Neurocutaneous Syndromes Flashcards
What are the 3 subtypes of neurofibromatosis?
NF1, NF2, and schwannomatosis
What is the most common type of neurofibromatosis?
NF1 (90%)
What is the gene involved and mode of inheritance for NF1?
NF1 gene (neurofibromas), AD –> negatively regulates Ras activations
-50% are sporadic mutations and mosaic/segmental dz can occur
Diagnostic criteria for NF1?
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
What NF1 findings occur in infancy?
Café-au-lait macules, plexiform neurofibromas, neurologic findings, macrocephaly, tibial dysplasia, sphenoid wing dysplasia
What findings of NF1 occur in the prepubertal stage?
Intertriginious freckling, optic gliomas, brainstem gliomas meningiomas, scoliosis
What are the cutaneous findings in NF1?
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)
Skeletal manifestations of NF1?
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
Neurologic manifestations of NF1?
Learning disabilities, autism, ADHD
- seizures
- hydrocephalus
- Optic glioma which can lead to blindness; seen w/ precocious puberty, astrocytomas, meningiomas, vestibular/acoustic schwannoma/neuroma, ependymoma
What other neoplasms can be seen in NF1?
Neurofibrosarcoma, rhabdomyosarcoma, pheochromocytoma, Wilms’ tumor and CML
- Nevus anemicus found in up to 50% of patients
- TRIPLE ASSOCIATION W/ NF1, JUVENILE XANTHOGRANULOMAS, AND JMML
What is the most common second mutation seen in neurofibroma to cause malignant transformation?
p53
What is the inheritance pattern and gene involved in NF2?
AD, mutations in SCH (schwannomin/merlin) which is a tumor supressor gene
What are the cutaneous findings in NF2
neurofibromas (lower #’s than NF1), more commonly subcutaneous type w/ overlying pigment/hair rather than intradermal. can have CALMS too
Neurologic findings in NF2?
Bilateral vestibular schwannomas (acoustic neuromas) is diagnostic –> deafness, tinnitus, unsteadiness, headache, meningiomas, astrocytomas and ependymas
Most common cause of death in NF2?
CNS tumors
Ocular findings in NF2?
Juvenile posterior sub capsular lenticular opacity/cataract
What are the genetics and genes associated with tuberous sclerosis complex?
AD, mutations in hamartin (TSC1) or tubers (TSC2) [tumor supressors]
What is the pathophysiology of tuberous sclerosis?
Tuberin and hamartin form complex that inhibit signal transduction of downstream efforts of mTOR –> results in abnormal cellular differentiation, proliferation and migration –> hamartomas
What are the main cutaneous findings of tuberous sclerosis?
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
What is the histology of the angiofibromas?
Dermal fibrosis w/ stellate fibroblasts, atrophic sebaceous glands, dilated capillaries, and loss of elastin
What is the histology of the shagreen patch?
Connective tissue nevus –> broad sclerotic collagen bundles and reduced elastin
Histology of the hypopigmented patches (ash-leaf spots)?
Normal number of melanocytes but there is decreased pigmentation
What are some treatments for facial angiofibromas in tuberous sclerosis?
Pulsed dye laser, ablative laser, excision, and topical rapamycin
What are the neurologic findings in tuberous sclerosis?
- cortical tubers
- subependymal nodules (can lead to hydrocephalus)
- subependymal giant cell astrocytomas
- seizures/infantile spasms
- hypsarrhythmia
- intellectual impairment
- paraventricular calcification
What neurologic features are associated with worse prognosis in tuberous sclerosis?
Infantile spasms, large number of cortical tubers, and early age of onset of seizures or intractable seizures
What is the number one cause of mortality in tuberous sclerosis?
Complications related to seizures
What are the renal findings in tuberous sclerosis?
Renal cysts, angiomyolipomas, and renal cell carcinoma
What is the treatment of the renal or hepatic angiomyolipomas and subependymal giant cell astrocytoma?
