Neurocutaneous Disorders Flashcards
What is the inheritance pattern of NF1?
Autosomal dominant
Which chromosome is home to the NF1 gene?
17q11.2
Which cellular pathway is disrupted in NF1?
Ras/MAPK pathways
List at least 4 RASopathies
NF1 Noonan syndrome Costello syndrome Capillary malformation arteriovenous malformation syndrome Cardiofaciocutaneous syndrome Legius syndrome NS with multiple lentigenes (leopard)
What are the diagnostic criteria for NF1?
Two or more of the following: 1)6 or more cafe au lait spots (>5 mm before puberty, >15 after) 2) >2 neurofibromas or 1 plexiform neurofibroma 3) inguinal or axillary freckling 4) optic glioma 5) >2 Lisch nodules (pigmented hamartomas of the iris) 6) Distinct osseus lesions (sphenoid dysplasia president thinking of bone cortex) 7) First degree relative with NF1
Name at least 6 clinical features that can be seen outside of those included in the NF1 diagnostic criteria?
Scoliosis Vascular dysplasias (moya moya included) Nerve sheath tumors Microcephaly Astrocytomas Sarcomas Pheochromocytomas Learning disabilities
By what age do most optic gliomas present for children with NF1
Before 6 years
What are the imaging characteristics of NF spots of myelin vacuolization?
Increased white matter volume of corpus callosum
Increased ADC signal T2 hyperintensity in brainstem, cerebellum, thalamus, internal capsule, CC but spares subcortical white matter and centrum semiovale
T1 isointense
Between what ages would you expect to see evolution of myelin vacuolization in NF1?
Generally develop between 2-12 years Regress through adolescence and usually gone by 20 yrs
Name at least 2 differences between NF spots or myelin vacuolization and astrocytomas on MRI
Tumor has mass effect, NF spots don’t Tumor enhances, NF spots don’t Tumor may have restricted diffusion in solid portion, NF spots don’t Elevated choline, decreased NAA and creatine on spectoscropy =tumor Levels relatively normal for NFspots
What is the inheritance pattern of NF2?
Autosomal dominant 50% sporadic/new mutations
Which chromosome is effected in NF1?
Chromosome 22 (22q12.2)
What are the clinical hallmarks of NF2?
Bilateral vestibular schwannomas Also have meningiomas, skin lesions and cataracts
What are the most common presenting symptoms of NF2 in childhood?
Seizures Facial nerve palsy (More so than hearing loss!) Barkovich neurocutaneous disorders
What are the diagnostic criteria for definite NF2?
Definite: 1) Bilateral vestibular schwannomas 2) first degree relative with NF2 and unilateral 8th nerve tumor under 30 or two of the following (neurofibroma, meningioma, glioma, schwannoma, juvenile posterior cortical cataracts)
What are the diagnostic criteria for presumptive/probable NF2?
1) unilateral vestibular schwannoma plus one of the following (meningioma, glioma, schwannoma, juvenile posterior cortical cataracts) 2) two or more meningiomas and unilateral vestibular schwannoma
What are the most common intrinsic spinal cord tumors in NF2 patients?
Ependymomas Astrocytomas Intramedullary Schwannomas Meningiomas
What is the inheritance pattern of tuberous sclerosis?
Autosomal dominant
What are the two genes associated with TS?
TSC1 and TSC2
Which chromosome is the locus for TSC1?
Chromosome 9
Which chromosome is the locus for TSC2?
Chromosome 16
What important molecular pathway is disrupted in TS and provides a good therapeutic target in TS?
MTOR pathway
What are the diagnostic criteria for definite TS?
Two major features or one major plus two minor features Major features: Facial angiofibromas Non traumatic ungual/periungual fibromas Hypomelanotic macules (>3) Shagreen patches (connective tissue nevi) Retinal hamartomas Cortical tuber Subependymal nodule SEGA Lymphangioleiomyomatosis Renal angiomyolipomas Minor features: Enamel pitting Hamartomaous rectal polyps Bone cysts Affected first degree relative White matter radial migration lines Gingival fibromas Non renal hamartomas Retinal achromatic patch Confetti skin lesions Renal cysts
What are the diagnostic criteria for probable TS?
One major and one minor feature Major features: Facial angiofibromas Non traumatic ungual/periungual fibromas Hypomelanotic macules (>3) Shagreen patches (connective tissue nevi) Retinal hamartomas Cortical tuber Subependymal nodule SEGA Lymphangioleiomyomatosis Renal angiomyolipomas Minor features: Enamel pitting Hamartomaous rectal polyps Bone cysts Affected first degree relative White matter radial migration lines Gingival fibromas Non renal hamartomas Retinal achromatic patch Confetti skin lesions Renal cysts
What are the diagnostic criteria for possible TS?
