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Med Gen Section 3 > Neurocutaneous Syndromes > Flashcards

Neurocutaneous Syndromes Flashcards

1
Q

What are the general symptoms of neurological disorders?

A 
delerium, delusions, dementia
syncope and seizures
coma
pain and parasthesias
dizziness and headache
hearing loss and impaired vision
involuntary movements and gait disorders
weakness
dysphasia and dysarthria
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2
Q

How do you clinically evaluate neurological disorders?

A

detailed clinical history
comprehensive neurological exam
comprehensive family history

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3
Q

How do you diagnose neurological disorders?

A

diagnostic evaluation of most common nongenetic causes
initial genetic testing (normally with high yield single/multigene testing, chromosomal microarray, etc based on clinical evaluation as appropriate)
clinical exome sequencing

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4
Q

Name the single gene Pharkomatoses (neurocutaneous) disorders.

A

Neurofibromatosis 1

Tuberous Sclerosis 1 and 2

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5
Q

Name the single gene Trinucleotide repeat expansion disorders.

A 
Fragile X
Huntington Disease
Spinocerebellar Ataxias
Freidrich Ataxia
Myotonic Dystrophy
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6
Q

Name the single gene Hereditary motor sensory neuropathies.

A

Charcot-Marie-Tooth disorders

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7
Q

Name the complex neuromuscular disorders.

A 
Alzheimer disease (commom)
Parkinson disease (common)
Prion disorders (rare)
Anterior horn cell diseases (Spinal Muscular Atrophy and ALS)
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8
Q

What is Tuberous Sclerosis?

A

AD
100% penetrant
TSC1 on 9q34 encodes hamartin (26% of patients) and TSC2 on 16p13.3 encodes tuberin (69% of patients)
tuberin and hamarin make a heterodimer which acts as a tumor suppressor (mTOR inhibition)
life expectancy usually normal but premature death can occur due to epilepsy, cardiac arrhythmias, renal disease, or complications of SEGA or pulmonary LAM

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9
Q

What are the clinical features of Tuberous Sclerosis?

A

Skin (100% will have some manifestations)- hypomelanotic “ashleaf macules, facial angiofibromas, shagreen patches, ungal fibromatoma
CNS (leading cause of morbidity and mortality)- subependymal glial nodules, cortical or subcortical tubers, subependymal giant cell astrocytomas (SEGA), seizures leading to MR, autistic phenotypes
Renal (80% have identifiable lesions by 10.5yo)- benign angiomyolipomas, malignant angiomyolipoma, renal cell carcinoma, TSC2/PKD1 continuous gene deletion syndrome, epithelial cysts, oncocytoma/benign adenomatous hamartoma
Heart- cardiac rhabdomyomas
Lung (normally just females ages 20-40 years)- lymphangiomyomatosis
Eye- retinal hamartomas

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10
Q

What is TSC2/PKD1 continuous gene deletion syndrome?

A

complication of ADPKD including cystic lesions in other organs (eg. liver) and Berry aneurysms
single FISH probe most appropriate if TSC + other findings consistent with this

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11
Q

What are the diagnostic criteria for Tuberous Sclerosis?

A

definite- 2 major OR 1 major and 2+ minor symptoms
possible- 1 major OR 2+ minor symptoms
(mutations identified in 85% of those who meet criteria)

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12
Q

List the major symptoms of Tuberous Sclerosis as per the diagnostic criteria.

A 
renal angiomyolipoma
angiofibromas (>3) or fibrous plaque
ungual fibromas (>2)
shagreen patch, multiple retinal hamartomas
hypomelanotic macules (>3; >5mm)
lymphangiolesiomyomatosis
cortical dysplasia (>3)
subependymal giant cell astrocytoma
subependymal nodules (>2)
cardiac rhabdomyoma
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13
Q

List the minor symptoms of Tuberous Sclerosis as per the diagnostic criteria.

A 
confetti skin lesions
dental enamel pits (>3)
intraoral fibromas (>2)
nonrenal hamartomas
retinal achromic patch
multiple renal cysts
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14
Q

What are the most common clinical manifestations of Perinatal TSC in neonates?

A

cardiac rhabdomyomas (39-86% of children with this will be affected with TSC)
arrhythmias
cerebral lesion
respiratory distress

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15
Q

How is TSC managed/monitored?

