‑ 13q USUHS

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

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

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

Neurofibromatosis ‑ 2 Meningiomas: multiple transitional type (NOT meningothelial) Meningioangiomatosis: cortical (intracortical) vascular tissue (resembles a malformation) meningothelial and fibroblast‑like cells USUHS

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 ?? USUHS

NEUROFIBROMATOSIS ‑ 2: MR Imaging Vestibular Schwannoma (Multiple) T1W: hypo‑ to isointense T2W: brighter Meningioma (Multiple) T2W: iso‑ to brighter USUHS

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

NEUROFIBROMATOSIS TYPE‑2 => MISME M ultiple I nherited S chwannomas M eningiomas E pendymomas USUHS

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

NEUROFIBROMATOSES NEUROFIBROMATOSIS 1 Lesions of Astrocytic/Neuronal Origin‑glioma, neurofibroma‑hamartoma, heterotopia NEUROFIBROMATOSIS 2 Lesions of Covering/Lining‑meningioma, schwannoma‑ependymoma USUHS

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

THE PHAKOMATOSES von Recklinghausen Disease MISME Syndrome Sturge‑Weber‑Dimitri Syndrome Bourneville Disease von Hippel‑Lindau Syndrome USUHS

STURGE-WEBER SYNDROME: Classic Triad Facial Neveus Flammeus Port-Wine Stain Seizures Mental Deficiency USUHS

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

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

STURGE-WEBER: Manifestations Seizures, Mental Decline Facial Angioma Angiomatous Overgrowth Leptomeningeal Angioma Cortical Atrophy w/Ca++ USUHS

STURGE-WEBER: Variants Facial and Intracranial w/o Eye Intracranial and Eye w/o Face Intracranial Alone (Cerebral and Leptomeningeal) Klippel-Trenaunay (?) USUHS

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

Association of PWS with SWS All 3 >> 1+2 >> 1 or 2 alone >> other locations medial aspect of eyelid (V1 or V2) USUHS

STURGE-WEBER: Orbit/Eye BUPHTHALMOS -congenital glaucoma -enlarged globe CHOROIDAL ANGIOMA EPISCLERAL TELANGIECTASIA ANGIOMATOUS OVERGROWTH EOM’s USUHS

STURGE-WEBER: Vascular Absence of cortical veins Poor filling of sagittal sinus Persistent Primitive Plexus (SAS) Recruitment of Medullary Veins Prominent Choroid Plexus USUHS

STURGE-WEBER: Pathology Facial Nevus Flammeus - dilated tortuous vv. - from Ectoderm originally overlying the affected brain USUHS

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 USUHS

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

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

STURGE-WEBER Gadolinium Enhancement Abnormal BBB in Cortex (Chronic ischemia) "Epi-Cortical" enhancement (slow flow in superficial veins) USUHS

STURGE-WEBER: Treatment Symptomatic (anticonvulsants) Cosmetic Tattooing Laser Treatment of Skin Hemispherectomy Aspirin ? Prevent thrombosis in telangiectasias USUHS

TUBEROUS SCLEROSIS Original “VOGT TRIAD” FACIAL NEVUS (ADENOMA SEBACEUM) SEIZURES MENTAL DEFICIENCY USUHS

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

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

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

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

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

Tuberous Sclerosis “Hamartomas” - CNS (Cortical Ventricular) - Retina (Phakoma) - Kidney (Angio Myo Lipoma - Aml) Angiofibromas Face (“Adenoma Sebaceum”) Nail Bed (“Fibromas”) USUHS

Tuberous Sclerosis: Rhabdomyomas - Heart “Hamartomas” Angiomyomatosis - Lung smooth muscle proliferation USUHS

Tuberous Sclerosis: Cutaneous "Adenoma Sebaceum" Peau D'orange Ash‑Leaf Macule Ungual Angiofibromas USUHS

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

Depigmentation: Ash‑Leaf Spots (Lance‑ Ovate Shape) Confetti‑ Like Hypopigmentation (Inverse Freckle) USUHS

Other Cutaneous Manifestations Subepidermal Fibrosis: Dorsal Surfaces "Shagreen Patch" "Peau D'orange" "Pigskin" "Elephant Hide" USUHS

TUBEROUS SCLEROSIS: Ocular PHAKOMA - benign astrocytic hamartoma LEUKOKORIA White light reflex Calcification Common Especially over Optic Nerve USUHS

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

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

TUBEROUS SCLEROSIS Renal Angiomyolipoma Multiple Simple Cysts Another cause of PCKD RCC Reported USUHS

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

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

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

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

CEREBELLO‑RETINAL HEMANGIOMATOSIS (von HIPPEL-LINDAU SYNDROME/VHL) USUHS

NEUROCUTANEOUS ANGIOMATOSES: STURGE‑WEBER‑DIMITRI KLIPPEL‑TRENAUNEY‑WEBER OSLER‑WEBER‑RENDU von HIPPEL‑LINDAU LOUIS‑BAR FABRY'S DISEASE USUHS

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

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

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 USUHS

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

von HIPPEL‑LINDAU Hemangioblastoma Cerebellum Retina Medulla, Cord Cysts/Tumor Kidney Liver Pancreas Epididymis and Endolymphatic Cystadenoma Pheochromocytoma -Adrenal (Certain Families -Type II) USUHS

Von HIPPEL-LINDAU: Six Classic Lesions Hemangioblastoma Retinal Angioma Pancreatic Cyst Renal Cysts and Ca Pheochromocytoma Epididymal Cystadenoma USUHS

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

von HIPPEL‑LINDAU: Risk for VHL (unselected pts.) Retinal Angiomatosis => 85% Hemangioblastoma => 19% Pheochromocytoma =>18% Renal Cell Carcinoma ?? Risk for 3p is 100% USUHS

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

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

von Hippel‑LINDAU: Pancreas Pancreatic cysts 18‑72% Pancreatic adenoma 7% microcystic ("glycogen rich") Pancreatic Ca reported in single family ISLET CELL TUMORS USUHS

HEMANGIOBLASTOMA: TRUE NEOPLASM Endothelial Origin HYPERVASCULAR capillary to sinusoidal dilated feeding artery dilated draining vein slow flow STROMAL Cells foamy, lipid‑laden USUHS

von HIPPEL‑LINDAU: HEMANGIOBLASTOMA Cerebellum 66% Retina ("angiomas") 58% Spinal Cord/Roots 28% Medulla 14% USUHS

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

ERYTHROPOIETIN in cyst fluid Elevated ESR Elevated Hct Recurrent or metachronous tumor may cause elevation of Hct USUHS

von HIPPEL-LINDAU: VISCERAL DISEASE Renal Cell Carcinoma Multiple Bilateral Conservative Surgery USUHS

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

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

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

Von Hippel-Lindau: Hemangioblastoma Cerebellum Retina Medulla, Cord Cysts/Neoplasms Kidney Liver Pancreas Epididymis Pheochromocytoma -Adrenal USUHS

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