Neurocutaneous Flashcards
Out of NF1, NF2, and Schwannomatosis, which is fully penetrant?
NF1 + NF2
Schwan = incomp penetrance
What is the freq of NF1?
one of most common AD disorders
1/1,900 - 1/3,500
What are the 7 major criteria for dx of NF1?
- > /= 6 CAL
- > /= 2 neurofibromas of any type WITH >/= 1 plexiform neurofibroma
- > /= 2 lisch nodules
- freckling in axilla or groin
- Optic glioma
- 1st deg relative w NF1
- Distinctive bony lesion
How big are the CAL spots in NF1? (in dx criteria)
> 5mm prepubertal
15mm post-pubertal
What is expressivity for NF1?
So fully penetrant but variable expressivity
What are the ocular manifestations seen in NF1?
- Lisch nodules = iris hamartomas –> in 85% >10y
- Optic gliomas = brain tumor that slowly grows; near the optic nerve –> <6y
When does an optic glioma need to be treated?
see this in NF1
treated when it starts affecting vision
1/2 of patients w pseudoarthrosis have ?
NF1
(this is when spinal surgery fails)
What are skeletal findings seen in NF1?
pseudoarthrosis (mainly tibia + fibula)
short stature
scoliosis ~10%
vertebral dysplasia
localized overgrowth
poor bone health
What are some nervous system findings in NF1?
- macrocephaly (30-45%)
- learning disab (30-65%)
- MRI brightspots on T2 (white matter)
- headache (10%)
- epilepsy (3.5-7%)
- cerebrovascular dysplasia (2-6%)
What explains the macrocephaly in NF1?
(30-45%)
this is due to increase in brain volume = megalencephaly
there are inc # of astrocytes (bc loss of NF1 promotes prolif of progen glial cells)
What are some common learning disabilities found in NF1?
(30-65%)
- visuospatial functions
- attention
severe ID is NOT assoc
Why are the MRI brightspots on T2 for NF1 concerning?
these are bright spots on white matter, so this represents dysplastic changes –> worry about low grade tumor
What disorder can we see Moya Moya?
NF1 (2-6%)
form of cerebrovascular dysplasia —> carotid artery in skull is blocked; “puff of smoke” on angiography
What is involved in NF1 vasculopathy?
- renal artery stenosis
- coarctation of the aorta
What is involved with NF1 CNS vasculopathy?
- ectatic vessels (enlarged) + intracranial aneurysms
- stenoses of internal carotid or more
- small telangiectactic vessels, like MoyaMoya
What type of tumors can we see in PNS for NF1?
plexiform neurofibroma (these are congenital that may not come to attn until later in life)
malignant peripheral nerve sheath tumors (neurofibrosarcomas ~10%)
What type of tumors can we see in CNS for NF1?
- pilocytic astrocytoma (20%)
(makes sense bc they have add # of astrocytes) - optic pathway & hypothalamic predominance (24%)
- high grade gliomas in >6y or outside optic pathway
if affecting an older kid, worry about high grade tumor
What type of non-nervous system tumors can we see in NF1? (acquired second hit)
- pheochromocytoma (0.105.7%)
- breast cancer
- GI stromal
- glomus tumors
- rhabdomyosarcomas
- NE-carcinoid tumors
- juvenile myelocytic leukemia
What is the only geno-pheno correlation to think about w NF1?
- mostly w del
coarse facial features, more neurofibromas, can have more mod ID, macrocephaly, higher burden of tumors
NF1 = what type of gene?
NF1 —> neurofibromin
tumor suppressor –> inv RAS pathway
review pathways a lil
yup yup
Legius syndrome is sim to what other disorder? How?
NF1
CALs, freckling, macrocephaly
(caused by SPRED1)
Mutation in SPREAD1 results in TURNING OFF negative regulation of?
this is Legius syndrome
neg reg of MAPK
(LOF mut, but it is a loss of an inhibitor —> so ramps up MAPK)
How is Legius syndrome DIF from NF1?
(SPRED1)
NOT see neurofibromas, lisch nodules, optic glioma, osseous lesions
What is Noonan syndrome with NF1/Noonan phenotype?
DIF from Noonan caused by genes in RAS pathway
this is really just kiddos w NF1 that have short stature, webbed neck, facial dysmorphism, pulmonary stenosis
What are the main physical features of Noonan syndrome?
