3. Phakomatoses
Neurofibromatosis type 1
Neurofibromatosis type 2
Tuberous sclerosis complex
Von Hippel-Lindau disease
Sturge-Weber disease
Osler-Weber-Rendu syndrome
Wybrun-Mason syndrome
Ataxia-telangiectasia
Klippel-Trenauny-Weber syndrome
Epidermal nevus syndrome
4. Neurofibromatosis type 1 (NF1)
• Von Recklinghausen, 90% of NF
• Most common neurocutaneous disorder, 1 in 3000 births
• Autosomal dominant, 100% penetrance, but variable expressivity
• Located on chromosome 17; NF1 gene encodes for neurofibromin
• 50% occur by spontaneous mutation without a family history
• Usually has an early onset and affects mainly Caucasians.
• Lesions
• 20% of cases develop CNS lesions
• 30% have mental retardation
• 5% develop malignant peripheral nerve sheath tumors
5. Neurofibromatosis type 1 (NF1)
• Neurofibromin protein
• Member of GTPase-activating protein (GAP) group
• Plays a role in inactivating p21-Ras
• p21-Ras works in growth factor signaling pathways
• With mutation of NF1 gene and absence of neurofibromin protein, p21-Ras
activation leads to increased cell proliferation and survival
6. Neurofibromatosi
s type 1 (NF1)
• Inclusion criteria are at least two of the
following:
• Six café au lait spots
• Two neurofibromas, one plexi-form
neurofibroma
• Axillary or inguinal freckling
• Osseous lesion (sphenoid dysplasia
or thinning of long bones or cortex)
• Optic glioma
• Two or more Lisch nodules (iris
hamartomas, only seen with NF1)
• A first-degree relative with NF1
7. Neurofibromas
• Boggy, cap-like lesions on skin involving the subcutaneous tissue
• Affects peripheral nerves and skin
• Consists of Schwann cells and fibroblasts, perineural cells, endothelial cells,
mast cells, pericytes, and intermediate cell types
• See increase in Schwann cells numbers with reduced association with axons
• Breakdown of perineural layer and disorganization of cells
• Nearly ubiquitous to NF1, indolent and benign
• Optimal management: careful observation
• Surgical intervention for symptomatic cases
8. Plexiform Neurofibromas
• Extend across length of nerve and involve multiple nerve fascicles or multiple
branches of large nerve
• Frequently involve nerve roots at multiple levels
• Potentially sizeable mass or diffusely thickened nerve tissue, invade adjacent
muscles/organs
• Spinal compression, myelopathy, quadriparesis/paraparesis
• Potential for degeneration to malignant peripheral nerve sheath tumors (5.9-
13%)
• Goal of tx: control of symptoms, not amenable to cure
• Good results with laminectomy for debulking and decompression
• Regrowth of tumor with return of sxs does occur
• Concern for kyphosis after multiple surgeries
9. Malignant Peripheral Nerve Sheath
Tumors
• 4%-10% of all NF1 patients
• Presents between 15-50 years of age
• Arise within plexiform neurofibromas
• Can be multifocal
• Highly malignant with rapid hematogenous dissemination
• Difficult to distinguish from plexiform neurofibromas
• Poor outcome – best outcome with radical resection
• Do not respond well to chemo or radiation
10. Spinal Nerve Root Tumors
• Spinal nerve root tumors are plexiform neurofibromas
• Nerve roots involved w/ enlargement of neural foramen
• Possible scalloping of vertebral bodies
• High cervical and lower lumbar spine - most common
• Can extend through foramen and compress cord
11.
