Week 8: RASopathies & skin/vascular disorders Flashcards
Tell me about tuberous sclerosis complex (TSC)
-TSC1/2, AD, 2/3 de novo
-~15% cases no variant identified, mosaicism
-100% penetrant
-Skin: hypopigmented macules, confetti skin lesions, shagreen patches, cephalic plaques, ungual fibromas, facial angiofibromas
-Eye: retinal hamartomas (benign), achromatic patches (colored spot on retina)
-Brain/CNS: CNS tumors leading cause of morbidity and mortality, cortical tubers, subependymal nodules, SEGAs, seizures, infantile spasms, DD, ID
-Heart: cardiac rhabdomyomas
-Kidneys: benign angiomyolipoma, epithelial cysts, RCC, malignant angiomyolipoma, oncocytoma
-Lung: LAM, multifocal micronodular pneumonocyte hyperplasia
-Other: neuroendocrine tumors
Tell me about NF1
-NF1, AD
-Big features part of diagnostic criteria: CALMs, axillary or inguinal freckling, neurofibromas, OPGs, Lisch nodules, osseous lesions
-Other features: learning disability, ADD/ADHD, ASD, short stature, macrocephaly, dysmorphisms, scoliosis, pulmonary valve stenosis, malignancies, HTN, osteoporosis
-Can also be mosaic/segmental–both super variable!
Tell me about NF2-related Schwannomatosis
-NF2 gene, AD
-Deletions associated with milder features
-Nonsense and frameshift variant=severe disease
-Features part of diagnostic criteria: bilateral vestibular schwannomas, an identical NF2 path variant in at least 2 anatomically distinct NF2-related tumors (Schwannoma, meningioma, ependymoma)
-Other findings: skin plaques, cortical wedge cataract, retinal hamartoma, mononeuropathy
Give some example of how NF2-related Schwannomatosis is different than NF1
-NF2 may have CALMs but they are not significant like in NF1 and part of the criteria
-Tumors in NF2 are not malignant but can still cause morbidity and mortality
-NF2 thought of more as adult-onset condition with diagnosis usually between 18-24yo
-Deletions in NF1 associated with more severe phenotype whereas deletions in NF2 associated with milder disease
Tell me about Noonan syndrome
-Several genes, most common PTPN11
-Prenatal features: polyhydramnios, lymphatic dysplasia, relative macrocephaly, cardiac and renal anomalies
-Feeding: Normal size at birth, feeding and weight gain issues, postnatal growth failure
-Growth: Bone maturity often delayed, short stature as adults, growth hormone can be effective
-Cardio: pulmonary valve stenosis, others too (ASD, VSD, AV canal defects, mitral valve anomalies, aortic coarctation, PDA, ToF), HCM, ECG abnormalities
-Dev/cognition: delayed early milestones, learning disability, impaired executive function and attention
-GU: generally mild renal anomalies, cryptorchidism in males, male puberty and fertility can be normal/delayed/inadequate, female puberty may be delayed but fertility usually normal
-Facial features: tall forehead, wide spaced eyes, downslanting palpebral fissures, low set/posteriorly rotated ears, facial features can dilute as age
-Musculoskeletal: thoracic scoliosis, pectus excavatum or carinatum, vertebral defects and upper limb anomalies, micrognathia, high arched palate
-Bleeding/lymphatic: abnormal bleeding or bruising, coagulation defects, lymphedema
-Ocular, audiologic, dermatologic: ptosis, strabismus, refractive errors, HL, follicular keratosis, CALMs and lentigines
-Malignancy: overall malignancy risk is 8x greater
Tell me about Costello syndrome
-AD, typically de novo, variants in HRAS
-Prenatal features: increased NT, polyhydramnios, short humeri and femurs, characteristic ulnar deviation of wrists, fetal tachycardia, preterm delivery
-Growth and feeding: birth weight and head circumference often increased, later becomes short stature, delayed bone age, partial/complete growth hormone deficiency, severe feeding difficulties
-Cardio: pulmonary stenosis, HCM, ECG abnormalities, mild aortic dilation, HTN
-Dev/cognition: DD, ID, social and outgoing personality, Chiari I malformation, hydrocephalus, syringomelia, seizures, tethered cord
-Facial features: coarse features, curly or sparse hair, low set ears with thick lobes, depressed nasal bride and wide nostrils, hypertelorism, epicanthal folds, downslanting palpebral fissures, ptosis
-Musculoskeletal: hypotonia, joint laxity, ulnar deviation, positional foot deformity, kyphosis, pectus abnormalities, dev hip dysplasia, osteoporosis in young adults
-Dermatologic: loose and soft skin, increased pigmentation, deep palmar and plantar creases, papillomas of face, prematurely aged skin, hair loss, thick toenails
-Malignancy: ~15% lifetime risk for malignant solid tumors
Tell me about cardiofaciocutanous syndrome (CFC)
