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MyDermatology-Bolognia > Ch. 61-Neurofibromatosis + Tuberous Sclerosis > Flashcards

Ch. 61-Neurofibromatosis + Tuberous Sclerosis Flashcards

1
Q

What is the inheritance pattern of most cancer syndromes?

A

AD

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2
Q

Inheritance pattern of NF? TS?

A

AD for both

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3
Q

What is the penetrance of NF-1? TS?

A

100% penetrant for both

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4
Q

What % NF-1 is de novo?

A

50%

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5
Q

Describe NF varaints 1-7

A

NF1
NF-2-acoustic schwanomma
NF-3: central and peripheral neurofibromas (MIXED)
NF-4: Vairant
NF-5: Segmental/Mosaic NF= CALMs/NFs affecting 1 or more dermatomes
NF-6: CALMs only, includes Legius syndrome
NF-7: late onset

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6
Q

Incidence NF-1

A

1 in 3000

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7
Q

What gene is mutated in NF-1? What does it code for?

A

NF1 gene—> Neurofibromin

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8
Q

What is the most common mutation in NF-1?

A

Mutation that results in truncated neurofibromin protein
Sometimes get a large microdeletion with more severe phenotype

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9
Q

Chromsomome of NF-1?

A

17q11.2

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10
Q

What is role of neurofibromin (1-what pathway 2-general role)

A

RAS-MAPK pathway that promotes cell survival and proliferation

Role played as tumor supressor (down regulates this pathway)

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11
Q

What drug can be used to block neurofibroma formaiton?

A

Imatinib (tyrosine kinase inhibitor)

-C-kit ligand is oversecreted by NF-/- (Loss of heterozygosity) schwaan cells, recruits mast cells (that are NF+/-) that secrete factors promoting neurofibroma genesis

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12
Q

Name 6 cutaneous findings in NF-1

A

CALMs (Need 6 or more, >5 or 15 mm)
Axillary./inguinal freckling
Neurofibromas (regular or plexiform)
Nevus anemicus
JXG

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13
Q

Name 3 ocular findings in NF-1

A

Lisch nodules (90%)
Choroidal nodules
Optic glioma (also under tumor section)
Neovascular glaucoma

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14
Q

Name 6 skeletal/MSK related findings in NF-1

A

Scoliosis
Spina bifida
Long bone cortex dysplasia (tibia)
Psuedoarthrosis
Osteopenia and osteoporosis
Short stature
Pectus deformity

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15
Q

Name 4 tumors in NF-1? (There are more)

A

Optic glioma
Malignant peripheral nerve sheath tumor
Breast cancer-5 fold risk
Pheo
Juvenile myelomonocytic leulemia
Non optic glioma CNS tumors

Rhabdomyosarcoma
Duodeanl carcinoid
Somatostatinoma
Parathyroid adenoma
GISTs

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16
Q

Name 3 cranial findings in NF-1

A

Sphenoid wing dysplasia
Macrocephaly
Hypertelorism

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17
Q

What are some neurologic related findings in NF-1

A

Learning difficulties
Unidentified bright objects on MRI
Seizures
Intellecutal disability

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18
Q

What is the main CV findings in NF-1? Name 3 others

A

Essential hypertension
Pulmonic stenosis, RAS, cerebrovascular anomalies

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19
Q

What is the diagnostic criteria for NF-1?

A

Need 2 of the following:

CAFESPOT

C: CALMS (6 or more, 5 mm prepubertal or 15 mm post)
A: Axillary/inguinal freckling
F: Fibroma-2 or more neurofibromas, or 1 plexiform
E: Eyes-lisch nodules 2 or more
S: Skeletal: Anterolateral bowing tibia or psueodoarthrosis long bone, or sphenoid dysplasia
P: Parental with NF
OT: Optic tumor (optic glioma

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20
Q

What is the ddx for multiple CALMS? Name 10

A
  1. NF-2
  2. Mosaic NF (NF-5)
  3. Multiple familial cafe au lait (NF-6)
  4. Legius (NF-1 like)
  5. McCune Albright Syndrome
  6. Constitutional Mismatch Repair Deficiency (CMMRD)
  7. Noonan/LEOPARD (Noonan syndrome with multiple lentigines)
  8. Ring Chromosome Syndrome
  9. Cowdens
  10. Banayan-Riley-Ruvalcaba syndrome

