a group of autosomal dominant genetic disorders with variable penetrance characterized by various skin abnormalities and an increased risk of nervous system tumors
Neurofibromatosis Type I
aka Von Recklinghousen’s disease
incidence 1/4000
neuro lesion
: neurofibromas
benign peripheral tumors of Schwann cells and fibroblasts; however - may undergo malignant transformation
usually assymptomatic, but can grow to produce compressive radiculopathy or neuropathy
other sequelae: hydrocephalus, scoliosis, short stature, HTN, epilepsy, mental retardation
other lesions
: café au lait spots, freckling of non-sun exposed skin, hamartomas of the iris (Lisch nodules), pseudoarthrosis of the tibia
Lisch nodules
are important because they can be detected far earlier than other lesions
genetics
: NF1 gene on chrom. 17 codes for neurofibromin protein which modulates ras G-protein pathways
Neurofibromatosis Type II
incidence 1/50,000
really doesn’t have a whole lot in common with NF1
neuro lesion
: bilateral vestibular schwannomas in 90% of cases; usually results in progressive unilateral deafness by in early 30s; management is via surgery, but not very effective
vestibular schwannomas always arise where oligodendrocytes give way to schwann cells along the nerve
also predisposed to meningiomas, gliomas, schwannomas of cranial and spinal nerves
other lesions
: skin lesions are seldom found; juvenile posterior subcapsular lenticular opacity (a type of cataract)
genetics
: NF2 gene on ch. 22q codes for neurofibromin 2, schwannomin or merlin (part of family of cytoskeletal proteins)
Tuberous Sclerosis
aka Bourneville’s Disease
incidence 1/29,000
characteristics
: cutaneous lesions, seizures, mental retardation
skin lesions
: adenoma sebaceum, ash leaf-shaped hypopigmented macules (best seen with Wood’s lamp), shagreen patches (yellowish thickenings in lumbosacral region), depigmented nevi
neuro lesions
: subependymal nodules which may be calcified are characteristic
predisposed to ependynomas and childhood astrocytomas (90% are subependymal giant cell astrocytomas)
benign neoplasms that develop in retina and walls of ventricles and may have mass effects
also predisposed to angiomyomas of kidney, liver, adrenals, pancreas; rhabdomyomas of the myocardium
treatment
: can only treat symptoms - anticonvulsants for seizures, education for retardation, etc
genetics
: mutations are found in both 9q (TSC-1) and 16p (TSC-2); code for tuberins which modulate GTPase activity
Von Hippel-Lindau Syndrome
incidence 1/40,000
characteristics
: retinal angiomas and cerebellar hemangioblastomas (slow-growing cystic tumors)
cerebellar hemangioblastomas may produce erythropoietin and result in polycythemia
other lesions
: hemangioma of spinal cord, hypernephroma, renal cell carcinoma (highly predisposed, phyochromocytoma, cysts of kidney, pancreas, epididymis, liver)
genetics
: VHL gene on 3p appears to be a tumor suppressor gene for Von Hippel-Lindau syndrome
Other Hereditary tumor syndromes
retinoblastoma: not very common, but gave us a lot of insight on tumor development (Knudson’s two hit hypothesis)
mutation of both copies of Rb gene on 13q (which controls cell cycle) gives rise to retinoblastoma
why only retinal tumors? no one knows
Li-Fraumeni: also fairly rare; predisposes to gliomas and breast cancer;
mutation in p53 gene on 17 is responsible
Summary of Hereditary Syndromes Associated with Brain Tumors
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