Systemic mTOR inhibitors (sirolimus and everolimus)
What are the complications of the renal portion of the disease in tuberous sclerosis?
Renal failure, catastrophic hemorrhage within renal angiomyolipoma, and renal hypertension (importantly this is the #2 cause of death in TSC)
What are the ocular findings in tuberous sclerosis?
Retinal phakomas (hamartomas)
What are the cardiac findings in tuberous sclerosis?
Cardiac rhabdomyomas which can lead to Wolf-Parkinson-White arrhythmias
What are the GI findings in tuberous sclerosis?
Hepatic cysts, hepatic angiomyolipomas (usually asymptomatic), and GI polyps/hamartomas
Dental findings in tuberous sclerosis?
Pits in the enamel and gingival fibromas
What are the lung findings in tuberous sclerosis?
Pulmonary lymphangioleiomyomatosis and pulmonary cysts
- Pneumothorax, chylothorax, hemoptysis, and pulmonary insufficiency
What is required for dx of tuberous sclerosis?
Presence of pathogenic mutation in TSC1/TSC2 or presence of two major criteria or one major and two minor criteria
What are the major and minor criteria for tuberous sclerosis?
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
What lesions in tuberous sclerosis are present in infancy to early childhood?
Hypomelanotic macules, confetti-like skin lesions, cardiac rhabomyomas, subependymal nodules, seizures
What findings in tuberous sclerosis occur in prepubertal children?
Angiofibromas, Shagreen patch, fibrous cephalic plaque, and dental pits. Also can see renal hamartomas
What findings in tuberous sclerosis occur in adolescence?
Ungual fibromas
What findings in tuberous sclerosis occur in adulthood?
Intraoral fibromas, pulmonary lymphangioleiomyomatosis (more in women), renal cysts
What is the inheritance pattern and gene involved in incontinentia pigmenti?
XLD loss of function mutation in nuclear factor-kappa B essential modulator (NEMO; IKBKG)
What is the pathophysiology of incontinentia pigmenti?
Mutation in NEMO prevents activation of NF-kappaB, a regulator of cell proliferation, inflammation and TNF-alpha induced apoptosis
What physical findings are seen due to the XLD nature of incontinetia pigmenti?
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
What are the 4 primary cutaneous stages of incontinentia pigmenti and when do they occur?
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
Other skin findings in incontinentia pigmenti besides the 4 major stages?
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
What is the histology of the vesicular stage of incontinentia pigmenti?
Eosinophilic spongiosis; intraepidermal vesicles containing eosinophils, apoptotic keratinocytes in epidermis
What is the histology of the verrucous stage of incontinentia pigmenti?
Papillomatosis, hyperkeratosis, and acanthuses of the epidermis; apoptotic cells in epidermis forming squamous eddies
What is the histopathology of the hyperpigmented stage of incontinentia pigmenti?
Marked pigment incontinence with numerous melanophages in the dermis; apoptotic cells may be seen in the epidermis
What is the histology of the hypopigmented stage of incontinentia pigmenti?
Epidermal atrophy, loss of melanin in basal layer, complete absence of pilosebaceous units and eccrine glands; apoptotic cells may be seen in epidermis
What neurologic abnormalities can be seen in incontinentia pigmenti?
Severely affected patients may develop seizures, developmental delay and intellectual impairment, and decreased visual acuity/blindness (due to retinal vascular changes and optic atrophy)
What disease occurs if a woman w/ a missense mutation in NEMO (mild phenotype of IP) can bear a male child with what condition?
Hypohidrotic ectodermal dysplasia with immunodeficiency
Systemic findings in incontinentia pigmenti?
Seizures, mental retardation, spastic paresis, retinal vascular anomalies, nonretinal anomalies (strabismus, cataracts, and optic atrophy), supernumerary nipples, nipple hypoplasia, breast hypoplasia or aplasia
What is the involved gene and inheritance of Legius syndrome?
AD SPRED1
What is the clinical appearance of Legius syndrome?
Cafe-au-lait macules, intertriginous freckling, and learning disabilities