12. Optic Gliomas
• Usually present between 18 months – 7 years
• Anterior optic pathway – 15% of NF1 patients
• Include optic nerve, chiasm or hypothalamus
• Visual impairment in 20-30% of patients
• HA, visual complaints, proptosis, endocrine disturbances, local mass effect,
hydrocephalus
• MRI is test of choice
• Tx: conservative management until MRI progression/sxs
• Subtotal resection is acceptable and preferable
• Adjuvant chemo: vincristine and carboplatin
• Radiation – risk of radiation necrosis, cognitive problems, visual loss, secondary
malignancy and moyamoya
14. Neurofibromatosis type 2 (NF2)
• Mulitple Inherited Schwannomas, Meningiomas, and Ependymomas (MISME)
• Occurs in 1 in 50,000 births
• Autosomal dominant transmission, 99% penetrance by 60 years old
• Located on chromosome 22, and the gene involved is Merlin
• Different types of mutations depict severity of disease
• Single codon/single amino acid missense, somatic mosaicism, splice site mutations,
large deletions – mild phenotypes
• Protein truncating, frameshift mutations – severe phenotypes
15. Neurofibromatosis type 2 (NF2)
• Inclusion criteria:
• Bilateral vestibular schwannoma
• A relative with NF2 and one vestibular schwannoma
• Two of the following:
• Neurofibroma, meningioma, glioma, schwannoma, or postcapsular cataract at a young age
• 20% have spinal nerve schwannomas (70% are intradural extramedullary, 15%
are extradural, and 15% are dumbbell)
• 2 to 10% of people with a vestibular schwannoma have NF2
16. Neurofibromatosis type 2 (NF2)
• Associated tumors
• Bilateral vestibular schwannomas
• Meningiomas
• Astrocytomas
• Hamartomas
• Spinal ependymomas (spinal astrocytomas are more common in NF1)
• Nerve root schwannomas.
• ***There are less café au lait spots and cutaneous neurofibromas.
There are no plexiform neurofibromas or Lisch nodules.***
17. Tuberous sclerosis complex
(TSC)
• Bourneville disease
• Autosomal dominant transmission, usually sporadic
• Located on chromosomes 9 (TSC1, hamartin) and 16 (TSC2, tuberin)
• Occurs in 1 in 10,000–100,000 births
• Proteins hamartin and tuberin
• Form tuberin-hamartin complex that controls mTOR
• Complex regulates cell proliferation through mTOR to inhibit activity of S6 kinase
18. Tuberous sclerosis complex
(TSC)
• Diagnosed by facial angiofibromas, periungual and subungual fibromas, or
fibrous plaque of the forehead or scalp
• Classic triad occurs in <50% of cases and includes:
• Mental retardation
• Seizures (infantile spasm)
• Adenoma sebaceum (angiofibromas)
• Skin lesions:
• Hypopigmented macules, shagreen patches, subungual fibromas, facial
angiofibromas
19.
20. Tuberous sclerosis complex
(TSC)
1.Associated tumors
1. Tubers (seen in 95% of cases)—multiple firm lesions that are hamartomas with
large dysplastic neurons and astrocytes in the thalamostriate sulcus, cortex, and
subependymal region. These cause candle guttering in the floor of the lateral
ventricle, frequently calcify, and occasionally enhance.
2. Subependymal giant cell astrocytoma (15% of cases)—located near the foramen of
Monro, rarely undergoes malignant change, grows slowly, and enhances.
3. Cardiac rhabdomyoma (30% of cases)
4. Renal angiomyolipoma (60% of cases)
5. Cysts in the lung, liver, and spleen
6. Pancreatic adenoma
7. Retinal hamartoma (>50% of cases)—rarely affects vision
22. Von Hippel-Lindau disease
• Autosomal dominant transmission
• 1 in 40,000 births
• Mutation of the VHL gene, a tumor suppressor gene on chromosome 3
• Gene product, pVHL, normally involved in the regulation of hypoxia-inducible genes;
for example, vascular endothelial, platelet-derived and transforming growth factors
• VHL syndrome rarely presents before 20 years and renal cell carcinoma usually
occurs near 40 years of age
23. Von Hippel-Lindau disease
• Diagnosis:
• Multiple CNS hemangioblastomas or
• One CNS hemangioblastoma and one visceral lesion with a first-order relative with
VHL
• 20% of hemangioblastomas are in patients with VHL.
