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Neurocutaneous Flashcards

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1
Q

Out of NF1, NF2, and Schwannomatosis, which is fully penetrant?

A

NF1 + NF2

Schwan = incomp penetrance

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2
Q

What is the freq of NF1?

A

one of most common AD disorders

1/1,900 - 1/3,500

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3
Q

What are the 7 major criteria for dx of NF1?

A
  1. > /= 6 CAL
  2. > /= 2 neurofibromas of any type WITH >/= 1 plexiform neurofibroma
  3. > /= 2 lisch nodules
  4. freckling in axilla or groin
  5. Optic glioma
  6. 1st deg relative w NF1
  7. Distinctive bony lesion
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4
Q

How big are the CAL spots in NF1? (in dx criteria)

A

> 5mm prepubertal
15mm post-pubertal

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5
Q

What is expressivity for NF1?

A

So fully penetrant but variable expressivity

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6
Q

What are the ocular manifestations seen in NF1?

A
  • Lisch nodules = iris hamartomas –> in 85% >10y
  • Optic gliomas = brain tumor that slowly grows; near the optic nerve –> <6y
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7
Q

When does an optic glioma need to be treated?

A

see this in NF1

treated when it starts affecting vision

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8
Q

1/2 of patients w pseudoarthrosis have ?

A

NF1

(this is when spinal surgery fails)

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9
Q

What are skeletal findings seen in NF1?

A

pseudoarthrosis (mainly tibia + fibula)

short stature

scoliosis ~10%

vertebral dysplasia

localized overgrowth

poor bone health

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10
Q

What are some nervous system findings in NF1?

A
  • macrocephaly (30-45%)
  • learning disab (30-65%)
  • MRI brightspots on T2 (white matter)
  • headache (10%)
  • epilepsy (3.5-7%)
  • cerebrovascular dysplasia (2-6%)
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11
Q

What explains the macrocephaly in NF1?

A

(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)

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12
Q

What are some common learning disabilities found in NF1?

A

(30-65%)
- visuospatial functions
- attention

severe ID is NOT assoc

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13
Q

Why are the MRI brightspots on T2 for NF1 concerning?

A

these are bright spots on white matter, so this represents dysplastic changes –> worry about low grade tumor

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14
Q

What disorder can we see Moya Moya?

A

NF1 (2-6%)

form of cerebrovascular dysplasia —> carotid artery in skull is blocked; “puff of smoke” on angiography

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15
Q

What is involved in NF1 vasculopathy?

A
  • renal artery stenosis
  • coarctation of the aorta
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16
Q

What is involved with NF1 CNS vasculopathy?

A
  • ectatic vessels (enlarged) + intracranial aneurysms
  • stenoses of internal carotid or more
  • small telangiectactic vessels, like MoyaMoya
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17
Q

What type of tumors can we see in PNS for NF1?

A

plexiform neurofibroma (these are congenital that may not come to attn until later in life)

malignant peripheral nerve sheath tumors (neurofibrosarcomas ~10%)

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18
Q

What type of tumors can we see in CNS for NF1?

A
  • 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

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19
Q

What type of non-nervous system tumors can we see in NF1? (acquired second hit)

A
  • pheochromocytoma (0.105.7%)
  • breast cancer
  • GI stromal
  • glomus tumors
  • rhabdomyosarcomas
  • NE-carcinoid tumors
  • juvenile myelocytic leukemia
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20
Q

What is the only geno-pheno correlation to think about w NF1?

A
  • mostly w del

coarse facial features, more neurofibromas, can have more mod ID, macrocephaly, higher burden of tumors

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21
Q

NF1 = what type of gene?

A

NF1 —> neurofibromin

tumor suppressor –> inv RAS pathway

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22
Q

review pathways a lil

A

yup yup

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23
Q

Legius syndrome is sim to what other disorder? How?

A

NF1

CALs, freckling, macrocephaly

(caused by SPRED1)

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24
Q

Mutation in SPREAD1 results in TURNING OFF negative regulation of?

A

this is Legius syndrome

neg reg of MAPK

(LOF mut, but it is a loss of an inhibitor —> so ramps up MAPK)

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25
Q

How is Legius syndrome DIF from NF1?

