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Neurocutaneous Flashcards

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
How is Legius syndrome DIF from NF1?
(SPRED1) NOT see neurofibromas, lisch nodules, optic glioma, osseous lesions
26
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
27
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*
28
What is the newer treatment for plexiform neurofibromas?
Selumetinib (~20% reduction in tumor volume)
29
What are the main features of NF2?
"central NF" mult benign CNS tumors BILAT vestibular schwannomas (tumors can cause hearing loss)
30
What is the incidence and prevalence of NF2?
inc: 1/33,000 live births prev: 1/56,000
31
What type of gene is NF2? what does it regulate?
neurofibromin-2 (merlin) = tumor suppressor regualtes cell-cell and cell-matrix adhesions
32
What is the major (Manchester) diagnostic criteria for NF2?
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
33
What portion of NF2 cases are mosaic?
1/4 of de novo cases = mosaic 50% cases = de novo
34
Almost all people w NF2 will develop ? by when?
Bilat VS by age 30
35
How prevalent is hearing loss in NF2?
35% w unilat hearing loss 9% bilat hearing loss also, 10% w tinnitus
36
What percentage of NF2 are asymp?
~11%
37
What NS manifestations do we see in NF2 that presetn symptoms?
- 12% focal weakness - 8% seizures - 8% balance dysfunction - 6% focal sensory loss
38
What skin findings do we see w NF2?
less common than w NF1 CAL (1-6) cutaneous neurofibromas/schwannomas
39
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
40
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
41
What is 2nd most common tumor in NF2?
Meningioma (mainly in females) tumor in meninges
42
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
43
Describe the Schwannoma found in NF2
80% have evidence on MRI Spinal cord or canal unless symptomatic --> usu just leave it alone
44
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
45
What are the main features of Schwannomatosis?
- multiple schwannomas W/O bilat VS - intracranial, spinal nerve root, peripheral nerve tumors - pain + neuro manifestations
46
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
47
Would the tumors assoc w NF2 or Schwan typically be more painful?
Schwan
48
Penetrance of Schwan?
incomplete pen
49
How many patients have segmentally distrib tumors in Schwanno?
33% there may also be rare malignant transformation of tumors
50
What skin findings do we see w Schwan?
none
51
What ocular findings do we see in Schwan?
none
52
What is inheritance pattern of Neurocutaneous Melanosis?
non-familial! mostly from embryonic postzygotic somatic mutation in NRAS
53
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
54
When there is melanin in the brain, we are thinking?
(som NRAS) Neurocut Melanosis
55
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
56
What happens to male w IP?
(X-dom NEMO) hemizygous males die in utero
57
When do hyperpigmented lesions start to appear in IP?
(X-dom NEMO) at birth
58
What are the Neuro abnorm assoc w IP?
(X-dom NEMO) (30-50%) 1. ID 2. Certicospinal tract dysfunction 3. seizire 4. microcephaly
59
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
60
Which of these can we see atrophic scarring?
IP (X-dom NEMO)
61
Which of these can we see spina bifida?
IP (X-dom NEMO) - can also see hemivertebrae, accessory ribs, syndactyly
62
Tuberous sclerosis complex genetic causes?
AD TSC1 19% TSC2 60% 2/3 sporadic 2% germline/gonadal mosaicism
63
TSC1 codes for? TSC2 codes for?
TSC1 - Hamartin TSC2 - Tuberin both of these form a heterodimer to regulate cell growth and tumorigenesis
64
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
65
Why could we see hydrocephalus w TS?
subependymal astrocytoma can cause obstructive hydrocephalus by blocking CSF
66
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
67
What cond woudl we see ungual fibromas?
(in nailbeds) TS
68
? % of those w TSC cannot ident mut by gen testing
10 - 25%
69
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)
70
What treatment is out there for subependymal Giant-cell astrocytomas ?
Everolimus this is in TS
71
What is the cause of Sturge-Weber Syndrome?
Som mut in GNAQ
72
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
73
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
74
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
75
What is the cause of Osler-Weber-Rendu syndrome? AKA HHT
90% GDF2 also ENG, ACVRL1, SMAD4
76
What are main clinical feat of HHT?
mucocutaneous telangiectasias visceral AVMs recurrent nosebleeds (usu childhood and worsen w age)
77
Where do we find the AVMs in HHT?
really anywhere - hands, lips, tongue, maybe even lungs
78
What is the cause of VHL?
VHL deletion lol - on chr3p25-26 this is tumor supp gene
79
What eye abnorm can we see in VHL?
retinal hemangioblastoma 45-60%
80
What hemangioblastomas can we see in VHL? (slow growing tumors in CNS)
retinal (45-60%) cerebellar and spinal (21-72%)
81
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

Medical Genetics (14 decks)

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