Neurocutaneous Disorders B&B

Question 1

phakomatoses

Answer 1

aka neurocutaneous disorders - genetic disorders which affect structures derived from ectoderm (skin, nerves, eyes)

Question 2

describe the mutation and genetic inheritance of neurofibromatosis 1 (von Recklinghausen disease)

Answer 2

mutation in NF1 on ch. 17, which encodes for neurofibromin tumor suppressor - this protein restricts RAS function!

autosomal dominant with 100% penetrance (children = 50/50 chance) however, classic example of variable expressivity

Question 3

describe the nerve, skin, and ocular findings of neurofibromatosis 1 (von Recklinghausen disease)

Answer 3

nerve: neurofibromas - benign tumors developing on cutaneous nerves, causing disfiguring bumps all over the body

eyes: Lisch nodules (brown spots on iris), optic gliomas (young age)

skins: cafe-au-lait spots (light brown macules), clustered freckles in skin folds (axilla, groin)

may also see bone abnormalities (curvature, facial deformity, scoliosis) and intellectual impairment

Question 4

child with optic glioma warrants work-up for…

Answer 4

neurofibromatosis 1 (von Recklinghausen disease): causes neurofibromas (cutaneous nerves) + optic gliomas + cafe au lait macules

AD inheritance with 100% penetrance by variable expressivity - mutation in neurofibromin tumor suppressor - this protein restricts RAS function!

Question 5

what are 2 possible causes of hypertension in a patient with neurofibromatosis 1 (von Recklinghausen disease)?

Answer 5

AD mutation in neurofibromin tumor suppressor —> neurofibromas (cutaneous nerves) + optic gliomas + cafe au lait macules

may also present with HTN due to renal artery stenosis or rarely, pheochromocytoma

Question 6

what types of malignant tumors do patients with neurofibromatosis 1 (von Recklinghausen disease) develop, and when?

Answer 6

AD mutation in neurofibromin tumor suppressor —> neurofibromas (cutaneous nerves) + optic gliomas + cafe au lait macules

some neurofibromas become malignant, but usually not skin lesions - deeper peripheral nerve sheath tumors, which occur in adolescence/adulthood and present as pain or sudden growth of neurofibroma deep to the skin

Question 7

describe the timeline of clinical findings that develop in patients with neurofibromatosis 1

Answer 7

AD mutation in neurofibromin tumor suppressor

0-2yrs: cafe au lait macules, bone abnormalities, optic gliomas

2-6yrs: Lisch iris spots, developmental delay (intellectual disability)

puberty: cutaneous neurofibromas

Question 8

Pt is a 5yo F presenting for evaluation due to concerns of developmental delay. The pt was adopted and there is no record of their FMH. Upon examination, there is evidence of intellectual disability. There are also small brown spots in bilateral iris, and light brown macules on the body. There are also clusters of freckles in the axilla and groin. The long bones appear to be curved.
What is the cause of this disorder?

Answer 8

neurofibromatosis 1 (von Recklinghausen disease): mutation in neurofibromin tumor suppressor - this protein restricts RAS function!

AD inheritance with 100% penetrance by variable expressivity

—> neurofibromas (cutaneous nerves - develop in puberty), Lisch nodules (brown spots in iris), optic gliomas, cafe au lait macules, freckles in axilla/groin, bone deformities, intellectual disability

Question 9

what is the major clinical feature of neurofibromatosis 2?

Answer 9

NF2 is less common than NF1, caused by AD mutation in NF2 gene

causes CNS tumors, almost all patients develop bilateral schwannomas (“acoustic neuromas”) —> hearing loss, tinnitus, ataxia (tumor of peripheral glia, not neurons!)

may also develop meningiomas

Question 10

patient with bilateral schwannomas should be worked up for…

Answer 10

neurofibromatosis 2: less common than NF1, caused by AD mutation in NF2 gene

causes CNS tumors, almost all patients develop bilateral schwannomas (“acoustic neuromas”) —> hearing loss, tinnitus, ataxia (tumor of peripheral glia, not neurons!)

may also develop meningiomas

Question 11

what is the hallmark and main clinical feature of tuberous sclerosis?

Answer 11

hallmark - hamartomas: benign malformations of cells/tissues (involves many organ systems)

main clinical feature - seizures due to CNS hamartomas, most common presenting feature

[mutation in hamartin (TSC1) or tuberin (TSC2) —> overactive mTOR]

Question 12

describe the mutation and genetic inheritance of tuberous sclerosis

Answer 12

AD mutation with variable expressivity, but 80% of cases are de novo

due to mutation in hamartin (TSC1 gene) or tuberin (TSC2 gene), which normally inhibit mTOR kinase

overactive mTOR —> cell growth, especially size (hamaratomas)

Question 13

what are 4 classic features of tuberous sclerosis, and which is the most common presenting feature?

Answer 13

1. seizures due to CNS hamartomas - most common presenting feature
2. “ash leaf spots” of hypopigmented skin lesions
3. angiofibromas on face
4. intellectual impairment

[mutation in hamartin (TSC1) or tuberin (TSC2) —> overactive mTOR]

Question 14

what are 3 types of CNS tumors that occur in patients with tuberous sclerosis?

