Chapter 62 Inherited EB Flashcards
keratin ___ and ___ assembles to form filament network of basal cell cytoskeleton
keratin 5 and 14
____ localizes to region referred to as inner plate on cytoplasmic surface of hemidesmosome and like plectin, functions in connection between hemidesmosomes and intermediate filaments
BP230
if negative –> mechanical fragility
collagen XVII also termed ___
BPAG2 / BP180
specific receptor for laminin 332
a6B4 - central role in organization of hemidesmosome
collagen XVII associates w/ laminin 332 and a6B4 integrin in adhesion structures termed
stable anchoring contacts
autoantigen in linear IgA bullous dermatosis
LAD-1
collagen XVII undergoes processing in keratinocyte cultures and in skin through action of
sheddases - membrane associated proteases that solubilizes cell surface receptors
major constituent of anchoring fibrils
collagen VII
collagen VII binds to the ___ chain on laminin 332
B3 chain
gold standard for diagnostic grouping of EB
electron microscopy
most severe of EBS subtypes, Dowling-Meara EBS - onset, manifestation?
at birth generalized oral mucosa more often involved (differ from Koebner) millium formation grouped or hepetiform blisters without scarring trunk, proximal extremities dystrophy of long nails hyperkeratosis of palms and soles (early childhood) flexural contractures esophageal involvement to pyloric atresia natal teeth
Generalized / Koebner EBS
at birth or early infancy
generalized
hands, feet, extremities - most involvement
post inflammatory hypo or hyperpigmentation
atrophy and milia - less frequent
palmoplantar hyperkeratosis, erosions
thickening of soles - later childhood
oral mucosa - mild erosive, improve with age
mildest, most common form of EBS, Localized EBS ?
infancy and childhood mild enough to escape reporting hyperhidrosis of palms, soles post inflamm pigmentary alteration follows trauma; hands and feet common; scalp least milia scarring absent nail rare
EBS of Ogna ?
infancy summer acral without scarring Norway onychogryphosis of great toenails
EBS with muscular dystrophy
at birth or shortly thereafter generalized progressive muscular dystrophy generalized HD1/plectin mutation
EBS w/ mottled pigmentation
at birth or early infancy
trunk, proximal extremities
reticular, increase w/ age
progressive pigmentation
EBS superficialis
subcorneal erosions, crusts post inflammatory pigmentary changes nail atrophic scarring milia
lethal acantholytic EBS
rare recessive at birth generalized dystrophic to absent nails complete alopecia neonatal teeth oral erosions respiratory involvement
ectodermal dysplasia skin fragility syndrome
suprabasilar at birth generalized alopecia palmoplantar keratoderma painful fissures nail dystrophy
which mutation coding for the most highly conserved regions of keratin ___ and ____ correlate w/ dowling meara
K5 and 14
milder forms, weber-cockayne codes for regions that are less conserved
mutations in EBS w/ mottled pigmentation
amino terminus of K5 (globular head domain responsible for keratin filament insertion to melanosomes)
mutations w/ EBS w/ muscular dystrophy
lack of expression or defective expression of plectin
disorganization of muscle sarcomeres
unique case of recessive dominant EBS associated w/ null mutations of_____ gene coding for BP230/BPAG1
dystonin
blistering w/ neuropathy
molecular defect of ectodermal dysplasia skin fragility syndrome - loss of function of desmosomal protein ______, encoded by PKP1
plakophilin 1
suprabasilar keratinocytes and outer root sheath cells
All JEB share common histopathologic feature of blister formation within _____ of BMZ
lamina lucida
Herlitz JEB ?
- generalized at birth
- later infancy - periorificial granulation tissue (mouth, eyes, nares)
- dystrophic nails or often lost during infancy
- tooth enamel pitting
- erosions of all stratified sq epithelial tissues (nasal, conjunctival, esophageal, tracheal, laryngeal, rectal, urethral)
- tracheolaryngeal stenosis or obstruction - horseness in early infancy is ominous sign
- failure to thrive, growth retardation
- mixed anemia, sepsis (common lethal)
Non-Herlitz JEB?
- survive infancy, clinically improve w/ age
- severity of blistering, oral erosions less than in lethal form
- lack of hoarseness (favorable prognostic sign)
- most common in childhood: scalp, nail lesions, periorificial nonhealing erosions w/ granulation tissue
laryngo-onycho-cutaneous syndrome ?
