Genetic Disorders affecting skin, brain, and muslce Flashcards
what are the phakmatoses? other syndromes that affect the skin and nervous system?
syndromes affecting the skin and nervous systems
embryonal in origin and usually arise from the neural crest
other: incontentienta pigmenti and Sturge-Weber
how would you describe the neurofibromatoses? how many types?
group of conditions characterized by cafe-au-lait macules w/ benign tumors arising from peripheral nerve sheaths
generally 2 types - up to 11 described
what is the most common neurocutaneous disorder?
NF1 (1:3,000 worldwide)
generally, what do we know about NF1? de novo rate?
AD
complete penetrance in adults (highly variable expression)
95% of those affected can be dx by 11y
pleiotropic effects (skin, eye, CNS)
50% of cases show spontaneous gene mutations -> advanced paternal age effect observed
what are the major dx criteria for NF1?
2 or more of:
- at least 6 CALMs at least 0.5 (prepuberty)/1,5(post puberty)
- skinfold freckling
at least 2 neurofibromas or 1 plexiform neurofibroma
- at least 2 lisch nodules or at least 2 choroidal anomalies
- optic pathway glioma
- sphenoid dysplasia, anterolateral bowing of the tibia, or pseudoarthritis of a long bone
- heterozygous PV in 100% of cells from unaffected tissue
- parent with NF1 by above criteria
what do we know about CALMs in NF1? typically coast of California or Maine?
tend to arise in 1st YOL and are usually 1st sign of NF1
80% of those with NF1 will have at least 5 CALMs by 1y
California (Maine is McCune-Albright)
what do we know about skinfold freckling in NF1?
second dx sign to appear (typically 3-5y)
present in 75% of those with NF1
most commonly exillary and inguinal areas but can be elsewhere
what do we know about dermal neurofibromas in NF1?
often appear around puberty, may increase in size and number during pregnancy, are always benign
seen on skin’s surface and can be palpated if beneath surface
extremely sensitive to changes in hormones
what do we know about plexiform neurofibromas in NF1?
found in 25% of the in NF1 w/ physical exam, up to 50% w/ MRI
usually congenital (esp. H&N)
can compress normal structures
can undergo malignant transformation and become malignant peripheral nerve sheath tumors
no surveillance
what do we know about malignant peripheral nerve sheath tumors in NF1?
most frequent malignant neoplasm in NF1
younger age of onset for NF1 people than gen pop
usually occur in adulthood
when do lisch nodules develop in people with NF1?
usually in early adolescence
present in 95% of people with NF1 by 20y
what impact can optic gliomas have on people with NF1?
5% -> vision loss, severe eye bulging, can also cause hydrocephalus
can result in precocious puberty if involving optic chasm
what is Leigus syndrome?
a condition that resembles NF1
how is one dx with Leigus syndrome?
at least 5 CALMs bilaterally and one other NF1-related dx criteria EXCEPT axillary inguinal freckling
pathogenic variant in SPRED1
parent with leigus syndrome by above criteria
what is the most common MSK finding in NF1? others?
scoliosis
sphenoid wing dysplasia, pseudoarthritis of a long bone
what other features can be associated with NF1?
short stature, relative-to-absolute macrocephaly, hypertension, educational difficulty, increased cancer risks, ADHD, speech problems
what cancers is someone with NF1 at increased risk for?
gliomas, malignant peripheral nerve sheath tumors, rhabdomyosarcoma, myeloproliferative and myelodysplasitc leukemias, pheochromocytoma, brca (XX)
what do we know about the NF1 gene?
chr 17
tumor suppressor
ubiquitously expressed, highest levels in CNS
highly mutable with high germline mutation rate and presumed high somatic mutations rate
what presentation would you expect in a pt with NF1 that has a deletion of the whole gene? 3bp in-frame deletion of exon 17? pAr1809 missense? codons 844-848 missense in CSRD? mutations near the 5’ end of the gene and mutation in the CSRD region?
gene deletion: large # of neurofibromas and early appearance of cutaneous neurofibromas; more frequent and severe cognitive abn; somatic overgrowth, large hands/feet and dysmorphic facies
3bp: typical pigmentation of NF1 w/o plexiform neurofibromas
pAr1809: Noonan-like features, pulmonic stenosis, short statue
codons 844-848: plexiforms, optic gliomas, spinal neurofibromas, malignancy
5’ and CSRD: increased risk of autism and gliomas
why is it difficult to determine a prognosis for a child with NF1?
50% of affected are mildly affected
1/3 develop serious complications
what is unique about segmental NF1?
occurs in ppl with somatic mosaicism for NF1 mutation
CALMs and freckles either follow dermatomal distribution of lines of Blaschko
rarely associated with plexiform or tumor formation
NF2 is also known as: _______. SPS means:
MERLIN-SPS
schwannoma predisposition syndromes
what types of SPS exist?
NF2/MERLIN-SPS SMARCB1-SPS LTZR1-SPS 22q-SPS SPS-NOS (not otherwise specified)
what is the avg age of onset and death in NF2?
onset: 18-24
death: 26
the majority of ppl with MERLIN-SPS have ______ by 30y. any other possibilities?
bilateral vestibular schwannomas
other: meningiomas, neurofibromas, ependymomas, astrocytomas
what do we know about genetic testing for NF2?
detects 66-90% of variants
not required for dx, not sufficient by itself
what do we know about TSC (tuberous sclerosis complex)?
two genes associated?
