Neurocutaneous Disorders

Question 1

Describe Tuberous Sclerosis Complex (TSC) (3)

Answer 1

• affects cell differentiation, proliferation, migration early in dvp’ment
• variety of hamartomatous lesions
• every organ sys

Question 2

TSC triad?

Answer 2

1. Intractable epilepsy
2. Mental retardation
3. Adenoma sebaceum (red papules on face)

Question 3

Genetic foci of TSC? (2)

Answer 3

• chromo 9q34 (TSC 1)

- chromo 16p13 (TSC 2)

Question 4

Proteins implicated in TSC? (2)

Answer 4

• TSC 1 = hamartin (tumor suppressor)
• TSC 2 = tuberin (tumor suppressor)
• cooperate to regulate cell growth and differentiation

Question 5

Phenotypic variability assoc w/ TSC?

Answer 5

• 2nd hit phenomenon
• flawed copy of a TSC gene by mutation, not enough to –> phenotype
• normal allele gets 2nd hit

Question 6

Biological hallmarks of TSC? (3)

Answer 6

• cortical tubers (abnormal glial/neural elements)
• subependymal nodules (SEN – obstruction/hydrocephalus)
• subependymal giant cell astrocytomas (SEGA)

Question 7

Skin lesions assoc w/ most TSC cases? (4)

Answer 7

• hypomelanotic (Ash leaf) macules
• thick subcutaneous tissue (shagreen patch)
• periungual or gingival fibromas
• adenoma sebaceum (face)

Question 8

Heart defects assoc w/ TSC? (3)

Answer 8

• rhabdomyomas
• cardiac conducting sys
• intracardiac mass @ birth

Question 9

Other organ system defects assoc w/ TSC? (3)

Answer 9

• renal cysts and angiomyolipomas
• retinal astrocytomas
• pulmonary cysts and lymphangioleiomyomatosis

Question 10

Cognitive impairments assoc w/ TSC? (3)

Answer 10

• earlier seizure onset
• intractable seizures
• infantile spasms

Question 11

Hallmark feature of Neurofibromatosis 1 (NF1)?

Answer 11

• cafe au lait spots
• macular, regular border
• usually 1st 2 yrs of life

Question 12

Dermal assoc’s of NF1? (3)

Answer 12

• skinfold freckling in 1st 5 yrs of life
• cutaneous neurofibromas (not pre-malignant)
• plexiform neurofibromas (could become malignant)

Question 13

What are Lisch nodules pathognomonic of and where are they?

Answer 13

• NF1

- found in iris

Question 14

Describe optic pathway gliomas? What disease?

Answer 14

• NF1
• CNS tumor
• astrocytomas
• dx before age 6
• decreased visual acuity, visual field defects

Question 15

MRI lesions from NF1? (2)

Answer 15

• UBOs = unID’d bright objects = hamartomas
• better seen on T2 images
• also sphenoid dysplasia or thinning of long bone cortex w/w/o pseudarthrosis

Question 16

Inheritance pattern of NF1?

Answer 16

• autosomal dominant
• 50% of cases are sporadic/new mutations
• chromo 17

Question 17

Inheritance pattern and hallmark feature of NF2?

Answer 17

• autosomal dominant

- bilateral acoustic neuromas (CN8)

Question 18

Common examples of tri-nt disorders? (5)

Answer 18

• Huntington disease
• Fragile X
• Kennedy disease
• Myotonic dystrophy
• Ataxia telangiectasia

Question 19

Presentation of HD? (4)

Answer 19

• autosomal dominant
• progressive chorea, rigidity, psych sx, and dementia
• onset around 30-40 yrs
• brain patho = neuronal death

Question 20

Role of 3-nt repeat in HD?

Answer 20

• (CAG)n >40
• higher # of repeats corr w/ earlier age of onset
• more freq juvenile HD w/ paternal transmission

Question 21

Features of Fragile X syndrome? (2)

Answer 21

• most common cause of inherited cognitive impairment

- mutation if >200 repeats (premutation @ 55-200 repeats)

Question 22

S/S of Fragile X premutation? (2)

Answer 22

• assoc temor/ataxia syndrome (FXTAS) in men over 50

- premature ovarian failure in women

Question 23

S/s of Sturge-Weber?

Answer 23

• sporadic, port-wine stain

- assoc w/ glaucoma and intracranial malformations

Question 24

Features of AT? (4)

Answer 24

• autosomal recessive
• loss of function mutation on chromo 11q22.3
• AT Mutated gene (expressed in all tissues, stalls cell cycle progression to repair DNA damages)
• heterozygotes have increased risk for breast cancer

Question 25

Clinical presentation of AT? (9)

Answer 25

- progressive cerebellar ataxia (> 1 yo) - abnormal eye movements - neuro abnormalities - occulocutaneous telangiectasias - immune deficiency (IgG/IgA, poor titers to pneumococcus) - pulmonary disease - increased malignancy incidence - radiation (chemo) sensitivity - insulin resistance (DM)

Question 26

Features of Friedrich Ataxia? (5)

Answer 26

- loss of function of frataxin gene on chromo 9q13 - expanded GAA repeat in intron 1 of both alleles - 600-1200 repeats --> loss of protein - ongoing somatic expansion of repeats --> progression - mitochond protein --> defects in iron metabolism/storage

Question 27

Clinical criteria for Friedrich Ataxia? (5)

Answer 27

- autosomal recessive - onset before 25 yo - ataxia of all 4 limbs - absence of lower limb reflexes - presence of pyramidal signs

Question 28

Organ sys defects assoc w/ FA?

Answer 28

- cerebellar ataxia by 5yo - posterior column degeneration - pyramidal weakness - hypertrophic cardiomyopathy - overt DM or impaired glc tolerance