- mutations of laminin a3 (LAMA3) gene
- triad of cutaneous erosions, nail dystrophy, mucocutaneous granulation (conjunctiva, larynx)
Generalized atrophic benign EB (GABEB) ?
at birth generalized relative paucity of oral erosions enamel pitting, extensive dental caries nail dystrophy atrophic scarring normal lifespan blistering improves w/ age progressive alopecia of scalp, body (after puberty onset)
Localized JEB ?
hands feet pretibial regions dystrophic nails, can be shed enamel pitting oral or nasal erosions absence of any internal involvement favorable prognosis
JEB w/ pyloric atresia ?
extreme mucosal and cutaneous fragility urological abnormalities hydronephrosis, nephritis rudimentary ears a6B4 integrin mutations
complete lack of expression of laminin 332
Herlitz
reduced expression of laminin 332
non-Herlitz
blistering occurs in lamina lucida region abnormalities of hemidesmosomes/anchoring filaments
GABEB
majority have abnormalities of collagen XVII/BP180
mutation in localized JEB
COL17A1
Localized DDEB ?
at birth, not appreciated until childhood repetitively traumatized areas (knees sacrum acra ) hypertrophic scarring milia nail dystrophy or loss oral and teeth - not common good prognosis normal lifespan
Generalized DDEB?
Pasini subtype of DDEB at birth widespread more severe blistering heal w/ scarring plaques, milia scar like flesh colored papules on trunk localize to extremities (get older) dystrophic/absent nails oral elsions
Bullous epidermolysis of NB - rare variant, gradually recedes after infancy
localized Recessive DEB
repetitively traumatized skin, often acral
scarring and milium
mild mucosal
severe RDEB / Hallopeau-Siemens ?
at birth
generalized
congenital absence of skin (Bart's syndrome)
progressive scarring
pseudosyndactyly ("mitten" of skin)
flexion contracture
NO periorificial (compare to severe JEB)
scalp - most commonly affected
progressive alopecia
oropharynx - limit tongue movement and narrows opening of oral cavity
loss of teeth
narrowing of airway - tracheostomy
esophageal strictures and webbing
can survive to teens/adult
SCC (50-80%) - extremely aggressiveblister cleavage in all dystrophic EB
sublamina densa
DEB associated with mutations coding for
COL7A1
EB pruriginosa ?
subtype of DEB
increased pruritus
glycine mutation
Kindler syndrome - decreased expression of
kindlin-1
mutation of KIND1
Kindler syndrome ?
at birth, infancy EB like trauma induced blisters blister subsides in later childhood progressive poikiloderma to sun exposed areas photosensitivity nail changes webbing of toes and fingers oral inflammation esophageal or ureteral strictures ectropion
reduplication of basement membrane
sublamina densa split
findings of TEM and IDIF in EBS and DDEB?
IDIF - No detectable loss of antigens
TEM - keratin filament clumping or anchofing filament abnormalities
findings of TEM and IDIF in recessive disease?
IDIF - loss of individual components of hemidesmosomes
TEM - can not distinguish
how to biopsy EB patients
10% of punch covers blister
90% covers intact skin
TEM findings in
dowling meara EBS
JEB
DEB
dowling meara EBS - clumping of keratin intermediate filaments in basal keratinocyte cytoplasm
JEB - rudimentary hemidesmosome
DEB - absent or altered anchoring fibrils
IDDF microscopy findings in
EBS
JEB
DEB
EBS - BP230, lamina densa protein coll Type IV on FLOOR
JEB - BP230 on roof, type IV on floor
DEB - coll VII, BP230 on roof
lack of staining with antibodies specific to laminin 332 support ____ diagnosis
JEB
lack of staining with collagen VII support ____ diagnosis
DEB
absence of staining for collagen XVII support _____ diagnosis
non-herlitz JEB / GABEB
prenatal diagnosis of EB
CVS at 8-10 weeks
amniocentesis at 2nd trimester
controlling exposure to heat prove helpful in ____
EBS
mitten pseudosyndactyly in _____ variant are in most need of surgical intervention
HS-RDEB
average survival rate after Dx of RDEB associated SCC is
5 years
often used to control local spread of carcinomas on limbs
amputation
chemoprevention of SCC
isotretinoin
treatment for advanced metastatic disease in RDEB
cetuximab
EGFR antagonist
esophageal lesions in _____ and _______
RDEB
JEB (Herlitz, non-herlitz)
respond to dilatation
colonic interposition in advanced cases
gastrostomy tube insertion for nutrition
eye leions of
dowling meara subtype
JEB and RDEB
DEB
dowling meara subtype - inflammation of eyelid
JEB and RDEB - corneal ulceration w/ scarring, obliteration of tear ducts, eyelid lesions
DEB - cicatricial conjunctivitis
corneal ulcerations (antibiotic ointments, cycloplegic agents to reduce cilicary spasms)
enamel defects in JEB and DEB lead to _____
dental caries
nutritional problems in EB
low selenium
iron overload
chronic anemia
predisposing to CHF, cardiomyopathy
greatest overall threat to nutritional well being
orpharyngeal and gastrointestinal lesions
_______ can certainly affect all severe EB subtypes
anemia of chronic disease
not responsive to oral supplementation
parenteral iron
recombinant EPO
transfusion for rapid correction
deficient vitamin D, zinc, osteoporosis noted in
RDEB
