Ch. 61-Neurofibromatosis + Tuberous Sclerosis Flashcards
What is the inheritance pattern of most cancer syndromes?
AD
Inheritance pattern of NF? TS?
AD for both
What is the penetrance of NF-1? TS?
100% penetrant for both
What % NF-1 is de novo?
50%
Describe NF varaints 1-7
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
Incidence NF-1
1 in 3000
What gene is mutated in NF-1? What does it code for?
NF1 gene—> Neurofibromin
What is the most common mutation in NF-1?
Mutation that results in truncated neurofibromin protein
Sometimes get a large microdeletion with more severe phenotype
Chromsomome of NF-1?
17q11.2
What is role of neurofibromin (1-what pathway 2-general role)
RAS-MAPK pathway that promotes cell survival and proliferation
Role played as tumor supressor (down regulates this pathway)
What drug can be used to block neurofibroma formaiton?
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
Name 6 cutaneous findings in NF-1
CALMs (Need 6 or more, >5 or 15 mm)
Axillary./inguinal freckling
Neurofibromas (regular or plexiform)
Nevus anemicus
JXG
Name 3 ocular findings in NF-1
Lisch nodules (90%)
Choroidal nodules
Optic glioma (also under tumor section)
Neovascular glaucoma
Name 6 skeletal/MSK related findings in NF-1
Scoliosis
Spina bifida
Long bone cortex dysplasia (tibia)
Psuedoarthrosis
Osteopenia and osteoporosis
Short stature
Pectus deformity
Name 4 tumors in NF-1? (There are more)
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
Name 3 cranial findings in NF-1
Sphenoid wing dysplasia
Macrocephaly
Hypertelorism
What are some neurologic related findings in NF-1
Learning difficulties
Unidentified bright objects on MRI
Seizures
Intellecutal disability
What is the main CV findings in NF-1? Name 3 others
Essential hypertension
Pulmonic stenosis, RAS, cerebrovascular anomalies
What is the diagnostic criteria for NF-1?
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
What is the ddx for multiple CALMS? Name 10
- NF-2
- Mosaic NF (NF-5)
- Multiple familial cafe au lait (NF-6)
- Legius (NF-1 like)
- McCune Albright Syndrome
- Constitutional Mismatch Repair Deficiency (CMMRD)
- Noonan/LEOPARD (Noonan syndrome with multiple lentigines)
- Ring Chromosome Syndrome
- Cowdens
- Banayan-Riley-Ruvalcaba syndrome
Others with weaker association
- NAME syndrome (Carney complex, also LAMB)
- Ataxia Telengiectasia
- Epidermal nevus syndrome (extensive epidermal and sebaceous nevi)
- Turner
- Russel Silver
- Fanconis anemia
- MEN1/2B
- BLoom
- Watson syndrome
- Westerhof syndrome
- 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
What are the features of Legius?
Multiple CALMs, axillary freckling
No other NF-1 stigmata (No lisch, no optic gliomas, no NFs)
Macrocephaly, lipoma, learning disability, hypopigmented macules
What are the features of McCune Albright? What gene?
GNAS1
CALMs-but segmental, larger, less uniform
Precocious puberty
Other endocrinopathies
Polyostotic fibrous dysplasia
What are the features of CMMR deficiency? What genes?
MSH2, MSH6, PMS2, MLH1
Multiple CALMs
Cancers: Medulloblastoma, lymphoma, glioblastoma, colonic polyps
What are the features of segmental NF (NF-5 formerly)
Neurofibromas alone or CALMS +- axillary freckling in block like pattern
Post zygotic NF-1 mutation in some which may involve the gonads
What are the features of Noonan with multiple lengitines? Gene?
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
What are the cutaneous findings of Cowdens? Gene?
PTEN
CALMS
Trichelommas
Lipomas
Neuromas
Cobblestoning oral mucosa
Name 4 cutaneous findings of Cowdens. What is the gene mutated?
