Neurocutaneous Disease

Question 1

phakomatoses

Answer 1

*genetic syndromes with characteristic neurologic, cutaneous, and often ocular manifestations
*examples: tuberous sclerosis, Sturge-Weber, and neurofibromatosis (NF1 and NF2)
*complete penetrance (everyone has symptoms) with variable expressivity (symptoms can be different)

Question 2

two-hit hypothesis of tumor formation

Answer 2

requires mutation in both alleles of a tumor suppressor gene (usually first copy is mutated from inherited mutation, and then 2nd hit is usually acquired)
*haploinsufficiency = symptoms that occur when 1 copy is hit
*2nd hit is known as loss of heterozygosity (LOH)

Question 3

NF1 gene - normal function

Answer 3

*NF1 gene codes for neurofibromin protein
*neurofibromin is responsible for shutting down cell growth by shutting down RAS phosphorylation (keeping RAS inactive to prevent tumor growth)
*when RAS is active (phosphorylated), if activates RAF, which activates MEK, which leads to cell growth and often tumors

Question 4

NF-1 clinical manifestations

Answer 4

*skin
*eye
*bone
*brain
*nerves

Question 5

NF-1 skin manifestations

Answer 5

*cafe au lait macules (flat, tan patches; can occur in people w/o NF-1)
*axillary and inguinal freckling
*neurofibromas

Question 6

NF-1 eye manifestations

Answer 6

*Lisch nodules: hamartomas of the iris (brown dots on the iris)

Question 7

NF-1 bone manifestations

Answer 7

SCOLIOSIS & SPHENOID WING DYSPLASIA

*scoliosis is the most common bony abnormality in NF-1
*sphenoid wing dysplasia is a diagnostic criteria
*other: cortical bone thinning +/- pseudoarthrosis

Question 8

NF-1 brain manifestations

Answer 8

*brain tumors (~20% of NF1 patients); most are optic pathway gliomas!
*other lesions on MR brain:
-UBOs
-scalp neurofibromas
-stroke, moya moya

Question 9

NF-1 diagnostic criteria

Answer 9

need 2 or more of the following:
* > 6 cafe au lait macules
*2+ cutaneous neurofibromas
*lisch nodules
*axillary/inguinal freckling
*plexiform neurofibroma
*1st degree relative with diagnosis of NF
*bony dysplasia

Question 10

gene defect in neurofibromatosis 1

Answer 10

*NF-1 on chromosome 17
*mode of inheritance: sporadic in 50% of cases or autosomal dominant inheritance
*follows the 2-hit hypothesis

Question 11

gene defect in neurofibromatosis 2

Answer 11

*schwannomin/merlin on chromosome 22
*sporadic in 50% of cases or AD
*follows the 2-hit hypothesis

Question 12

NF-2 clinical manifestations

Answer 12

*vestibular schwannomas (bilateral; most common presentation of NF-2)
*intracranial meningiomas
*spinal cord ependymomas

Question 13

bilateral vestibular schwannomas is indicative of?

Answer 13

neurofibromatosis 2 (NF-2)

Question 14

NF-2 diagnostic criteria

Answer 14

need at least 1 of the following:
*bilateral vestibular schwannomas
*family hx of NF2 + unilateral vestibular schwannoma + two other characteristic NF2 tumors
*unilateral vestibular schwannoma + 2 other characteristic tumors
*multiple meningiomas + 2 other characteristic tumors

Question 15

gene defect in tuberous sclerosis

Answer 15

*TSC1 (hamartin) or TSC2 (tuberin)
*defect in tumor suppressor gene
*follows the 2-hit hypothesis

Question 16

mode of inheritance of tuberous sclerosis

Answer 16

autosomal dominant
*follows the 2-hit hypothesis

Question 17

pathophysiology of tuberous sclerosis

Answer 17

*normal tuberin & hamartin activate a cell STOP pathway, involving mTOR
*when these proteins are mutated, the STOP pathway on cell proliferation is unregulated and therefore cells can grow unregulated, leading to tumor formation

Question 18

tuberous sclerosis - notable skin findings

Answer 18

*ash leaf macules (hypopigmented)
*facial angiofibromas
*periungual fibromas
*Shagreen patch

Question 19

tuberous sclerosis - neurologic manifestations

Answer 19

*brain tumors:
-cortical tubers
-subependymal nodules
-subependymal giant cell astrocytoma

*seizures, developmental delay, and neuropsychiatric symptoms are high

Question 20

gene defect - Sturge-Weber Syndrome

Answer 20

*mutation in GNAQ

Question 21

mode of inheritance in Sturge-Weber Syndrome

Answer 21

sporadic

Question 22

Sturge-Weber Syndrome - clinical features

Answer 22

*port wine stain (capillary malformation) on half of face with tissue hypertrophy
*glaucoma (increased intraocular pressure)
*seizures
*vascular malformations within the pia mater (tram-track calcifications on CT)