Others with weaker association

  1. NAME syndrome (Carney complex, also LAMB)
  2. Ataxia Telengiectasia
  3. Epidermal nevus syndrome (extensive epidermal and sebaceous nevi)
  4. Turner
  5. Russel Silver
  6. Fanconis anemia
  7. MEN1/2B
  8. BLoom
  9. Watson syndrome
  10. Westerhof syndrome
  11. Hunter disease

Others that Bolognia mentions:
-Tuberous Sclerosis
-Piebaldism
-Familial progressive hyper and hypopigmentation
-Mukamel Syndrome
-Partial unilateral lentiginosis
-Gastrocutaneous syndrome
-Tay syndrome
-Tricho-hepato-enteric syndrome
-Johnson McMillin syndrome

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21
Q

What are the features of Legius?

A

Multiple CALMs, axillary freckling
No other NF-1 stigmata (No lisch, no optic gliomas, no NFs)
Macrocephaly, lipoma, learning disability, hypopigmented macules

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22
Q

What are the features of McCune Albright? What gene?

A

GNAS1
CALMs-but segmental, larger, less uniform
Precocious puberty
Other endocrinopathies
Polyostotic fibrous dysplasia

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23
Q

What are the features of CMMR deficiency? What genes?

A

MSH2, MSH6, PMS2, MLH1

Multiple CALMs

Cancers: Medulloblastoma, lymphoma, glioblastoma, colonic polyps

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24
Q

What are the features of segmental NF (NF-5 formerly)

A

Neurofibromas alone or CALMS +- axillary freckling in block like pattern

Post zygotic NF-1 mutation in some which may involve the gonads

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25
Q

What are the features of Noonan with multiple lengitines? Gene?

A

Short stature/growth retardation
Characteristic facies with hypertelorism
Cardiac defects—> pulm valve stenosis, conduction
Testicular abnormalities
Hearing loss

Skin:
-KP atrophicans
-melanocytic nevi
-cafe noir?

PTPN11

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26
Q

What are the cutaneous findings of Cowdens? Gene?

A

PTEN

CALMS
Trichelommas
Lipomas
Neuromas
Cobblestoning oral mucosa

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27
Q

Name 4 cutaneous findings of Cowdens. What is the gene mutated?

A

PTEN

Trichelommomas
CALMs
Lipomas
Neuromas
Cobblestoning oral mucosa

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28
Q

Name 3 cancers associated with Cowdens

A

Gi polyps
Breast carcinoma
Thyroid

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29
Q

Name 3 additional features Ring chromsome syndrome

A

CALMS
Microcephaly
Mental retardation
Short stature

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30
Q

What gene mutated in Watson Syndrome? Name 5 feeatures

A

NF-1
Axillary and inguinal freckling

Mental retardation
Short stature
Pulm valve stenosis
Lisch nodules

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31
Q

What are the features of Jaffe Campanacci syndrome?

A

-Disseminated non ossifying FIBROMAS of long and jaw bones

-Hypogonadism or cryptothcidism

-Giant cell granulomas

NF-1 mutation

*Can get CALMS, neurofibromas

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32
Q

What age do cutaneous neurofibromas tend to occur?

A

Ages 4-5 at earliest, but typically more around puberty and pregnancy

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33
Q

What are the types of neurofibromas and their clinical findings?

A

Cutaneous: pink, tan or brown soft papulonodules, slightly rubbery, can be few mm to several centemetres, eventually become dome shaped or pedunculated, early lesions may be barely elevated and show the buttonhole sign

Subcutaneous: Firmer and less well circumscribed, 1/4 can have tumor related local complications

Blue-red macules (thick walled blood vessels and neurofibromatous tissue)

Psueo atrophic macules : collagen in the reticular dermis)

Plexiform: Track along nerves, create tender, firm nodules or masses in subcutis with “bag of worms” consistency under palpation, or can infiltrate into fascia, muscle or internal structures

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34
Q

What % of NF-1 patients have plexiform NFs

A

25%

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35
Q

What are 3 complications of plexiform NFs

A

Soft tissue and bony hypertrophy
Distortion of head and neck or extremtiies
NErve impingement nest