PTEN
Trichelommomas
CALMs
Lipomas
Neuromas
Cobblestoning oral mucosa
Name 3 cancers associated with Cowdens
Gi polyps
Breast carcinoma
Thyroid
Name 3 additional features Ring chromsome syndrome
CALMS
Microcephaly
Mental retardation
Short stature
What gene mutated in Watson Syndrome? Name 5 feeatures
NF-1
Axillary and inguinal freckling
Mental retardation
Short stature
Pulm valve stenosis
Lisch nodules
What are the features of Jaffe Campanacci syndrome?
-Disseminated non ossifying FIBROMAS of long and jaw bones
-Hypogonadism or cryptothcidism
-Giant cell granulomas
NF-1 mutation
*Can get CALMS, neurofibromas
What age do cutaneous neurofibromas tend to occur?
Ages 4-5 at earliest, but typically more around puberty and pregnancy
What are the types of neurofibromas and their clinical findings?
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
What % of NF-1 patients have plexiform NFs
25%
What are 3 complications of plexiform NFs
Soft tissue and bony hypertrophy
Distortion of head and neck or extremtiies
NErve impingement nest
What is the clinical presentation to PNFs
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
Name 4 clinical findgins that may indicate malignant degeneration of PNF into neurofibromasarcomas
-rapid growth
-increased firmness
-persistent pain
-new neuro deficit
What investigations/referrals are needed at NF-1 diagnosis?
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
What are 4 annual evalutions needed in NF-1
Derm exam (if PNF present)
-PET CT if suspected
Neuro exam
+- MRI
BP measurement
Breast cancer screening at age 40
What is Crowe’s sign
Numerous 1-3 mm brown macules (more akin to lentigines >ephelids) in intertrigiinous regions, neck, and sometimes entire skin surface
Axilla most common
When does axillay freckling start?
Ages 4-6 after CALMS, before neurofibromas
What % NF-1 get JXGs? When do they occur?
15-35% get 1 or more in first 2-3 years of life, can be early sign if co-existing with CALM
What % NF-1 get nevus anemicus? How old?
30-50%, favor mid trunk and chest, more evident after rubbing the skin
How can sphenoid wing dysplasia present?
Pulsating exopahtlmos
What is psuedoarthrosis
False joint formation
At what age do the majority of people meet criteria for NF-1
Age 8-97% have met it
What order do these findings come in:
-CALMs
-freckling
-lisch
-neurofibromas
-sphenoid wing or psuedoarthrosis
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
Pathology of NF
Un-encapsulated dermal spindle cell tumor (fibroblasts, schwaan, perineural cells) with wavy elongated nuclei
Mast cells
Pathology of plexiform NF
Large hypertrophied nerves surrounded by spindle shaped fibroblasts and schwaan cells in myxcoid matrix
Approach to child with 6+ CALMS > 5mm
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
What are 2 considerations in a kid with NF-1 + HTN?
Pheo—>urine tests
RAS—> doppler u/s
DDx for unilateral lentigines in axila or groin?
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
What is prevalence NF-2?
1 in 40 000
What is hallmark tumor NF-2?
Vestibular schwannoma
Name 6 key features of NF-2 (tumors, skin, transmission, gene)
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
Name 5 features of the CALMS in McCune Albright
-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
What is the best test for detecting malignant change in PNFs
PET CT
Name 2 therapies under investigtion for NF-1
Imatinib (inhibitor of C-kit on mast cells_
Rapamycin (sirolimus) = Mtor inhibitor
Semultenib and other MAPK pathway inpiters
Prevalence of TS
1 in 10 000-30 000
What % TS are de novo
50%
What genes are mutated in TS and what proteins do they make
TSC1- hamartin
TSC2- Tuberin
What is the function of tuberin and hamartin
Interact with each other to downregulate MTOR signallying and thus cell growth and differentiation
Name 6 cutaneous features of TS
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
Name 2 characteristic oral findings in TS
Gingival fibromas
Dental enamel pits -90%
Name 2 ocular findings in TS
Retinal hamartomas
Acrhomatic retinal patches
Retinal astrocytoma
What is a pulmonary feature of TS
Lymphangioleiomyomatosis
What are 3 renal features of TS
Multiple bilateral angiomyolipomas
Cysts
RCC
What are 2 endocrine features of TS
HypoTSH
Precocious puberty
Name 5 neurologic features of TS
Cortical tubers (>90%)
Supendymal nodules (80%)
Supenedemylu giant cell astrocytoma
Seizues including infantile spasms
Intellectual impairment
Name 2 CV findings in TS
WPW
Myocardial rhabdomyoma
What are the major features of TS?