A

(SPRED1)

NOT see neurofibromas, lisch nodules, optic glioma, osseous lesions

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26
Q

What is Noonan syndrome with NF1/Noonan phenotype?

A

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

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27
Q

What are the main physical features of Noonan syndrome?

A
  • 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

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28
Q

What is the newer treatment for plexiform neurofibromas?

A

Selumetinib (~20% reduction in tumor volume)

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29
Q

What are the main features of NF2?

A

“central NF”

mult benign CNS tumors
BILAT vestibular schwannomas

(tumors can cause hearing loss)

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30
Q

What is the incidence and prevalence of NF2?

A

inc: 1/33,000 live births
prev: 1/56,000

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31
Q

What type of gene is NF2? what does it regulate?

A

neurofibromin-2 (merlin) = tumor suppressor

regualtes cell-cell and cell-matrix adhesions

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32
Q

What is the major (Manchester) diagnostic criteria for NF2?

A

has to meet ONE of these:

  1. Bilat vestibular schwannomas (VS) (pt of cranial nerve)
  2. 1st deg relative w NF2 AND unilateral VS
  3. 1st deg relative w NF2 OR unilat VS AND 2 of:
    - meningioma, cataract, glioma, neurofibroma
    - schwannoma, cerebral calcification
  4. Mult meningioma (2+) AND 2 of:
    - unilat VS, cataract, glioma, neurofibroma, schwannoma, cerebral calcification
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33
Q

What portion of NF2 cases are mosaic?

A

1/4 of de novo cases = mosaic

50% cases = de novo

34
Q

Almost all people w NF2 will develop ? by when?

A

Bilat VS by age 30

35
Q

How prevalent is hearing loss in NF2?

A

35% w unilat hearing loss
9% bilat hearing loss

also, 10% w tinnitus

36
Q

What percentage of NF2 are asymp?

A

~11%

37
Q

What NS manifestations do we see in NF2 that presetn symptoms?

A
  • 12% focal weakness
  • 8% seizures
  • 8% balance dysfunction
  • 6% focal sensory loss
38
Q

What skin findings do we see w NF2?

A

less common than w NF1

CAL (1-6)
cutaneous neurofibromas/schwannomas

39
Q

What ocular manifestations do we see in NF2?

A
  • 33% decreased visual acuity
  • retinal hamartoma + epiretinal membrane
  • posterior sub-capsular lens opacity
  • corneal damage
  • intra-orbital tumors
40
Q

posterior sub-capsular lens opacity is seen in ? What is it?

A

NF2

type of cataract; opacities right under the ens capsule

Rarely affects vision
may be present early

41
Q

What is 2nd most common tumor in NF2?

A

Meningioma (mainly in females)

tumor in meninges

42
Q

If a child has (cranial) meningioma, we are thinking?

A

NF2

lifetime risk for NF2 is 75%

can be a single one to meningioma en-plaque

43
Q

Describe the Schwannoma found in NF2

A

80% have evidence on MRI

Spinal cord or canal

unless symptomatic –> usu just leave it alone

44
Q

Describe the Ependymoma found in NF2

A

(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
45
Q

What are the main features of Schwannomatosis?

A
  • multiple schwannomas W/O bilat VS
  • intracranial, spinal nerve root, peripheral nerve tumors
  • pain + neuro manifestations
46
Q

What is the dx criteria for Schwannomatosis?

A
  • 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
47
Q

Would the tumors assoc w NF2 or Schwan typically be more painful?

A

Schwan

48
Q

Penetrance of Schwan?

A

incomplete pen

49
Q

How many patients have segmentally distrib tumors in Schwanno?

A

33%

there may also be rare malignant transformation of tumors

50
Q

What skin findings do we see w Schwan?

A

none

51
Q

What ocular findings do we see in Schwan?

A

none

52
Q

What is inheritance pattern of Neurocutaneous Melanosis?

A

non-familial!

mostly from embryonic postzygotic somatic mutation in NRAS

53
Q

What are main findings of Neurocut Melanomis?

A

(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

54
Q

When there is melanin in the brain, we are thinking?