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36
Q

What is the clinical presentation to PNFs

A

Hyperpigmented plaques that may be misdiagnosed as CAFE au laits (if not palpated)

Congenital melanocytic nevi

Circumscribed sagging pink mass

May have overlying hyperpigmentation and hypertrichosis

CAN BE INTERNAL-need full body MRI

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37
Q

Name 4 clinical findgins that may indicate malignant degeneration of PNF into neurofibromasarcomas

A

-rapid growth
-increased firmness
-persistent pain
-new neuro deficit

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38
Q

What investigations/referrals are needed at NF-1 diagnosis?

A

1) Derm exam (esp. if PNG present)
+- surgical consult for disfiguring neurofibroma
+- Pet CT if suspect PNF

2) Optho assx (prior to 8 years)

3) Ortho if scoliosis or tibial bowing

4) Neuro exam, head circ, developmental eval
+- orbital/brain/spine mri if neuro symptoms

5) CV
-BP assx, +- pheo assx if HTN
-if murmur—> cardiology

6) Endo assx if percocious pubery

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39
Q

What are 4 annual evalutions needed in NF-1

A

Derm exam (if PNF present)
-PET CT if suspected

Neuro exam
+- MRI

BP measurement

Breast cancer screening at age 40

40
Q

What is Crowe’s sign

A

Numerous 1-3 mm brown macules (more akin to lentigines >ephelids) in intertrigiinous regions, neck, and sometimes entire skin surface

Axilla most common

41
Q

When does axillay freckling start?

A

Ages 4-6 after CALMS, before neurofibromas

42
Q

What % NF-1 get JXGs? When do they occur?

A

15-35% get 1 or more in first 2-3 years of life, can be early sign if co-existing with CALM

43
Q

What % NF-1 get nevus anemicus? How old?

A

30-50%, favor mid trunk and chest, more evident after rubbing the skin

44
Q

How can sphenoid wing dysplasia present?

A

Pulsating exopahtlmos

45
Q

What is psuedoarthrosis

A

False joint formation

46
Q

At what age do the majority of people meet criteria for NF-1

A

Age 8-97% have met it

47
Q

What order do these findings come in:
-CALMs
-freckling
-lisch
-neurofibromas
-sphenoid wing or psuedoarthrosis

A

CALM (birth-2)—> freckling—>LISCH nodules (4-6)—> Neurofibromas (puberty, as early as 4-5)

*PNF and skeletal defects congenital usually, dont increase in freeqyency over time

48
Q

Pathology of NF

A

Un-encapsulated dermal spindle cell tumor (fibroblasts, schwaan, perineural cells) with wavy elongated nuclei

Mast cells

49
Q

Pathology of plexiform NF

A

Large hypertrophied nerves surrounded by spindle shaped fibroblasts and schwaan cells in myxcoid matrix

50
Q

Approach to child with 6+ CALMS > 5mm

A

1) Segmental? Mosaic NF-1
2) Assess for other features NF-1 (freckling, NFs, lisch nodules or optic gliomas (slit lamp), relatives, sphenoid or tibial dysplasia)
3) If negative, genetic testing
4) If still negative or dont do it—-> annual physical and eye exam

51
Q

What are 2 considerations in a kid with NF-1 + HTN?

A

Pheo—>urine tests
RAS—> doppler u/s

52
Q

DDx for unilateral lentigines in axila or groin?

A

1) Legius
2) Mosaic NF-1 (NF-5)
3) Partial unilateral lentiginosus
4) Large speckled lengitinous nevus

*Last 2 often sharply demarcated at midline
*PUL and NF-1 can co-exist.If CALMS and lengitines, more likely also NF-1

53
Q

What is prevalence NF-2?

A

1 in 40 000

54
Q

What is hallmark tumor NF-2?

