Inherited Tumor Syndromes

• Neurofibromatosis type 1 – peripheral form, 1/3000; 20% involve CNS; accounts for 90% of all cases of NF
• Autosomal dominant on chromosome 17 (but 50% spontaneous); Caucasians affected more
• Criteria for diagnosis – need 2 of following:
• 2 neurofibromas (or one plexiform)
• 6 café au lait spots
• axillary or inguinal freckling
• osseous lesions (thin long bones, sphenoid dysplasia)
• optic glioma
• 2 Lisch nodules
• family history of NF1
• Associated tumors: malignant peripheral nerve sheath tumors, optic glioma, astrocytoma, ependymoma, hamartomas in white matter and basal ganglia, spinal hamartomas/astrocytomas
• Associated with scoliosis, widened spinal canal, posterior vertebral body scalloping (from dural ectasia), patulous dura, meningocele, renal artery stenosis, mental retardation, seizure, acqueductal stenosis with hydrocephalus, microphthalmia, retinal phakomatosis, moya-moya disease, aneurysms, AVM
• 1:4000, autosomal dominant, chromosome 17, variable expression
• skin: café au lait spots, subcutaneous neurofibromas, mollusca fibrosa (cutaneous fibromas), plexiform neuroma, axillary freckles
• ocular: lisch nodules (melanocytic hamartomas of iris)
• neoplasia: leukemia, neuroblastoma, medullary thyroid cancer, MEN syndromes
• neurologic: MR, epilepsy in 10-15%
• intracranial neoplasm: optic nerve glioma, multiple meningiomas
• spinal neoplasm: meningioma, neurofibroma, glioma
• peripheral nerve neoplasm – neurofibroma
• skeletal – scoliosis
• 5% of neurofibromas undergo malignant degeneration
• Neurofibromatosis type 2 – central form, CNS usually affected
• 1:50,000, autosomal dominant, chromosome 22
• skin: plaques (well circumscribed, raised area, rough and associated with excess hair)
• bilateral CN VIII tumors
• no lisch nodules
• rare café au lait spots, cutaneous neurofibromas, and plexiform neurofibromas
• Autosomal dominant on chromosome 22
• Hallmark is vestibular schwannoma (usually bilateral); 5% of patients with vestibular schwannoma have NF2
• Criteria for diagnosis – need bilateral vestibular schwannoma (or family history and one vestibular schwannoma) and 2 of the following:
• Neurofibroma
• Schwannoma
• Meningioma
• Glioma
• Postcapsular cataract
• Associated tumors: meningiomas, astrocytomas, hamartomas, spinal ependymomas and schwannomas
• Osseous changes due to tumors NOT dural ectasias
• Rarely see café au lait spots, plexiform neurofibromas, cutanous neurofibromas (cutaneous lesions are usually schwannomas); Lisch nodules not seen; no vascular malformation/risk of stroke (as with type 1)
• Other Neurofibromatosis Syndromes
• Type III – Combination of NF-1 and NF-2
• Type IV – Heterogenous form
• Type V – Segmental FN
• Type VI – Café-au-lait spots without neurofibroma
• Type VII – Late onset, but typical presentation
• Tuberous Sclerosis – Bourneville’s disease, 1/100,000
• 1:30,000, autosomal dominant on chromosome 9 (tuberin) and 11 (hamartin), variable expression
• pathology: dysplastic neuronal/glial cells located periventricular (periventricular nodules, “candle guttering”), in white matter (heterotopias), and in cortex (tubers)
• subependymal giant cell astrocytomas
• primitive renal tumors, cystic lung hamartomas
• shagreen patches in 20%
• skin: adenoma sebaceum (end of 1 year old) in 80-90%; depigmented areas of trunk (ash spots), occasional fibromas and café au lait spots
• neuro: MR in 60%; seizures in up to 100%
• neoplasia: renal cell carcinoma in 50%; multiple tumors of heart common (rhabdomyomas)
• CT may show subependymal areas of calcium deposition
• MRI shows uncalcified subependymal tubers
• Autosomal dominant but often sporadic; chromosomes 9 and 11
• Classic triad (seen in less than half): mental retardation, seizures, adenoma sebaceum (angiomatous facial lesions)
• Associated with facial angiofibroma, periungual/subungual fibromas, fibrous plaque on forehead/scalp, hydrocephalus, moya moya, aortic aneurysms, ash leaf hypopigmented macules, shagreen patches (subepidermal orange peel fibrosis of lower trunk), cystic metacarpals, salaam spasms (flexor myoclonus treated with ACTH), aggressive behavior; 90% have skin lesion by 10 years of age
• Associated tumors: tubers (95%, firm hamartomas of large dysplastic neurons and astrocytes in thalamostriate sulcus, cortex, subependymal region), SEGA, cardiac rhabdomyoma, renal angiomyolipoma, cysts of lung/liver/spleen, pancreatic adenoma, retinal hamartoma (in most patients but rarely affects vision)
