B-33 - Eb Disorders

Front 1

Name the Major EB Simplex subtypes (4) and the Minor EB Simplex subtypes (3)

Back 1

Major:
EBS, Weber-Cockayne
EBS, Koebner
EBS, Dowling-Meara
EBS with muscular dystrophy
Minor:
EBS with mottled pigmentation
AR EBS
EBS superficialis

Front 2

Name the Major JEB subtypes (4) and the Minor JEB subtypes (2)

Back 2

Major:
JEB, Herlitz
JEB, non-Herlitz
JEB w/ pyloric atresia
EBS with muscular dystrophy*
Minor:
JEB inversa
JEB, localized (mitis)

Front 3

Name the Major DEB subtypes (3) and the Minor DEB subtypes (6)

Back 3

AD DEB
AR DEB, Hallopeau-Siemens
AR DEB, Non-Hallopeau-Siemens
Minor:
DDEB, pretibial
DDEB, pruriginosa
RDEB, inversa
RDEB, centripetalis
DEB, transient bullous dermolysis of the newborn
DEB, autosomal dominant/autosomal recessive heterozygote

Front 4

What is the most common form of EBS? How does it manifest?

Back 4

Weber-Cockayne
aka "localized EBS"
MN: "Webs & Socks" limited to palms and soles
Manifests later in life. May see hyperhidrosis & Hyperkeratosis of palms and soles.

Front 5

Describe the Generalized (Koebner) Variant

Back 5

Generalized bulla formation,  with heat/friction
Presents AT BIRTH or infancy
Improves with age (normal lifespan, just like Weber-Cockayne)
Mild Mucosal involvement
Nails u/s normal
Hyperhidrosis + hyperkeratosis of palms & soles

Front 6

What is the most severe form of EBS?

Back 6

Dowling-Meara
aka Herpetiformis

Front 7

How does EBS-Dowling Meara present? Other key clinical findings? EM findings?

Back 7

Generalized blisters
Large in the newborn (seen AT BIRTH)
increased morbidity & mortality (usu die w/in 1st year)
Difficult to tell from dystrophic/junctional EB
Herpetiform-like in later infancy or childhood
Non-scarring
PPK with ↑ age
Oro-esophageal erosions
Nail involvement (but re-grow) +/- dystrophy
Natal teeth
Clumped tonofilaments on EM

Front 8

Which form of EBS has EM finding of clumped tonofilaments?

Back 8

EBS-Dowling Meara (Herpetiformis)
MN "Drowning in clumps"

Front 9

Where is the keratin defect for EBS Dowling Meara?

Back 9

K5 K14 -- The End Terminal rod domains (very critical for keratin function) therefore more severe defect than other EBS (Weber Cockayne)

Front 10

Describe EB Simplex superficialis (EBSS)

Back 10

Superficial peeling of skin, no overt blistering, unknown defect
Histo: intraepidermal blister just beneath granular layer

Front 11

Name mutation in Naegeli-Franceschetti-Jadassohn syndrome

Back 11

KRT14
Absense of dermatoglyphics; reticulate hyperpigmentation of skin; thickening of palms and soles; abnormal sweating

Front 12

Name the mutation in Dowling-Degos disease

Back 12

KRT5
Has progressive, disfiguring hyperpigmentation in a reticular pattern on the flexural areas

Front 13

Where is the split in JEBs? Is it present at birth? what about nail and lip involvement?

Back 13

Split: Lamina lucida, components of the hemidesmisomes
Erosions present at birth
See sloughing of nails & peri-oral involvement with sparing of lips

Front 14

How is JEB inherited?

Back 14

AR

Front 15

Describe EM and teeth findings in Herlitz type JEB (aka Lethal JEB)

Back 15

EM: markedly reduced or absent hemidesmosomes
Enamel hypoplasia characteristic of ALL JEB types
Teeth Pitting (“cobblestoning”)
Can lead to early caries (also seen in AR DEB)

Front 16

What % of patients with Herlitz type JEB die by 2 yrs old? What about non-Herlitz?

Back 16

Herlitz: 50% by age 2y/o die

Non-Herlitz: normal lifespan

Front 17

Generalized blistering, large erosions—buttocks, perioral, trunk, scalp
Peri-oral granulation tissue with sparing of lips
Blisters heal with atrophy, but no milia
Periungual and fingerpad blistering, erosions  nail sloughing/anonychia
Oral & laryngeal involvement with hoarseness
Dental enamel dysplasia w/ “cobblestoning

Back 17

Herlitz type aka Lethal JEB

Front 18

What is the mutation in Herlitz type JEB aka Lethal JEB?

Back 18

AR

Pathophysiology: Premature termination codon or non-sense mutation within any of the 3 protein subunits of laminin-5 (on chromo 1q32)

LAMA3 (laminin α3-chain), LAMB3 (laminin β3-chain), LAMC2 (laminin γ2-chain)

Front 19

Defect in:
LAMA3 (laminin α3-chain), LAMB3 (laminin β3-chain), LAMC2 (laminin γ2-chain)

Back 19

Herlitz type JEB (aka Lethal JEB)

Front 20

What is the mutation in Non-Herlitz / GABEB?