A

Vestibular schwannoma

55
Q

Name 6 key features of NF-2 (tumors, skin, transmission, gene)

A

Vestibular scwhannoma
Meningiomas
Spinal tumors

AD transmission
NF2 gene is on chromosome 22q12 and encodes cytoskeleton associated protein

No lisch nodules or mental retardation/learning distbility

2/3 patients have cutaneous schwannomas
50% CALMS but rarely >6

Can have neurofibromas as well, but not a centrla feature

56
Q

Name 5 features of the CALMS in McCune Albright

A

-pigementary mosaicism
-larger
-linear or segmental distribution (e.g. broad bands along lines of blaschko)
-usually dont cross mideline
-irregular border-coast of Maine

Common sides head, neck, trunk, buttocks

57
Q

What is the best test for detecting malignant change in PNFs

A

PET CT

58
Q

Name 2 therapies under investigtion for NF-1

A

Imatinib (inhibitor of C-kit on mast cells_
Rapamycin (sirolimus) = Mtor inhibitor
Semultenib and other MAPK pathway inpiters

59
Q

Prevalence of TS

A

1 in 10 000-30 000

60
Q

What % TS are de novo

A

50%

61
Q

What genes are mutated in TS and what proteins do they make

A

TSC1- hamartin
TSC2- Tuberin

62
Q

What is the function of tuberin and hamartin

A

Interact with each other to downregulate MTOR signallying and thus cell growth and differentiation

63
Q

Name 6 cutaneous features of TS

A

Facial angiofibromas -80%
Fibrous plaque of the forehead -20%
Hypomelanoic macules-90-100%
Shagreen patch (40-50%)
Ungual fibromas (30-60%)
Collagenomas
Molluscum pendulum
CALMS

64
Q

Name 2 characteristic oral findings in TS

A

Gingival fibromas
Dental enamel pits -90%

65
Q

Name 2 ocular findings in TS

A

Retinal hamartomas
Acrhomatic retinal patches
Retinal astrocytoma

66
Q

What is a pulmonary feature of TS

A

Lymphangioleiomyomatosis

67
Q

What are 3 renal features of TS

A

Multiple bilateral angiomyolipomas
Cysts
RCC

68
Q

What are 2 endocrine features of TS

A

HypoTSH
Precocious puberty

69
Q

Name 5 neurologic features of TS

A

Cortical tubers (>90%)
Supendymal nodules (80%)
Supenedemylu giant cell astrocytoma

Seizues including infantile spasms
Intellectual impairment

70
Q

Name 2 CV findings in TS

A

WPW
Myocardial rhabdomyoma

71
Q

What are the major features of TS?

A

Major:
FAST TAN CLARK
-F: facial angiofibromas (3+) OR fibrous cephalic plaque
-A: Ash leaf-hypomelanotic macules (3+, 5 mm or larger)
-Shagreen patch
-Tumors, koenan (ungual fibromas (2+))

Tubers cortical
Astrocytoma, giant cell (sub epdendymal)
Nodules, subependymal

Cardiac rhabdoymoma
Lymph-
angioleiomyomatosis
Retinal hamartomas
Kidney tumors-angiomyolippomas (2+ in any organ)

72
Q

What are the minor features of TS

A

Confetti skin lesions
3+ dental enamel pits
Intra-oral fibromas
Retinal achromic patch
Mutliple renal cysts
Non renal hamartomas

73
Q

How to make diagnosis TSC

A

2 major
1 major + 2 minor

74
Q

What is first cutaneous sign in TSC? When do the other signs appear?

A

Hypomelanotic macules first, often birth or first few months
—> Angiofibromas (4-6)
—> Shagreen (8-10)
—> periungual fibromas

75
Q

What is the msot specific cutaneous lesion of TSC

A

Gutatte leukoderma or confetti macules

76
Q

What % healthy kids have nevus depigmentosus?

A

1-4%

77
Q

What% TSC have CALMS?

A

30%

Usually less than 6

78
Q

What is a shagreen patch histopathologically speaking? What is its appearance clinically?