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)
What are the minor features of TS
Confetti skin lesions
3+ dental enamel pits
Intra-oral fibromas
Retinal achromic patch
Mutliple renal cysts
Non renal hamartomas
How to make diagnosis TSC
2 major
1 major + 2 minor
What is first cutaneous sign in TSC? When do the other signs appear?
Hypomelanotic macules first, often birth or first few months
—> Angiofibromas (4-6)
—> Shagreen (8-10)
—> periungual fibromas
What is the msot specific cutaneous lesion of TSC
Gutatte leukoderma or confetti macules
What % healthy kids have nevus depigmentosus?
1-4%
What% TSC have CALMS?
30%
Usually less than 6
What is a shagreen patch histopathologically speaking? What is its appearance clinically?
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
What are the 2 types of koenen tumors
1-peringual fibromas-prox or lateral nailfold often on toenails
2-subungual fibromas-longitudinal red streaks with proximal narrowing, can lead to longitudinal groove
Molluscum pendulum-what is it
Soft pedunculated skin colored papules and nodules, look like acrochordongs, favor flexures
What is the most common type of retinal hamartoma
Flat translucent lesion> mulberry lesion>tranaistional type
Most ocular lesions in TSC do not lead to vision loss
What is included in TSC-asscoaited neuropsuchiatric disorders
ADHD
Autism
Psyh condditions
Aggressivebehaivor
Difference between subependymal nodules vs. Supependymla giant cell asterocytoma
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
What are 2 types of cortical dysplasia in TSC
Tubers-glioneural hamartoma
Cerebral white matter radial migration lines
What % TSC patients show infantile spasms
70%
-start at 3 mo of age
What is the natural history of cardiac rhadomyomas in TSC
Can be detected prenatally, in over 80% TSC, but often involute in first 3 yrs
May predispose to WPW
What should you think of when TSC patient has multiple renal cysts?
May have contiguous gene syndsrome with both TSC2 and PKD (polycystic kidney disease) gene are lost
What is lymphangioleiomyomatosis
Asymptomatic and occurs in 30-40% of women, appears as cysts on CT
Rare in men,
Approach to child with 3+hypomelanotic macules
- Woods lamp
-If lesions localized in block pattern or lines of blaschko—> “Segmental nevus depigmentosus” or pigmentary mosaicism - ?preceding inflamatory —>. Post inflammatory hypopigmentation
- Depigmentes lesions—> acquired=vitiligo, congenital or mid extremities and abdomen with normal/darker island= Piebaldism
- 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 - Normal workup—> Consider genetic testing esp if affected fam member
- Annual physical, renal ultrasound and repeat cranial MRI with repeat assessment for cutaneous findings or renal lesions
IF NOTHING just call multiple nevus depigemntosus
Approach to multiple hypomelanotic macules?
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First line test suspected TSC no hx seizures
Echo
What is ddx for multiple facial angiofibromas
MEN type 1–> facial angiofibromas, gingival papules, collagenomas, hypomelanotic macules
Birt Hogg Dube
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>
MTOR inhibitors—> sirolimus (rapamycin), everlimus
Treatment for angiofibromas?
Topical rapamycin
Name 12 tests/assessments needed in newly diagnosed TSC
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
