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Dermatology Board Prep > DERM (09) Genodermatoses > Neurocutaneous Syndromes > Flashcards

Neurocutaneous Syndromes Flashcards

1
Q

What are the 3 subtypes of neurofibromatosis?

A

NF1, NF2, and schwannomatosis

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2
Q

What is the most common type of neurofibromatosis?

A

NF1 (90%)

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3
Q

What is the gene involved and mode of inheritance for NF1?

A

NF1 gene (neurofibromas), AD –> negatively regulates Ras activations

-50% are sporadic mutations and mosaic/segmental dz can occur

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4
Q

Diagnostic criteria for NF1?

A

Must have >2 of the following:

  • Six café-au-lait macules >0.5cm prepubertal or >1.5cm postpubertal
  • intertriginous freckling
  • Plexiform neurofibroma or >2 dermal neurofibromas
  • >2 lisch nodules
  • Optic nerve glioma
  • Pathogenic skeletal dysplasia (tibial or sphenoid wing dysplasia)
  • Affected first-degree relative
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5
Q

What NF1 findings occur in infancy?

A

Café-au-lait macules, plexiform neurofibromas, neurologic findings, macrocephaly, tibial dysplasia, sphenoid wing dysplasia

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6
Q

What findings of NF1 occur in the prepubertal stage?

A

Intertriginious freckling, optic gliomas, brainstem gliomas meningiomas, scoliosis

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7
Q

What are the cutaneous findings in NF1?

A

Neurofibroma: soft papule that invaginates upon finger pressure (buttonholing)

  • Plexiform neurofibroma: overlying CALM and/or hypertrichosis, feels like a “bag of worms” texture seen in 25% of patients
  • Malignant peripheral nerve sheath tumor (MPNST): rapid enlargement or pain of plexiform neurofibroma (10% risk)
  • CALM (typically >6, increased size and number if first 5 years
  • Axillary freckling (Crowe’s sign)
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8
Q

Skeletal manifestations of NF1?

A

Sphenoid wing dysplasia: pulsating exophthalmos can be noted, though often asymptomatic

  • macrocephaly
  • scoliosis
  • congenital tibial pseudarthroses
  • additional skeletal abnormalities: thoracic cage asymmetry, osteoporosis, and pathological fractures
  • short stature
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9
Q

Neurologic manifestations of NF1?

A

Learning disabilities, autism, ADHD

  • seizures
  • hydrocephalus
  • Optic glioma which can lead to blindness; seen w/ precocious puberty, astrocytomas, meningiomas, vestibular/acoustic schwannoma/neuroma, ependymoma
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10
Q

What other neoplasms can be seen in NF1?

A

Neurofibrosarcoma, rhabdomyosarcoma, pheochromocytoma, Wilms’ tumor and CML

  • Nevus anemicus found in up to 50% of patients
  • TRIPLE ASSOCIATION W/ NF1, JUVENILE XANTHOGRANULOMAS, AND JMML
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11
Q

What is the most common second mutation seen in neurofibroma to cause malignant transformation?

A

p53

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12
Q

What is the inheritance pattern and gene involved in NF2?

A

AD, mutations in SCH (schwannomin/merlin) which is a tumor supressor gene

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13
Q

What are the cutaneous findings in NF2

A

neurofibromas (lower #’s than NF1), more commonly subcutaneous type w/ overlying pigment/hair rather than intradermal. can have CALMS too

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14
Q

Neurologic findings in NF2?

A

Bilateral vestibular schwannomas (acoustic neuromas) is diagnostic –> deafness, tinnitus, unsteadiness, headache, meningiomas, astrocytomas and ependymas

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15
Q

Most common cause of death in NF2?

A

CNS tumors

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16
Q

Ocular findings in NF2?

A

Juvenile posterior sub capsular lenticular opacity/cataract

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17
Q

What are the genetics and genes associated with tuberous sclerosis complex?