A

Collagenoma

-skin colored hyper or sometimes hypopigemented plaques with uneven surface, can be up to 10 cm, can have pigskin apperance due to prominent depressed follicular opening
-often on lumbosacral area
-appear around 2 yrs
-50% TSC have them

79
Q

What are the 2 types of koenen tumors

A

1-peringual fibromas-prox or lateral nailfold often on toenails
2-subungual fibromas-longitudinal red streaks with proximal narrowing, can lead to longitudinal groove

80
Q

Molluscum pendulum-what is it

A

Soft pedunculated skin colored papules and nodules, look like acrochordongs, favor flexures

81
Q

What is the most common type of retinal hamartoma

A

Flat translucent lesion> mulberry lesion>tranaistional type

Most ocular lesions in TSC do not lead to vision loss

82
Q

What is included in TSC-asscoaited neuropsuchiatric disorders

A

ADHD
Autism
Psyh condditions
Aggressivebehaivor

83
Q

Difference between subependymal nodules vs. Supependymla giant cell asterocytoma

A

80% kids have nodules by 2 years, almost all patients have bypuberty(along ventricularsurface on MRI)

SEGAs only in 5-15%, pften during childhood, and can lead to neurological symptoms and show conrtrast enhancement on MRI

84
Q

What are 2 types of cortical dysplasia in TSC

A

Tubers-glioneural hamartoma
Cerebral white matter radial migration lines

85
Q

What % TSC patients show infantile spasms

A

70%
-start at 3 mo of age

86
Q

What is the natural history of cardiac rhadomyomas in TSC

A

Can be detected prenatally, in over 80% TSC, but often involute in first 3 yrs

May predispose to WPW

87
Q

What should you think of when TSC patient has multiple renal cysts?

A

May have contiguous gene syndsrome with both TSC2 and PKD (polycystic kidney disease) gene are lost

88
Q

What is lymphangioleiomyomatosis

A

Asymptomatic and occurs in 30-40% of women, appears as cysts on CT

Rare in men,

89
Q

Approach to child with 3+hypomelanotic macules

A
  1. Woods lamp
    -If lesions localized in block pattern or lines of blaschko—> “Segmental nevus depigmentosus” or pigmentary mosaicism
  2. ?preceding inflamatory —>. Post inflammatory hypopigmentation
  3. Depigmentes lesions—> acquired=vitiligo, congenital or mid extremities and abdomen with normal/darker island= Piebaldism
  4. ECHO (1st test to do if no hx seizures)/CRANIAL MRI/OPTHO EXAM
    -CARDIAC rhabdomyomas or supepy nodules or tumors or retinal hamartomas or acromic patches—> TS
  5. Normal workup—> Consider genetic testing esp if affected fam member
  6. Annual physical, renal ultrasound and repeat cranial MRI with repeat assessment for cutaneous findings or renal lesions

IF NOTHING just call multiple nevus depigemntosus

90
Q

Approach to multiple hypomelanotic macules?

A

https://d1niluoi1dd30v.cloudfront.net/C20131144449/B9780702062759000611/f061-020-9780702062759.jpg?Signature=T1HiatODqwOi7LwdQOQhQqYgpZ%7EvuEoE3al%7ErQVnywvfEPYj3t9bct%7E1QX8yQe4-WvnATnZM7yvqvtfDcwJUXnqJ7gy%7Eg1jArs9IAh4nDq%7E-A9qjJ-eGmK8fTuvZIUntkksasxqAlNBt1Vc0dcwErG2jQ7KhZfPgIqeHKikNTX0_&Expires=1659803317&Key-Pair-Id=APKAICLNFGBCWWYGVIZQ

91
Q

First line test suspected TSC no hx seizures

A

Echo

92
Q

What is ddx for multiple facial angiofibromas

A

MEN type 1–> facial angiofibromas, gingival papules, collagenomas, hypomelanotic macules

Birt Hogg Dube

93
Q

What are 2 therapies shown to lead to regression of SEGAs, control of seizures and reduction in size of angiomyolipomas and helpful in lung function with lymphangioleiomyomatosis>

A

MTOR inhibitors—> sirolimus (rapamycin), everlimus

94
Q

Treatment for angiofibromas?

A

Topical rapamycin

95
Q

Name 12 tests/assessments needed in newly diagnosed TSC

A

Heart:
Echo
EKG

Brain:
Brain MRI
EEG-if TAND or abnormal sx
Neurodevelopmental assessment -if features TAND

Detailed Derm

Dental

Optho assx

Renal:
Abdo MRI (> U/S or CT)
BP measurement

Lung: High res CT + PFT (women 18+, men if symptoms)

Genetics

MyDermatology-Bolognia (31 decks)

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