• Cerebellar hemangioblastoma is Lindau tumor.
• Cerebellar hemangioblastoma + an extra CNS lesion is Lindau disease.
• Retinal hemangioblastoma is von Hippel tumor. May be associated with
polycythemia vera.
24. Von Hippel-Lindau disease
1.Associated tumors
1. Hemangioblastomas (seen in 60% of cases)—cerebellum (65%), brainstem (20%),
and spinal cord (15%)
2. Retinal hemangioblastoma (50% of cases)
3. Renal cell carcinoma (30% of cases) and angiomatosis
4. Pheochromocytoma (10% of cases)
5. Cysts (60% of cases)—liver, pancreas, and kidney
6. Epididymal cystadenoma
25. Pheochromocytomas
• Threat of peripoperative hypertensive crisis induced by anesthetics or
analgesics
• Pre-op functional tests: 24-hour urine free cortisol or plasma metanephrine and
normetanephrine concentrations
• Pre-op CT, MRI, or radionucline studies
• Pre-op alpha-blockade prior to beta-blockade to minimize risk of
catecholamine crisis
• Resection is treatment of choice
26. Sturge-Weber disease
• Encephalotrigeminal angiomatosis
• Not genetic
• 1 in 50,000 births
• Characterized by:
• Port-wine stain (facial nevus flam meus, often in the distribution of the first
division of the trigeminal nerve)
• Ipsilateral venous malformation of the leptomeninges (enhances), choroid of
the eye, or choroid plexus.
27.
28. Sturge-Weber disease
• Other findings:
• Ipsilateral cortical (especially parietooccipital) tram-track calcifications
• Glaucoma (30–60%)
• Mental retardation
• Atrophy of the ipsilateral hemisphere with contralateral seizures, hemiparesis,
hemisensory loss, and homonymous hemianopsia
• Ipsilateral calvarial thickening and a large frontal sinus
30. Osler-Weber-Rendu syndrome
• Disease is characterized by:
• Multiple mucocutaneous telangiectasias (in the skin, GI, and GU tracts)
• Visceral vascular malformations (AVMs of the liver, lung, brain, and spinal cord), and
rarely aneurysms
• 50% of brain symptoms are due to pulmonary arteriovenous (AV)-fistulas with
paradoxical emboli and abscesses
• Other symptoms include hepatic encephalopathy, GI or GU hemorrhage, and
epistaxis (85%)
• One-third of patients with multiple AVMs have HHT or Wyburn–Mason
syndrome
31.
32. Others
• Wyburn-Mason - unilateral cutaneous vascular nevi of the face and trunk with
retinal, optic nerve, visual pathway, and midbrain AVMs. Retinal AVMs are
known as racemose angiomas.
• Ataxia telangiectasia - oculocutaneous telangiectasias and cerebellar ataxia
(caused by anterior vermian atrophy). There is a defect in DNA repair,
transmission is autosomal recessive, and symptoms begin in childhood. It is
associated with an increase in infections and cancer, and death usually occurs
by 20 years.
• Klippel-Trenaunay-Weber - angioosteohypertrophy (overgrowth of vessels and
bones). One limb is usually enlarged. It is associated with leptomeningeal AVMs
(some spinal) and dermatomal cutaneous hemangiomas.
• Epidermal nevus syndrome - ipsilateral nevus and bone thickening associated
with mental retardation, seizures, hemiparesis, and gyral malformations
36. Phenylketonuria
• Deficiency of phenylalanine hydroxylase in the liver
• Cannot convert phenylalanine to tyrosine
• Phenylalanine accumulates and causes defective myelination
• Inheritance is autosomal recessive on chromosome 12
• Diagnose by increased urine phenylpyruvic acid and serum phenylalanin
• Clinical findings
• Fair-skinned children
• Blue eyes
• Musty odor
• Treatment is by limiting intake of l-phenylalanine to decrease mental
retardation.