- epicanthal folds
- ptosis
- downslanting palp fissures (95%)
- triangular facies
- high nasal bridge
- low-set, posterior rotated ears
- thickened pinnae/helix (90%)
these can evolve over time, so sometimes adults get missed until feat more prominent later
What is the newer treatment for plexiform neurofibromas?
Selumetinib (~20% reduction in tumor volume)
What are the main features of NF2?
“central NF”
mult benign CNS tumors
BILAT vestibular schwannomas
(tumors can cause hearing loss)
What is the incidence and prevalence of NF2?
inc: 1/33,000 live births
prev: 1/56,000
What type of gene is NF2? what does it regulate?
neurofibromin-2 (merlin) = tumor suppressor
regualtes cell-cell and cell-matrix adhesions
What is the major (Manchester) diagnostic criteria for NF2?
has to meet ONE of these:
- Bilat vestibular schwannomas (VS) (pt of cranial nerve)
- 1st deg relative w NF2 AND unilateral VS
- 1st deg relative w NF2 OR unilat VS AND 2 of:
- meningioma, cataract, glioma, neurofibroma
- schwannoma, cerebral calcification - Mult meningioma (2+) AND 2 of:
- unilat VS, cataract, glioma, neurofibroma, schwannoma, cerebral calcification
What portion of NF2 cases are mosaic?
1/4 of de novo cases = mosaic
50% cases = de novo
Almost all people w NF2 will develop ? by when?
Bilat VS by age 30
How prevalent is hearing loss in NF2?
35% w unilat hearing loss
9% bilat hearing loss
also, 10% w tinnitus
What percentage of NF2 are asymp?
~11%
What NS manifestations do we see in NF2 that presetn symptoms?
- 12% focal weakness
- 8% seizures
- 8% balance dysfunction
- 6% focal sensory loss
What skin findings do we see w NF2?
less common than w NF1
CAL (1-6)
cutaneous neurofibromas/schwannomas
What ocular manifestations do we see in NF2?
- 33% decreased visual acuity
- retinal hamartoma + epiretinal membrane
- posterior sub-capsular lens opacity
- corneal damage
- intra-orbital tumors
posterior sub-capsular lens opacity is seen in ? What is it?
NF2
type of cataract; opacities right under the ens capsule
Rarely affects vision
may be present early
What is 2nd most common tumor in NF2?
Meningioma (mainly in females)
tumor in meninges
If a child has (cranial) meningioma, we are thinking?
NF2
lifetime risk for NF2 is 75%
can be a single one to meningioma en-plaque
Describe the Schwannoma found in NF2
80% have evidence on MRI
Spinal cord or canal
unless symptomatic –> usu just leave it alone
Describe the Ependymoma found in NF2
(these begin in the ependymal cells in the brain and spinal cord that line the passageways where the CSF flows)
- usu in cervical spine or medulla
- in 5-10% NF2 cases
- low malignant index w usu v slow progression
- rarely needs treatment
What are the main features of Schwannomatosis?
- multiple schwannomas W/O bilat VS
- intracranial, spinal nerve root, peripheral nerve tumors
- pain + neuro manifestations
What is the dx criteria for Schwannomatosis?
- 2+ non-intradermal Schwannomas
- No evidence of bilat VS on brain MRI
OR
- 1 histology confirmed Schwann, Unilat VS, or intracranial meningioma AND affected fam member
Would the tumors assoc w NF2 or Schwan typically be more painful?
Schwan
Penetrance of Schwan?
incomplete pen
How many patients have segmentally distrib tumors in Schwanno?
33%
there may also be rare malignant transformation of tumors
What skin findings do we see w Schwan?
none
What ocular findings do we see in Schwan?
none
What is inheritance pattern of Neurocutaneous Melanosis?
non-familial!
mostly from embryonic postzygotic somatic mutation in NRAS
What are main findings of Neurocut Melanomis?
(som NRAS)
- abnormal pigmented nevi:
Giant hairy pigmented nevi
Mult hyperpigmented nevi
Large congen melanocytic nevi
Leptomeningeal melanoma
CSF:
- inc proteins
- dec glucose
- cytology = melanocytes
CNS
- seizures
- hydrocephalus
When there is melanin in the brain, we are thinking?
(som NRAS)
Neurocut Melanosis
Incontinentia Pigmenti has what main skin findings?