A

brain (MRI every 1-3 yesrs, EEG, and developmental screening)
kidney (abdominal MRI every 1-3 years, BP annually, GFR annually)
lung (PFT + 6 minute walk, high resolution chest CT every 5-10 years)- only for women older than 18
eye (annual opthalmology exam)
heart (ECHO on children, ECG all ages every 3-5 years)
skin (annual exam)
teeth (exam every 6 months)

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16
Q

How is TSC treated?

A

neurosurgery
anticonvulsants
mTOR inhibitors (Rapamycin, Everolimus)

17
Q

What is Neurofibromatosis Type I/ Von Recklinghausen’s Disease?

A

AD
variable expressivity, though 100% penetrance (age dependent)
50% de novo mutations
mutations to the NF1 gene (encodes for neurofibromin)
pathophysiology: tumor suppressor, control of RAS signaling, GTPase activating protein

18
Q

What are the diagnostic criteria of Neurofibromatosis Type 1/ Von Recklinghausen’s Disease?

A

2+ of the following:
6+ cafe au lait macules (>5mm diameter in prepubertal individuals and >15mm diameter in postpubertal individuals)
>2 neurofibromas of any type or >1 plexiform neurofibroma
freckling in the axillary or inguinal regions
optic glioma (can cause vision loss, developed in first 6 years of life)
>2 Lisch nodules (iris hamartomas- do not cause vision loss)
a distinctive osseous lesion such as sphenoid dysplasia or tibial pseudoarthrosis
first degree relative with NF1 as defined by above

19
Q

What are other clinical features of NF1?

A

short stature
scoliosis
macrocephally
learning difficulties
precocious puberty (associated with OC lesions)
HTN (increased incidence of renal artery stenosis and pheochromocytoma)
reduced life expectancy (8 years lower than general population) due to malignant tumors
leukemia and myelodysplastic syndromes (more frequent in children with NF1 than general population)
rhabdomyosarcomas, pheochromocytomas, GI stromal tumors
breast cancer (women with NF1)
ADHD, bone cysts, pes cavus, speech delay, and facial coarsening (in patients with large NF1 deletions)

20
Q

What are the known phenotype/genotype correlations for NF1?

A

whole NF1 deletion –> large number and early appearance of neurofibromas, more frequent and severe cognitive abnormalities, and sometimes somatic overgrowth (large hands and feet) and dysmorphic facial features
3bp inframe deletion of exon 17 –> typical pigmentary features of NF1 but no cutaneous or surface plexiform neurofibromas

21
Q

What evaluations are required for NF1 after initial diagnosis?

A

physical exam (especially of the skin, skeleton, cardio, and neuro)
opthalmologic evaluation with slit lamp of irises
developmental assessment in children
other studies as needed for clinically apparent signs/symptoms
screening MRI (controversial)

22
Q

What surveillance is required for patients with NF1?

A

regular bp monitoring
annual physical exam
annual eye exam in early childhood (less frequent in older children and adults)
regular developmental assessment by screening questions in children
other studies as needed for clinically apparent signs and symptoms
attention to orthopedic concerns
monitoring of those with abnormal CNS, skeletal system, or cardiovascular system as appropriate

23
Q

What treatments are available for NF1?

A

surgical removal of cutaneous/subcutaneous neurofibromas (if disfiguring or in inconvenient location)
surgical de-bulking of plexiform neurofibromas (for pain ,nerve impingement, or obstruction)
optic gliomas often regress spontaneously
brain stem gliomas and astrocytomas (slow growing so conservative management recommended)
attention to orthopedic complications
bp monitoring (renal artery compression, pheochromocytomas)

24
Q

What is Neurofibromatosis 2?

A 
AD
completely penetrant (age dependent)
22q- Merlin/Schwannomin (cytoskeletal protein)
50% de novo
average age at death is 36 yo
average age of first symptoms is 22 yo
average age of diagnosis is 27 yo
25
Q

What are some other symptoms of NF2?

A 
multiple schwannomas
peripheral nerve sheath tumors
vestibular schwannomas
intracranial meningiomas
spinal tumor
lens opacities
26
Q

What are the diagnostic criteria for NF2?