• Supependymal hamartomas
• Radiology:  Typically posterior to foramen of Monro, isointense to gray matter, calcify with age, do not enhance on CT, may enhance on MRI
• 10% transform to giant cell astrocytoma
• Giant cell astrocytoma
• Radiology:  Enlarging enhancing (both CT and MRI) lesion that invades parenchyma, hydrocephalus is common
• Generally benign course
• Small percentage undergo malignant transformation
• Cortical hamartomas (tubers)
• Radiology:  Initially decreased T1, increase T2; over time become isointense on T1; calcify with age; 30% enhance
• Number of lesions correlates with degree of retardation
• Heterotopic islets
• Candle guttering is seen in the floor of the lateral ventricles with frequent calcification; occasionally enhance
• Associated with West sydrome (infantile spasm and hypsarrythmia in EEG), treated with ACTH
• Sturge-Weber – no genetic transmission; possibly due to congested cortical drainage due to venous stasis and hypoxia leading to atrophy and dystrophic calcification
• Port-wine stain (nevus flammeus) in V1 distribution, ipsilateral venous angioma of leptomeninges, choroid of eye, choroid plexus, glaucoma
• Hemispheric atrophy with hemiparesis/hemisensory loss/homonymous hemianopsia, intracortical parietooccipital tram-track calcifications (in middle cortical layer), seizures, mental retardation, ipsilateral skull thickening with large frontal sinus, prominent subependymal veins
• facial angioma association with leptomeningeal venous angioma
• Capillary nevus – port wine stain in 1^st and 2^nd division of CN V
• Atrophic hemisphere – ipsilateral to nevus; parietooccipital calcifications in cortex (not vessels)
• epilepsy in 75%
• homonymous hemianopsia in 30%; MR in 50%
• Eye disorders – congenital glaucoma (bupthalmous), choroidal angioma
• Skull xrays – tram-tracking (linear calcifications)
• Angio – meningeal venous angiomas
• Von Hippel Lindau – 1/40,000
• Autosomal dominant, chromosome 3, mixed penetrance
• Usually presents as young adult (age 10-30)
• 20% of hemangioblastoma patients have vHL
• associated with hemangioblastoma (Lindau tumor), retinal neurofibroma (von Hippel tumor), renal cell carcinoma, pheochromocytoma, cyst in liver/pancreas/kidney, epididymal cystadenoma
• Criteria for diagnosis: multiple hemangioblastomas (or one with family history)
• Visceral abnormalities:
• Retinal angiomas
• Renal cell cancer
• Pheochromocytoma
• Pancreatic adenoma/cyst
• Erythrocytosis
• Cysts and hemangiomas in liver and epididymis
• Retinal hemangioblastomas – may cause sudden blindness
• Cerebellar hemangioblastoma
• Spinal cord hemangioblastoma
• Rendu-Osler-Weber – hereditary hemorrhagic telangiectasia; 50% have CNS lesions, usually due to pulmonary AVF; most present with epistaxis
• Autosomal dominant
• Ryburg-Mason syndrome – unilateral cutaneous vascular nevi in face and trunk; AVM of retina/optic nerve/visual pathway/midbrain
• Summary of Hereditary Syndromes Associated with CNS Neoplasm
• Neurofibromatosis type I (von Recklinhausen's Disease)
• Gene: NF1 (17q)
• Gene Product: Neurofibromin (GTPase activating protein)
• Nervous System Neoplasms: neuroma, schwannoma, meningioma, optic glioma
• Neurofibromatosis type II
• Gene: NF2 (22q)
• Gene Product: Merlin (cytoskeletal protein)
• Nervous System Neoplasms: schwannoma, glioma, ependymoma, meningioma
• Tuberous sclerosis
• Gene: TSC1 (9q) or TSC2 (16p)
• Gene Product: Hamartin (unknown function) from TSC1, or Tuberin (GTPase activating protein) from TSC2
• Nervous System Neoplasms: astrocytoma
• von Hippel-Lindau
• Gene: VHL (3p)
• Gene Product: pVHL (moderator of mRNA elongation)
• Nervous System Neoplasms: hemangioblastoma of retina, cerebellum and spinal cord; pheochromocytoma
• Li-Fraumeni
• Gene: p53 (17p)
• Gene Product: TP53 (cell cycle and transcriptional regulator)
• Nervous System Neoplasms: malignant glioma
• Retinoblastoma
• Gene: RB1 (13q)
• Gene Product: RB (cell cycle regulator)
• Nervous System Neoplasms: retinoblastoma, pinealoblastoma, malignant glioma
• Turcot
• Gene: APC (5q) - stands for Adenomatous Polyposis Coli
• Gene Product: APC (cell adhesion)
• Nervous System Neoplasms: medulloblastoma, malignant glioma
• Gorlin (basal cell nevus syndrome)
• Gene: PTCH (9q) - "patched"
• Gene Product: PTH (developmental regulator)
• Nervous System Neoplasms: medulloblastoma