A

AD, mutations in hamartin (TSC1) or tubers (TSC2) [tumor supressors]

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18
Q

What is the pathophysiology of tuberous sclerosis?

A

Tuberin and hamartin form complex that inhibit signal transduction of downstream efforts of mTOR –> results in abnormal cellular differentiation, proliferation and migration –> hamartomas

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19
Q

What are the main cutaneous findings of tuberous sclerosis?

A

Adenoma sebaceum (facial angiofibromas), hypopigmented “ash-leaf” macules (confetti pattern pretibially; first cutaneous finding), shagreen patch (which is a connective tissue nevus), periungual fibromas (“Koenen tumors”), and cafe au lait macules

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20
Q

What is the histology of the angiofibromas?

A

Dermal fibrosis w/ stellate fibroblasts, atrophic sebaceous glands, dilated capillaries, and loss of elastin

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21
Q

What is the histology of the shagreen patch?

A

Connective tissue nevus –> broad sclerotic collagen bundles and reduced elastin

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22
Q

Histology of the hypopigmented patches (ash-leaf spots)?

A

Normal number of melanocytes but there is decreased pigmentation

23
Q

What are some treatments for facial angiofibromas in tuberous sclerosis?

A

Pulsed dye laser, ablative laser, excision, and topical rapamycin

24
Q

What are the neurologic findings in tuberous sclerosis?

A
  • cortical tubers
  • subependymal nodules (can lead to hydrocephalus)
  • subependymal giant cell astrocytomas
  • seizures/infantile spasms
  • hypsarrhythmia
  • intellectual impairment
  • paraventricular calcification
25
Q

What neurologic features are associated with worse prognosis in tuberous sclerosis?

A

Infantile spasms, large number of cortical tubers, and early age of onset of seizures or intractable seizures

26
Q

What is the number one cause of mortality in tuberous sclerosis?

A

Complications related to seizures

27
Q

What are the renal findings in tuberous sclerosis?

A

Renal cysts, angiomyolipomas, and renal cell carcinoma

28
Q

What is the treatment of the renal or hepatic angiomyolipomas and subependymal giant cell astrocytoma?

A

Systemic mTOR inhibitors (sirolimus and everolimus)

29
Q

What are the complications of the renal portion of the disease in tuberous sclerosis?

A

Renal failure, catastrophic hemorrhage within renal angiomyolipoma, and renal hypertension (importantly this is the #2 cause of death in TSC)

30
Q

What are the ocular findings in tuberous sclerosis?

A

Retinal phakomas (hamartomas)

31
Q

What are the cardiac findings in tuberous sclerosis?

A

Cardiac rhabdomyomas which can lead to Wolf-Parkinson-White arrhythmias

32
Q

What are the GI findings in tuberous sclerosis?

A

Hepatic cysts, hepatic angiomyolipomas (usually asymptomatic), and GI polyps/hamartomas

33
Q

Dental findings in tuberous sclerosis?

A

Pits in the enamel and gingival fibromas

34
Q

What are the lung findings in tuberous sclerosis?

A

Pulmonary lymphangioleiomyomatosis and pulmonary cysts

  • Pneumothorax, chylothorax, hemoptysis, and pulmonary insufficiency
35
Q

What is required for dx of tuberous sclerosis?

A

Presence of pathogenic mutation in TSC1/TSC2 or presence of two major criteria or one major and two minor criteria

36
Q

What are the major and minor criteria for tuberous sclerosis?

A

Major: >=3 angiofibromas or fibrous cephalic plaques, >=3 Hypomelanotic macules >5mm in diameter, >= ungual fibromas, Shagreen’s patch, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyomas, lymphangioleiomyomatosis, >=2 angiomyolipomas

Minor: >= 3 dental enamel pits, >=2 intraoral fibromas, “confetti”-like skin lesions, Nonrenal hamartomas, Multiple renal cysts, Retinal achromic patch

37
Q

What lesions in tuberous sclerosis are present in infancy to early childhood?