37.
38. Homocystinuria
• Increased homocysteine in the blood, urine, and CSF
• Deficiency of cystathionine beta-synthase
• Inheritance is autosomal recessive on chromosome 21
• Physically similar to Marfan syndrome (tall and thin), but with:
• Mental retardation
• Increased incidence of stroke
• Lens dislocations
• Arachnodactyly.
39.
40. Maple Syrup Urine Disease
• Causes decreased branched-chain amino acid catabolism
• Inheritance is autosomal recessive
• Deficiency of branched-chain α-keto acid dehydrogenase
• Death occurs by 4 weeks unless leucine, isoleucine, and valine intake is limited
• Symptoms include
• Poor feeding, vomiting, failure to thrive
• Characteristic “burned sugar smell of the urine.”
41. Hartnup disease
• Autosomal recessive disorder
• Defect in neutral amino acid transport in the proximal tubule of the nephron
with inability to reabsorb neutral amino acids
• Develop niacin (VitB3) deficiency with pellagra-like symptoms
• Dermatitis
• Diarrhea
• Dementia
• Death
43. Niemann-Pick
• Deficiency of sphingomyelinase with accumulation of sphingomyelin and
cholesterol
• Inheritance is autosomal recessive with chromosomal abnormalities on 11 and
18
• Occurs usually in infants 3 to 9 months with death in 2 years
• Clinical signs:
• Cherry-red spot (50%)
• Supranuclear paresis of vertical gaze
• Psychomotor retardation
• Hepatosplenomegaly
• Niemann–Pick cells or “foam cells” are large vacuolated histiocytes and
lymphocytes. Accumulation occurs in the brainstem, cerebellum, spinal cord,
and visceral organs.
44.
45. Gaucher
• Most common sphingolipidosis
• Deficiency of glucocerebrosidase with accumulation of glucocerebrosides
• Inheritance is autosomal recessive
• Develops in late childhood, usually nonneuropathic with accumulation in the
liver, spleen, marrow, and lung with symptomatic hypersplenism with anemia
and thrombocytopenia
• There are rare infantile and juvenile forms affecting neurons and causing death
by 2 years
46. Fabry
• Deficiency of α-galactosidase with accumulation of ceramide trihexoside
• Inheritance is X-linked recessive with onset in adolescence.
• Causes painful dysesthesias
• Deposits accumulate in blood vessel walls, cornea, kidneys, cardiac muscle
fibers, and noncortical neurons
• Symptoms:
• Hypertension
• Renal failure
• Congestive heart failure
• Death by myocardial infarction or stroke
47. Tay-Sachs
• Deficiency of hexosaminidase A with accumulation of GM2 ganglio-sides in gray
matter
• Autosomal recessive with onset by 6 months and death by 4 years.
• Clinical signs:
• Cherry-red spots
• Macrocephaly
• NO visceromegaly
50. Krabbe
• Deficiency of galactocerebroside β-galactosidase on chromosome 14
• Accumulation of galactocerebro-side from myelin sheaths in lysosomes
• Inheritance is autosomal recessive
• Onset 3–6 months and death by 2 years
• Clinical signs:
• Psychomotor delay
• Microcephaly
51. Adrenoleukodystrophy (ALD)
• Deficiency of lipid oxidation in peroxisomes with accumulation of long chain
fatty acids
• Involves the ATP binding cassette, subfamily D (ALD), member 1 (ABCD1 gene)
• Inheritance is X-linked recessive
• Onset is 3–10 years with death in 3–5 years
• Symptoms:
• Behavioral and intellectual deterioration
• Visual, auditory, and motor decline
• Adrenal insufficiency with bronze skin
53. Hurler
• Deficiency of α-l-iduronidase with accumulation of mucopolysaccharides (MPS)
• Urine contains heparin and dermatan sulfate
• Inheritance is autosomal recessive
• Onset at 1 year and death by 5–10 years from cardiac or respiratory causes.