A

(som NRAS)

Neurocut Melanosis

55
Q

Incontinentia Pigmenti has what main skin findings?

A

(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

56
Q

What happens to male w IP?

A

(X-dom NEMO)

hemizygous males die in utero

57
Q

When do hyperpigmented lesions start to appear in IP?

A

(X-dom NEMO)

at birth

58
Q

What are the Neuro abnorm assoc w IP?

A

(X-dom NEMO)

(30-50%)
1. ID
2. Certicospinal tract dysfunction
3. seizire
4. microcephaly

59
Q

What are the ocular abnorm assoc w IP?

A

(X-dom NEMO)

(30%)
- retinal detachment
- fibrovascular retrolental membrane
- optic atrophy
- papillitis
- abnormal retinal pig
- nystagmus
- strabismus
- cataracts
- visual loss

60
Q

Which of these can we see atrophic scarring?

A

IP (X-dom NEMO)

61
Q

Which of these can we see spina bifida?

A

IP (X-dom NEMO)

  • can also see hemivertebrae, accessory ribs, syndactyly
62
Q

Tuberous sclerosis complex genetic causes?

A

AD

TSC1 19%
TSC2 60%

2/3 sporadic
2% germline/gonadal mosaicism

63
Q

TSC1 codes for?
TSC2 codes for?

A

TSC1 - Hamartin
TSC2 - Tuberin

both of these form a heterodimer to regulate cell growth and tumorigenesis

64
Q

What are main tumors found in TS?

A

> 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

65
Q

Why could we see hydrocephalus w TS?

A

subependymal astrocytoma can cause obstructive hydrocephalus by blocking CSF

66
Q

What are Neuro manifestations (aside from tumors) w TS?

A

90-96% intractable seizures, usu infantile spasms
- 85% w/in 2yo
40-50% behavioral and cognitive dysfunction
- autism

67
Q

What cond woudl we see ungual fibromas?

A

(in nailbeds)
TS

68
Q

? % of those w TSC cannot ident mut by gen testing

A

10 - 25%

69
Q

what 2 manifestations can arise from TSC1/2 mutations that affect immature-appearing smooth muscle?

A
  • angiomyolipoma (renal)
  • lymphangiomyomatosis (infiltration of abnorm smooth muscle cells in LUNGS)
70
Q

What treatment is out there for subependymal Giant-cell astrocytomas ?

A

Everolimus

this is in TS

71
Q

What is the cause of Sturge-Weber Syndrome?

A

Som mut in GNAQ

72
Q

Wha tis the defining clinical feature of Sturge-Weber Syndrome?

A

(som GNAQ)

facial port wine stain in VI DISTRIB of trigeminal nerve associated w leptomeningeal angiomatosis

73
Q

What is facial port wine stain in VI DISTRIB of trigeminal nerve associated w leptomeningeal angiomatosis caused by?

A

seen in Sturge-Weber Synd (som GNAQ)

the primitive cerebral venous plexus fails to regress in 1st trimester

74
Q

What are other complications aside from port wine stain assoc w SturgeWS?

A

(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

75
Q

What is the cause of Osler-Weber-Rendu syndrome? AKA HHT

A

90% GDF2
also
ENG, ACVRL1, SMAD4

76
Q

What are main clinical feat of HHT?

A

mucocutaneous telangiectasias

visceral AVMs

recurrent nosebleeds (usu childhood and worsen w age)

77
Q

Where do we find the AVMs in HHT?

A

really anywhere - hands, lips, tongue, maybe even lungs

78
Q

What is the cause of VHL?

A

VHL deletion lol
- on chr3p25-26

this is tumor supp gene

79
Q

What eye abnorm can we see in VHL?

A

retinal hemangioblastoma

45-60%

80
Q

What hemangioblastomas can we see in VHL?

(slow growing tumors in CNS)

A

retinal (45-60%)
cerebellar and spinal (21-72%)

81
Q

Aside from hemangioblastomas, what other tumors can we see in VHL?

A

15-77% cystic tumors of pancreas, 50-70% kidney, and x% epididymus

20-50% RCC

10-20% pheochromocytoma

Medical Genetics (14 decks)

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