(X-dom NEMO)
3-4 stage lesion
1. vesiculobullous at birth or neonatal period (in groups of linear streaks)
2. Evolve into verrucous lesions after 6w
3. Hyperpig brown/gray brown macules “splashed”
4. atrophic stage - pale hairless patch/streak
What happens to male w IP?
(X-dom NEMO)
hemizygous males die in utero
When do hyperpigmented lesions start to appear in IP?
(X-dom NEMO)
at birth
What are the Neuro abnorm assoc w IP?
(X-dom NEMO)
(30-50%)
1. ID
2. Certicospinal tract dysfunction
3. seizire
4. microcephaly
What are the ocular abnorm assoc w IP?
(X-dom NEMO)
(30%)
- retinal detachment
- fibrovascular retrolental membrane
- optic atrophy
- papillitis
- abnormal retinal pig
- nystagmus
- strabismus
- cataracts
- visual loss
Which of these can we see atrophic scarring?
IP (X-dom NEMO)
Which of these can we see spina bifida?
IP (X-dom NEMO)
- can also see hemivertebrae, accessory ribs, syndactyly
Tuberous sclerosis complex genetic causes?
AD
TSC1 19%
TSC2 60%
2/3 sporadic
2% germline/gonadal mosaicism
TSC1 codes for?
TSC2 codes for?
TSC1 - Hamartin
TSC2 - Tuberin
both of these form a heterodimer to regulate cell growth and tumorigenesis
What are main tumors found in TS?
> 80% cortical tuber
—> isolated areas of brain parenchyma w abnorm cell and laminar devel
80% subependymal nodules
—-> enlarges and protrudes into ventricles
? % subependymal astrocytoma
—> pref for ventricular wall near foramina of Monro
—> causes hydrocephalus
Why could we see hydrocephalus w TS?
subependymal astrocytoma can cause obstructive hydrocephalus by blocking CSF
What are Neuro manifestations (aside from tumors) w TS?
90-96% intractable seizures, usu infantile spasms
- 85% w/in 2yo
40-50% behavioral and cognitive dysfunction
- autism
What cond woudl we see ungual fibromas?
(in nailbeds)
TS
? % of those w TSC cannot ident mut by gen testing
10 - 25%
what 2 manifestations can arise from TSC1/2 mutations that affect immature-appearing smooth muscle?
- angiomyolipoma (renal)
- lymphangiomyomatosis (infiltration of abnorm smooth muscle cells in LUNGS)
What treatment is out there for subependymal Giant-cell astrocytomas ?
Everolimus
this is in TS
What is the cause of Sturge-Weber Syndrome?
Som mut in GNAQ
Wha tis the defining clinical feature of Sturge-Weber Syndrome?
(som GNAQ)
facial port wine stain in VI DISTRIB of trigeminal nerve associated w leptomeningeal angiomatosis
What is facial port wine stain in VI DISTRIB of trigeminal nerve associated w leptomeningeal angiomatosis caused by?
seen in Sturge-Weber Synd (som GNAQ)
the primitive cerebral venous plexus fails to regress in 1st trimester
What are other complications aside from port wine stain assoc w SturgeWS?
(som GNAQ)
55-90% Seizures
- 75% onset in 1st yr of life
- inc risk w those bilat leptomeningeal angiomatosis
60% glaucoma
- usu ipsilat
50% DD
What is the cause of Osler-Weber-Rendu syndrome? AKA HHT
90% GDF2
also
ENG, ACVRL1, SMAD4
What are main clinical feat of HHT?
mucocutaneous telangiectasias
visceral AVMs
recurrent nosebleeds (usu childhood and worsen w age)
Where do we find the AVMs in HHT?
really anywhere - hands, lips, tongue, maybe even lungs
What is the cause of VHL?
VHL deletion lol
- on chr3p25-26
this is tumor supp gene
What eye abnorm can we see in VHL?
retinal hemangioblastoma
45-60%
What hemangioblastomas can we see in VHL?
(slow growing tumors in CNS)
retinal (45-60%)
cerebellar and spinal (21-72%)
Aside from hemangioblastomas, what other tumors can we see in VHL?
15-77% cystic tumors of pancreas, 50-70% kidney, and x% epididymus
20-50% RCC
10-20% pheochromocytoma