• Symptoms include gargoyle face, mental retardation, dwarfism, corneal
opacities, conduction deafness, hepatosplenomegaly, cardiac dysfunction,
skeletal abnormalities, and thick meninges that may cause spinal cord
compression
• On electron microscopy, can see Zebra bodies.
54. Hunter
• Deficiency of iduronate sulfatase
• Inheritance is X-linked recessive
• Urine contains heparin and dermatan sulfate
• Presentation is similar to Hurler disease but milder
• No mental retardation, less corneal clouding, and slower progression
• Skin pebbling and peripheral nerve entrapment
56. MELAS
• Mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome
• Transmission from maternal mitochondrial DNA
• Patients have encephalopathy, elevated serum and CSF lactic acid levels,
stroke-like episodes with cortical blindness, or hemianopia
57. MERRF
• Myoclonic epilepsy with ragged red fibers
• Transmission from maternal mitochondrial DNA with onset in early childhood
• Patients have myoclonic epilepsy and ragged red fibers on muscle biopsy
58. Leber hereditary optic neuropathy
• Transmission from maternal mitochondrial DNA with onset in adulthood
• Patients develop a progressive painless loss of central vision
60. Lesch-Nyhan
• X-linked recessive inheritance with deficiency of hypoxanthine-guanine
phosphoribosyltransferase (HGPRT) enzyme
• There is accumulation of uric acid with self-mutilation and choreoathetosis
61. Zellweger
• Cerebrohepatorenal syndrome
• Autosomal recessive inheritance with defects in the peroxin genes with death in
a few months
• There are decreased liver peroxisomes and accumulation of long-chain fatty
acids
• There is cortical dysgenesis and white matter degeneration with hepatorenal
dysfunction
Editor's Notes
Group of disorders with dermatologic, ophthalmologic, and neurological findings
Associated with cranial or spinal neoplasms
Incidence of CNS tumors of roughly 10%
Includes optic gliomas, plexiform/neurofibromas, brainstem gliomas and cerebellar gliomas
Present in first year of life, growth highly variable
May have large areas of hyperpigmentation with fine hair overlying the plexiform neurofibromas
Detected in thoracic region of 20% of pts, abdomen/pelvis in 44% of pts on CT
Attempt to cure: leads to unacceptable morbidity associated with resection of nerve roots
35% of malignant peripheral nerve sheath tumors first develop when pts are younger than 20 yo
Neurofibromas (discrete or plexiform) resected only if symptomatic
Rarely, can cause compression of motor nerve w/ distal weakness
Resect if significant pain or for cosmetic disfigurement
May recur years later at resection site
Plexiform neurofibromas
Involve large nerves/nerve roots making resection difficult
Complete resection often leads to deficits/disability
Consider resection if cosmetic disfigurement, pain, or defecit
No chemotherapy proven to successfully treat
Plexiform neurofibroma growth stimulated by radiation
Skin tumors – schwannomas, neurofibromas, mixed tumors
Café au lait spots in 33%
Prototypical and pathognomonic – bilateral acoustic schwannomas
Care at tertiary care center along with age at diagnosis and presence of intracranial meningiomas are primary determinants of risk for mortality
Small tumors with either no sxs or only audiologic scs – unsure
Schwannomas: differ from neurofibromas in that tumor is extrinsic to nerve and separate from majority of axons
-Neurofibromas have axons running through the tumor
-Can also involve CN 3 and 5
Two phenotypes:
Gardner: milder disease, fever tumors, later onset
Wishart phenotype: more tumors, earlier onset, rapid progression
Concern for radiosurgery causing secondary malignant peripheral nerve sheath tumors
Intrancranial meningiomas
~50% of NF2, multiple in 40% of NF2 patients
Differ from sporadic meningiomas
Occur earlier in life, higher mitotic index, greater nuclear pleomorphism, higher proliferation potential