Answer 14

1. cortical tubers - distort the cortex, cause seizures (key clinical finding)
2. subependymal nodules (ependyma = lining of ventricles)
3. low grade astrocytoma usually at interventricular foramen —> hydrocephalus

Question 15

90% of cardiac rhabdomyomas occur in which patients?

Answer 15

children with tuberous sclerosis

embedded in ventricular wall, usually asymptomatic, rarely cause obstruction or arrhythmia

Question 16

what type of renal tumors do patients with tuberous sclerosis get? what is the long-term effect of this?

Answer 16

[mutation in hamartin (TSC1) or tuberin (TSC2) —> overactive mTOR]

renal angiomyolipomas: multiple/bilateral proliferation of epithelioid cells around vessels, may hemorrhage

—> renin-dependent HTN, chronic kidney disease (compression of normal renal tissue)

Question 17

You are reviewing a patient’s chart. They first presented as a child with seizures and patches of hypo-pigmentation. They were followed closely for developmental delays. At age 8, they were admitted for hydrocephalus, and a low-grade astrocytoma was removed from the interventricular foramen. They later developed fibrous papules across their face, as well as leathery “orange peel” patches on their lower back. Recent imaging has identified bilateral tumors within the kidneys, which are producing renin. What does this patient have?

Answer 17

tuberous sclerosis: mutation in hamartin (TSC1) or tuberin (TSC2) —> overactive mTOR

—> seizures (CNS hamartomas), “ash leaf spots”, angiofibromas (face), intellectual impairment, cardiac rhabdomyomas, Shagreen patches (“orange peel”, lower back), ungual fibromas (nail), renal angiomyolipomas

Question 18

describe the mutation and genetic inheritance of Sturge-Weber Syndrome

Answer 18

spontaneous somatic mutation with mosaicism of GNAQ gene —> abnormal capillary formation/growth

no family history here! mutation occurs AFTER fertilization

Question 19

what are the 3 classic features of Sturge-Weber Syndrome?

Answer 19

spontaneous somatic mutation of GNAQ gene, causing abnormal capillary formation/growth

1. port-wine stain (nevus flammeus) - unilateral, in region of CN V1/2, due to slow blood flow, grows with child
2. leptomeningeal angioma - on SAME SIDE as port-wine stain, may cause seizures
3. glaucoma - infancy or early adulthood

Question 20

newborn with port wine stain + seizures + glaucoma =

Answer 20

Sturge-Weber Syndrome: spontaneous somatic mutation of GNAQ gene, causing abnormal capillary formation/growth

1. port-wine stain (nevus flammeus) - unilateral, in region of CN V1/2, due to slow blood flow, grows with child
2. leptomeningeal angioma - on SAME SIDE as port-wine stain, may cause seizures
3. glaucoma - infancy or early adulthood

Question 21

describe the mutation and genetic inheritance of von Hippel-Lindau Disease

Answer 21

mutation of VHL gene on ch. 3 which encodes for VHL tumor suppressor - normally causes ubiquitination of hypoxia-inducible factor

mutation causes constitutive signaling of hypoxia inducible factor —> cells behave as if hypoxic —> blood vessel growth

autosomal dominant but requires 2 hits - develops late childhood/young adulthood

Question 22

when does von Hippel-Lindau Disease begin to present and why?

Answer 22

autosomal dominant but requires 2 hits - develops late childhood/young adulthood

mutation of VHL gene on ch. 3 which encodes for VHL tumor suppressor - normally causes ubiquitination of hypoxia-inducible factor

mutation causes constitutive signaling of hypoxia inducible factor —> cells behave as if hypoxic —> blood vessel growth

Question 23

how does von Hippel-Lindau Disease present?

Answer 23

VHL mutation results in loss of ubiquitination of hypoxia-inducible factor —> blood vessel growth (cells act hypoxic)

—> hemangioblastomas in CNS (cerebellum, spinal cord, retina) + renal cysts/ bilateral renal cell carcinoma + pheochromocytomas

Question 24

Pt is a 14yo F presenting for genetic counseling. In the past year, a cerebellar hemangioblastoma and an adrenal pheochromocytoma have been identified. Testing reveals a mutation on chromosome 3. What is the diagnosis?

Answer 24

von Hippel-Lindau Disease: mutation of VHL on ch. 3 = loss of ubiquitination of hypoxia-inducible factor —> blood vessel growth (cells act hypoxic)

—> hemangioblastomas in CNS (cerebellum, spinal cord, retina) + renal cysts/ bilateral renal cell carcinoma + pheochromocytomas

AD but develops in late childhood because it requires “2 hits”

Question 25

match the following presentations with the most likely neurocutaneous disorder:
a. benign tumors of cutaneous nerves + optic gliomas
b. hamartomas
c. bilateral schwannomas
d. hemangioblastomas
e. leptomeningeal angiomas

1. neurofibromatosis 1
2. neurofibromatosis 2
3. tuberous sclerosis
4. Sturge-Weber Syndrome
5. von Hippel-Lindau Disease

Answer 25

neurofibromatosis 1 —> neurofibromas (cutaneous nerves) + optic gliomas

neurofibromatosis 2 —> bilateral schwannomas

tuberous sclerosis —> hamartomas (benign malformation of tissues)

Sturge-Weber —> leptomeningeal angiomas (capillary-venous malformation)

von Hippel-Lindau Disease —> hemangioblastomas (clumps of capillaries)