AD
80% of cases represent de novo mutaions
pleiotropic (eyes, brain, skin, heart, kidneys, lungs)
broad variability of expression and can have reduced penetrance
TSC1 AND TSC2
what features lead to a clinical dx of TS?
facial angiofibromas or forehead plaques
nontraumatic ungual or periungual fibromas
at least 2 hypomelanotic macules
shagreen patches
multiple retinal nodular hamartomas
cortical tuber
subependymal nodule
if you see a cardiac tumor on ultrasound, there is a 75% the fetus has:
TS
what are the clinical criteria for a person with TSC?
definite: 2 major or 1 major + 2 minor
probable: 1 major + 1 minor
possible: either 1 major or at least 2 minor features
the proteins associated with TSC1/2 work together to ______.
what pathway?
regulate cell proliferation and have a tumor suppressor function
mTOR
how many individuals with pathogenic mutations for TS will not be detected by testing?
10%
what syndrome is characterized by port-wine stains? where are they typically located?
Sturge-Weber syndrome
superior palpebral fissures or above (trigeminal nerve)
what things, other than port-wine stains can be seen in SWS?
asymmetry of the face, glaucoma, enlarged lobe of the eye, retinal detachment angiomatous malformation, seizures
what XL condition is associated with IKBKG (75% of mutations are detected in carrier females)?
Incontinentia pigmenti
how many stages as seen in IP? how are its manifestations expressed?
4
along the lines of Blaschko
what are the stages of IP?
vesicular
verrucous
hyperpigmented
atrophic
what can be seen in invividuals with IP other than skin findings?
seizures
dental anomalies (missing or malformed teeth in 80%)
Ophthalmological abn
what finding is indicative of McCune-Albright syndrome?
coast of Maine CALMs
can develop puberty by 3-4y, and premature ovarian failure in females
what conditions are a group of myogenic disorders characterized by progressive muscle weakness and wasting? most common ones?
muscular dystrophies
myotonic (MD1/2)
dystrophinopathies (DMD, Becker, etc.)
emery-driefuss
facioscapulohumeral
Limb-Girdle
what complex are MD genes related to?
dystrophin-glycoprotein complex (DGC)
describe the classic presentation of DMD?
progressive proximal symmetrical muscle weakness with onset <5y, calf enlargement, wheelchair dependency < 13y
Gower’s sign when standing
sway-back posture and winging of scapula
head falls back when being lifted in supine
pull through (when being lifted)
describe the classic presentation of Becker?
progressive, symmetrical muscle weakness/wasting often with calf enlargement
cramping with activity, flexion contractures of elbows, wheelchair dependency >16y, preservation of neck flexor integrity
describe DMD-related cardiomyopathy:
20-40y in males, later in females
typically no sign of muscle disease
progression to death is 3-5y in males and >10y in females
what types of testing can we do for DMD? how effective is it?
CK (elevated)
nondetecable dystrophin on skeletal muscle biopsy
mutation analysis
80% of DMD and 95% of BMD with del/dup
seq alonge: 35% DMD and 25% BMD
what should be on our DDx list for muscle disorder?
MD, myopathies, IEMs, GSD, Mito, malignant hyperthermia syndromes
what neurological diseases are most commonly seen?
neuronal migration, structure, metabolism, other (Rett, PMD, etc.)
what populations are at increased risk to be a carrier for Tay-Sachs? this is an infantile form of what deficiency?
AJ, French canadian, Cajun
hexosaminidase A
when does death typically occur in an infant with tay sachs?
by age 4y
what are the first signs of tay-sachs? when?
mild motor weakness, myoclonic jerks may develop, exaggerated startle to loud noises
3-6mo (typical at birth)
what are the features and cause of Miller-Dieker syndrome (MDS)? prognosis?
gene deletion at 17p13.3 (LIS1) -> affect neuronal migration -> smooth brain
glabeller furrowing, arched brows, upturned nose, seizures, feeding problems, severe delays
most die by 2y
decscribe the presentation of Rett syndrome?
typical at birth, by 1y head size is not growing as should (ultimately microcephalic), signs of development regression
what are the stages of Rett syndrome?
1: early onset stagnation (6-180mo) - delayed developmental progress
2: rapid developmental regression (weeks to months, 1-4y) loss of acquired skills,
3: pseudostationary phase -> years to decades, preserved walking ability with prominent hand apraxia/dyspraxia, inapparent slow neuromotor regression
4: late motor deterioration, lasts decades, complete wheelchair dependency, severe disability, sudden explained death at higher rate than controls
what gene is associated with Rett syndrome? role?
GT effiacacy?
MECP2
abn lead to inability to silence certain genes involved in the development of tissues in multiple areas (brain may be most vulnerable)
seq -> 80% of variants
del/dup -> another 8%
when should you consider testing apparent XY individuals for Rett gene mutations?
classical features as seen in XX (XXY? mosaic?)
moderate to severe MR, impaired language development and movement disorders
severe neonatal encephalopathy with seizures (relentless downhill course)