A

one of the following:
bilateral vestibular schwannoma
1st degree relative with NF2 plus (unilateral VS) OR (>2) schwannoma, glioma, meningioma, neurofibroma, posterior subcapsular lense opacity
unilateral VS and >2 of meningioma, glioma, schwannoma, PSLO, or neurofibroma
multiple meningiomas (>2) AND (unilateral VS OR >2 glioma, schwannoma, neurofibroma, cataract)

27
Q

What are the clinical symptoms of Hereditary Motor and Sensory Neuropathy?

A 
chronic motor and sensory polyneuropathy
distal muscle weakness and atrophy
mild to moderate sensory loss
absent deep tendon reflexes
high arched feet (pes cavus)
affected children with slow running and poor balance
tripping and sprained ankles
28
Q

What is Hereditary Motor and Sensory Neuropathy?

A 
genetically heterogenous (AD/XLR/AR)
>90 genes/loci associated
most classical types with normal lifespan
CMT1 associated with gene duplications or point mutations in PMP22 (peripheral myelin protein 22)
HNPP (hereditary neuropathy with predisposition to pressure palsy) associated with PMP22 deletions or truncating mutations
29
Q

What is the typical disease course in the “classical phenotype” of Hereditary Motor and Sensory Neuropathies?

A

normal early developmetnal milestones –> gradual weakness and sensory loss during first 2 decades of life (pes cauvs, sensory loss in stocking and glove distribution, atrophy of distal extremities)

30
Q

How are Hereditary Motor and Sensory Neuropathies diagnosed?

A

first need to be distinguished from many causes of acquired (non-genetic) neuropathies
clinical diagnosis based on family history, characteristic findings on physical exam, EMG/NCV testing and occasionally sural nerve biopsy, or molecular genetic testing available on a clinical basis

31
Q

How are Hereditary Motor and Sensory Neuropathies managed?

A

special shoes and/or ankle/foot orthoses (typically by third decade)
gripping exercises for hand weakness
orthopedic surgery as needed for severe pes cavus deformity and hip dysplasia
acetomenophen or NSAIDs for muscle pain
tricyclic antidepresants, carbamazepine, or gabapentin for neuropathic pain
prevention of secondary complications (daily heel cord strengthening exercises)
avoidance of drugs/medications such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantain (known to cause nerve damage)
genetic counseling

32
Q

What is Alzheimer Disease?

A

complex inheritance
~25% familial (90% late onset after 65 yo and 10% early onset prior to 65 yo)
typically duration of disease is 8-10 years with range of 1-25 years (death usually from malnutrition and pneumonia)

33
Q

How is late onset Alzheimer Disease diagnosed?

A

definitive relies on clinical neuropathic assessment post-mortum
neuropathic findings of beta-amyloid plaques and intraneuronal neurofibrillary tangles remains gold standard
clinical diagnosis based on signs of slowly progressive dementia and findings of gross cerebral cortical atrophy on neuroimaging (correct 80-90%)
strongest genetic risk factor known is APOEe4 allele (late onset)- participates in receptor mediated endocytosis of lipoprteins and important in neuroplasticity and inflammation in addition to removing Abeta peptides
hets 3x higher risk; homozygotes 12x higher risk

34
Q

What are the clinical features of Alzheimer Disease?

A 
confusion
agitation
poor judgement
withdrawl
language disturbances
hallucinations
35
Q

How is early onset Alzheimer Disease diagnosed?

A

three forms of early onset caused by mutations in APP (encodes beta-amyloid plaque precursor protein), PSEN1, or PSEN2 (presenilins are the catalytic subunits of gamma-secritases that are responsible for cleavage of APP into AB peptides)- testing available in clinical labs
AD inheritance

36
Q

What is Parkinson Disease?

A

neurodegenerative disease
underlying pathogenesis: loss of domaninergic neurons in the substantia nigra with Lewy bodies
most cases are sporadic (though high concordance with MZ twins suggests genetic component) with some that are AD/AR
Gaucher Disease highly associated (PARK-GBA)

37
Q

What are the clinical findings associated with Parkinson Disease?

A

resting tremor
bradykinesia
rigidity
postural instability

Med Gen Section 3 (13 decks)

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