One major or two minor features Major features: Facial angiofibromas Non traumatic ungual/periungual fibromas Hypomelanotic macules (>3) Shagreen patches (connective tissue nevi) Retinal hamartomas Cortical tuber Subependymal nodule SEGA Lymphangioleiomyomatosis Renal angiomyolipomas Minor features: Enamel pitting Hamartomaous rectal polyps Bone cysts Affected first degree relative White matter radial migration lines Gingival fibromas Non renal hamartomas Retinal achromatic patch Confetti skin lesions Renal cysts
What are the current imaging recommendations in TS?
Brain MRI every 1-3 years until 25 years Renal US every 1-3 years lifelong Cardiac echo in infancy
What are two non-eponymous names for Sturge-Weber?
Encephalotrigeminalangiomatosis Meningofacial angiomatosis
What is Sturge-Weber syndrome?
A developmental disorder marked by angiomatosis of the face, choroid of the eye and leptomeninges
What is the gene responsible for Sturgeon-Weber syndrome?
GNAQ Thought to cause endothelin dyseregulation.
What medication can be used in management of NF2 associated vestibular schwannomas?
Bevacizumab Continuum audio neuroonc 2020 Hearing improvement and tumor shrinkage in 50% patients Scott R Plotkin et al. Otol Neurotol. 2012 Aug.
Which medication was approved in April 2020 for management of plexifoem neurofibromas in NF1 patients?
Selumetinib Continuum audio neuro onc 2020 familial nervous system tumor syndromes
Which are the three most common locations for nervous system hemangioblastomas in Von Hippel Lindau disease?
Cerebellum Spinal cord Retina
What are the characteristic imaging findings of nervous system hemangioblastomas?
Post-contrast enhancing cysts with mural nodules
Usually multiple not singular
What is the gene responsible for Von hippel lindau?
VHL Chaperones HIF genes (hypoxia inducible factors).
These become overexpressed causing angiogenesis, proliferation, apoptosis through VEGF pathway
Which seizure types are commonly seen in patients with Sturge-Weber?
Infantile Spasms (90%) Tonic Atonic Myoclonic
What are some pathological hallmarks of Sturge-Weber?
Angioma (matted together capillaries and small veins)confined to the pia mater Arteries are less involved and becomes fibrotic Adjacent calcifications (thought to be dystrophic changes due to abnormal circulation) Subtle polymicrogyria (sometimes too small to be seen on MRI)
What is the pathophysiologic cause of Sturge-Weber?
Migration of abnormal neural crest cells from prosencephalon and anterior mesencephalon. Earlier change is more likely to cause SWS vs later more likely to have only port wine stain. Barcovich neurocutaneous disorders
What are the imaging hallmarks of Sturge-Weber?
MR:
Post-Contrast enhancement of the angioma with dilated deep medullary veins due to shunting.
Calcifications best seen on susceptibility weighted images.
To some extent on T2 Perfusion weighted imaging shows hyperperfusion early, hypoperfusion late
What disorder is depicted in this image?
Sturge Weber Syndrome
What are some of the extra-axial manifestations of Sturge Weber seen on MRI? (think skull and eye)
Skull abnormalities: Hyperintense T2 marrow or enhancement ipsilateral to the lesion that can include facial bones. Can also have leptomeningeal angiomatosis. Remember it may not be prominent early, so many people advocate for imaging after 1 year
Eye abnormalities: Seen in 30%. Can have eye angiomas, glaucoma or retinal detachment
Barkovich Neurocutaneous Disorders
What is the genetic inheritance pattern of Von Hippel Lindau?
Autosomal dominant
(incomplete penetrance)
Name at least 3 of the characteristic tumors seen in Von Hippel Lindau
Retinal angiomas
Cerebellar/spinal cord hemangioblastomas
Renal Cell Carcinomas
Pheochromocytomas
Liver/kidney angiomas
papillary cystadenoma of the epididymis
What are the diagnostic criteria for Von Hippel Lindau?
1) More than one hemangioblastoma of the CNS
2) One hemangioblastoma with visceral manifestation of disease
3) One manifestation of the disease + family history
Which chromosome is the VHL gene located on?
3p25.3
What type of tumor is depicted here?
Extra credit: What disorder might it make you think of?
CNS Hemangioblastoma (small mural nodule, large cyst)
Extra Credit: Von Hippel Lindau
What mass is depicted here? (Hint, this patient has NF1)
Orbital plexiform neurofibroma
What condition does this patient likely have?
NF1 (plexiform neurofibroma)
What genetic mutation might you test this infant for?
Tuberous Sclerosis
Depicts
If you saw this scan in one of your TSC patients, what would you be worried about?
subependymal giant cell astrocytoma (SEGA)