A

Hypomelanotic macules, confetti-like skin lesions, cardiac rhabomyomas, subependymal nodules, seizures

38
Q

What findings in tuberous sclerosis occur in prepubertal children?

A

Angiofibromas, Shagreen patch, fibrous cephalic plaque, and dental pits. Also can see renal hamartomas

39
Q

What findings in tuberous sclerosis occur in adolescence?

A

Ungual fibromas

40
Q

What findings in tuberous sclerosis occur in adulthood?

A

Intraoral fibromas, pulmonary lymphangioleiomyomatosis (more in women), renal cysts

41
Q

What is the inheritance pattern and gene involved in incontinentia pigmenti?

A

XLD loss of function mutation in nuclear factor-kappa B essential modulator (NEMO; IKBKG)

42
Q

What is the pathophysiology of incontinentia pigmenti?

A

Mutation in NEMO prevents activation of NF-kappaB, a regulator of cell proliferation, inflammation and TNF-alpha induced apoptosis

43
Q

What physical findings are seen due to the XLD nature of incontinetia pigmenti?

A

It is fatal in males, seen in a woman with mosaicism from the lyonization in affected females (random inactivation of the affected X chromosome) which results in the Blaschkooid pattern of cutaneous involvement

44
Q

What are the 4 primary cutaneous stages of incontinentia pigmenti and when do they occur?

A

Birth to 1 month: Vesicular stage (reactivation can occur w/ illness or trauma)

1 month to ~2 years: Verrucous stage (usually resolved by 8 weeks)

Up to adolescence: Hyperpigmented (can resolve by 1 year) [Note: this does not have to involve previously vesicular/verrucous areas]

Persistent: Hypopigmented: atrophic hypopigmented streaks

45
Q

Other skin findings in incontinentia pigmenti besides the 4 major stages?

A

Can have alopecia on the scalp and other areas (cicatricial alopecia), nail dystrophy, subungual tumors, pegged or conical teeth, anodontia, delayed dentition

note: patients do not have to go through all 4 stages and can have some simultaneously

46
Q

What is the histology of the vesicular stage of incontinentia pigmenti?

A

Eosinophilic spongiosis; intraepidermal vesicles containing eosinophils, apoptotic keratinocytes in epidermis

47
Q

What is the histology of the verrucous stage of incontinentia pigmenti?

A

Papillomatosis, hyperkeratosis, and acanthuses of the epidermis; apoptotic cells in epidermis forming squamous eddies

48
Q

What is the histopathology of the hyperpigmented stage of incontinentia pigmenti?

A

Marked pigment incontinence with numerous melanophages in the dermis; apoptotic cells may be seen in the epidermis

49
Q

What is the histology of the hypopigmented stage of incontinentia pigmenti?

A

Epidermal atrophy, loss of melanin in basal layer, complete absence of pilosebaceous units and eccrine glands; apoptotic cells may be seen in epidermis

50
Q

What neurologic abnormalities can be seen in incontinentia pigmenti?

A

Severely affected patients may develop seizures, developmental delay and intellectual impairment, and decreased visual acuity/blindness (due to retinal vascular changes and optic atrophy)

51
Q

What disease occurs if a woman w/ a missense mutation in NEMO (mild phenotype of IP) can bear a male child with what condition?

A

Hypohidrotic ectodermal dysplasia with immunodeficiency

52
Q

Systemic findings in incontinentia pigmenti?

A

Seizures, mental retardation, spastic paresis, retinal vascular anomalies, nonretinal anomalies (strabismus, cataracts, and optic atrophy), supernumerary nipples, nipple hypoplasia, breast hypoplasia or aplasia

53
Q

What is the involved gene and inheritance of Legius syndrome?

A

AD SPRED1

54
Q

What is the clinical appearance of Legius syndrome?

A

Cafe-au-lait macules, intertriginous freckling, and learning disabilities

DERM (09) Genodermatoses (13 decks)

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