NF2 tumors do not respond to chemotherapy
Lesions addressed when symptomatic
Vestibular schwannomas
Possibly single or multiple fraction stereotactic radiosurgery
Surgery only when tumor growth or progressive hearing loss
Risk injury to the facial nerve
Surgical options: radical resection, partial resection, decompression
Suboccipital retrosigmoid, traslabyrinthine, middle cranial fossa
WHO Grade I
In 6-18% of TSC patients
Mixed glinoneuronal lineage
If sxs: elevated intracranial pressure, lethargy, visual field deficits, behavioral or cognitive decline
NSx: Ranges from shunt placement to tumor resection
Resection at first sign of sxs or documented growth on imaging
Treatment is leaning towards more aggression
Shunts can sometimes be avoided
Smaller lesions are easier to resect
Sudden death associated with SGCTs
Excessive morbidity/mortality with delayed treatment
Decreased life expectancy associated with :
Renal disease, complications from intracranial tumors, hemorrhage (aortic aneurysms/lymphangiomyomatosis of lungs), status epilepticus, cardiac rhabdomyomas
Varies from small, circumscribed to large, hemorrhagic and necrotic (1g to 4 kg)
Mean 7 cm / 200 g
Small tumors have rim of compressed adrenal gland
Lobulated, yellow-red-brown
Familial tumors are bilateral and multicentric, and adjacent medulla may appear hyperplastic
Chromaffin reaction: Fresh tumor turns dark brown if add potassium dichromate at pH 5-6 (Zenkers)
Zellballen (small nests or alveolar pattern), trabecular or solid patterns of polygonal / spindle shaped cells in rich vascular network
Cells have finely granular basophilic or amphophilic cytoplasm
Intracytoplasmic hyaline globules
Round / oval nuclei with prominent nucleolus and variable inclusion-like structures (Hum Pathol 1980;11:205)
May have marked pleomorphism
Capsular and vascular invasion common in benign behaving tumors
Nests outlined by sustentacular cells
The congestion in the cortical draining veins is believed to cause stasis, hypoxia, progressive atrophy, and dystrophic calcifications in the middle layers of the cortical gray matter
Wyburn
AKA Bonnet-Dechaume-Blanc syndrome, retinoencephalofacial angiomatosis
Non-hereditary, congenital, rare (fewer than 100 cases)
AVMs in the retina, visual pathways, midbrain, and face
Usually unilateral, asx
Clinical: neuropsychiatric changes, headaches, seizures, stroke, hemiparesis, visual-field abnormalities, SAH, ICH, elevated ICP
Extracranial AVMs can be life-threatening oral hemorrhages or epistaxis
Cherry red spots develop as the retinal ganglion cells enlarge and finally burst from intracellular accumulation of lipids; thus, the red choroid is seen through the retina upon funduscopic examination
Gaucher cells have wrinkled tissue paper appearance from stored glucocerebroside. Patient may develop cherry red spots.
There is cavitation of the white matter, with sparing of the subcortical U-fibers. The basal ganglia and thalamus appear hyperdense on CT. Globoid cells are large macrophages around blood vessels. Psycho-sine accumulation kills oligodendrocytes.
There is cavitation of the parietooccipital white matter. Disease is generally fatal but may be treated with Lorenzo oil and a diet low in long chain fatty acids.
Scheie syndrome is a milder rare form of Hurler disease with autosomal recessive inheritance. There is no mental retardation or neuronal storage. It may produce spinal cord compression from thickened dura, corneal opacities, and carpal tunnel syndrome.
The eye pathology is limited to the retinal ganglion cell layer, especially the maculopapillary bundle. Degeneration is evident from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nuclei. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells. Also, experiments suggest that normal, non-LHON-affected retinal ganglion cells produce less of the potent superoxide radical than other normal central nervous system neurons.