-Most de novo, most common gene BRAF
-Prenatal features: polyhydraminos, prematurity, subjective decrease in fetal movement, maternal hyperemesis gravidarum
-Growth/feeding: severe feeding difficulties, reflux, constipation, growth normal at birth then weight and length drop and head size preserved, growth hormone def in some
-Cardio: structural abnormalities (pulmonary stenosis, ASD, VSD, valve abnormalities), HCM, less commonly ECG abnormailites
-Dev/cognition: learning difficulties, speech delays, motor delays, seizures, abnormal EEG, hydrocephalus
-GU: cryptorchidism, renal cysts and stones, hydronephrosis, hydroureter, some with precocious puberty
-Facial features: high forehead, relative macrocephaly, hypertelorism, downslanting palpebral fissures, short nose with anteverted nares, so much more I’m not typing (see lecture slide 35)
-Musculoskeletal: hypotonia, lax joints, pectus excavatum, scoliosis, kyphosis, gait disturbance, short neck, flat feet
-Ocular and audiologic: strabismus, nystagmus, astigmatism, myopia and more, optic nerve hypoplasia, cortical blindness, cataracts, recurrent ear infections, narrow ear canals
-Ectodermal defects: hyperkeratosis, CALMs, skin infections, palmoplantar hyperkeratosis, range of hair textures and amount, sparse to absent eyelashes and brows, fast growing nails
For the following categories, differentiate between Noonan, Costello, and CFC:
-Birth parameters
-GI
-Development/cognition
-Facial features
-Musculoskeletal
-Bleeding/bruising
-Dermatologic/ectodermal
-Malignancy risk
Birth parameters:
-N: avg at birth
-C: birth weight and length usually high for gestational age
-CFC: avg at birth
GI
-N: Gi issues milder and resolve earlier
-C: GI issues severe and long lasting
-CFC: GI issues severe and long lasting
Development/cognition
-N: DD/ID mild
-C: more severe ID
-CFC: more severe ID
Facial features
-N: broad, webbed neck common
-C: face more coarse than Noonan
-CFC: face broader, longer, more coarse than Noonan but not as coarse as Costello
Musculoskeletal
-N: NA
-C: ulnar deviation of wrists
-CFC: NA
Bleeding/bruising
-N: bleeding/bruising problems common
-C: bleeding problems rare
-CFC: bleeding problems rare
Dermatologic/ectodermal
-N: lentingines common in subtype
-C: papillomata in perianal/periasal region more common, loose skin
-CFC: progressive formation of nevi, sparse hair and eyebrows common
Malignancy risk
-N: predisposition not as high as Costello
-C: predisposition to ca
-CFC: ca risk unclear
Tell me about incontinentia pigmenti (IP)
-IKBKG gene, X-linked dominant
-Usually noted at birth or within few weeks
-Progresses through 4 stages: vesicular, verrucous, hyperpigmented, hypopigmented
-Areas affected: skin, hair, nails, teeth, eyes, CNS
Tell me about epidermolysis bullosa
-Group of disorders: EB simplex, junctional EB, dystrophic EB, Kindler syndrome
-Missing or dysfunctional skin protein that results in skin fragility and blistering
-Other features are variable
-EBS and DDEB: AD (mostly)
-JEB, RDEB, KS: AR
Tell me about Sturge Weber syndrome
-A rare vascular disorder characterized by the association of a facial birthmark called a port-wine birthmark (capillary malformations), abnormal blood vessels in the brain, and eye abnormalities such as glaucoma
-Mutations in GNAQ
-Facial CM in high risk zones
-Glaucoma
-Leptomeningeal enhancement, seizures, stroke, DD
Define capillary malformation (CM)
-Dilated capillaries that enlarge and darken over time
-Usually appear as flat pink or red spots on skin
Define arteriovenous malformations (AVMs)
Abnormal tangle of blood vessels that forms when arteries and veins are irregularly connected and don’t have capillaries between the two to diffuse pressure
Tell me about HHT
-Disorder of vascular dysplasia
-Nose bleeds, telangiectasias, large AVMs in lung/liver/brain, complications from bleeding or shunting, GI bleeding, anemia, pulmonary hypertension
-If clinical dx inconclusive (need 3 +: nose bleeds, mucocutaneous telangiectasia, visceral AVMs, family hx), can use genetic testing to assist with hx
-Genes: ACVRL1, ENG, GDF2, SMAD4
-AD
-Age related and variable penetrance
-Management includes screening for AVMs not visible from physical exam that have potential for catastrophic events
-Will test unaffected minors
Tell me about CM-AVM
-Condition affecting blood vessels
-Capillary malformations, cranial and extracranial AVMs (skin, muscle, spine)
-Also reported: telangiectasias, nosebleeds, cardiac overload, lymphatic malformations
-AD, reduced penetrance, 20-30% de novo
-Genes: RASA1, EPHB4, unknown (40%)