Back 20

AR with defects in laminin 5 or BP Ag2 (aka “BP 180” or “collagen type XVII ”)

Front 21

What chromosome is Laminin 5 on? BPAg2?

Back 21

Laminin-5 genes on chromo 1q32 S2 Herlitz

BPAg2 --> COL17A1 gene on chromo 10q24

Front 22

Bullae that heal with atrophic scars
Nail dystrophy & scarring alopecia
Generally with a normal lifespan
↓ blisters with time

Back 22

Non-Herlitz / GABEB

Front 23

Defect in JEB w/ Pyloric Atresia

Back 23

Defect: a6B4 integrin gene

a6 integrin --> ITG-A6 gene on chromosome 2

B4 integrin --> ITG-B4 gene on chromosome 17q11

Front 24

More common in males (♂ > ♀)

Skin findings are S2 Herlitz variant

Defining characteristics:
Pyloric atresia
GU abnormalities: strictures of urethra or ureters, hydronephrosis, renal failure

Back 24

JEB with Pyloric Atresia

Front 25

Back 25

EBS with Muscular Dystrophy

Front 26

EBS with Muscular Dystrophy Inheritance? Defect?

Back 26

AR

Plectin gene (500 kd)
MN – PHAT, PLAKIN, PHYSICALLY DISABLED

Plectin is found in both hemidesmosomes & skeletal muscles

Front 27

Mild blistering
Mild nail dystrophy
No dental anomalies

Back 27

EBS with Muscular Dystrophy

Front 28

JEB:
Mild blistering
No mucosal involvement
Almost always dental enamel hypoplasia

Back 28

JEB - Mitis variant

Front 29

JEB with
Blisters/erosions on skin folds

Back 29

JEB - Inverse form

Front 30

Defect in Dystrophic EB?

Back 30

Collagen VII defect due to COL7A1 gene on chromo 3p21

Same gene for both AD & AR DEB

Front 31

This type of EB can also have:
Eye --> blindness
Esophagus --> strictures
Small intestine --> malabsorption, anemia, vitamin & nutritional deficiencies
Large intestine --> constipation, strictures
GU tract --> strictures, obstruction

Back 31

Dystrophic EB (more likely than EBS and JEB to have extracutaneous)

Front 32

Onset at birth to early infancy

Blistering predominates on extensor surfaces of extremities (dorsum of hands, elbows, knees, and lower legs)

Milia associated with scarring

80% have nail dystrophy

Less severe, generally healthy, normal stature

Back 32

Dominant dystrophic DEB

Front 33

The Pathophysiology of this EB is: Glycine mutations (glycosylation sites) --> defective triple helix assembly

Back 33

Dominant Dystrophic DEB

Front 34

What are the two variants of AD Dystrophic EB?

Back 34

Albopapuloid Pasini Variant

Cockayne-Touraine (Hyperplastic) Variant

Front 35

More widespread distribution

Albopapuloid lesions -->
Hypopigmented scar-like papules on trunk

+ Mucosa & teeth involvement

Back 35

Albopapuloid Pasini Variant of AD Dystrophic EB

Front 36

Limited acral distribution --> Extremity bullae heal with scarring +/- hyperplastic

NO albopapuloid lesions

NO mucosal or teeth involvement

Back 36

Cockayne-Touraine (hyperplastic) Variant

Front 37

Extensive blistering at birth
Dramatic improvement in 1st few months of life
Blistering u/s ends by age 2 y/o
Mild atrophy/scarring
No other abnormalities

Defect: Type VII collagen

Thought to be caused by delay in transfer of Collagen VII from basal keratinocytes to underlying ECM

Back 37

Transient Bullous Dermolysis of the Newborn (Transient EB)

Front 38

Defect for Transient Bullous Dermolysis of the Newborn

Back 38

Type VII Collagen

Front 39

What is pseudosyndactyly?

Back 39

Mitten deformities of hands and feet -- seen in Recessive Dystrophic (Hallopaeu-Siemens)

Front 40

What skin cancer are pt's with recessive dystrophic EB (hallopeau-siemens are risk for)?

Back 40

SCC (40% of pts by age 30)

Front 41

What is the pathophysiology of recessive dystrophic EB (hallopaeu-siemens)?

Back 41

Type VII Collagen:

Pathophysiology: Stop codon mutation --> NO fibrils

Front 42

Describe AR DEB - Non-Hallopeau-Siemens

Back 42

Can have all the findings of AR DEB, but less severe

Bullae mainly on acral bony prominences--> can look very S2 AD DEB

Fragility improves w/ age

Front 43

What is the pathophysiology of AR DEB, non-Hallopeau-Siemens?

Back 43

Pathophysiology: Missence or frameshift mutation in collagen 7 gene --> defective anchoring fibrils

Front 44

Compare the life span of the different types of DEB?

Back 44

AD DEB : Normal

AR DEB: Hallopeau-Siemens
Death within 1st 3 decades of life

AR DEB: Non-Hallopeau-Siemens (variable, if mild then normal lifespan)

Front 45

What is BART Syndrome?

Back 45

Localized congenital absence of skin (aplasia cutis)

Phenotypic pattern seen in EB pts

M/C occurs in DEB pts (either AD or AR), but can occur in any EB type

DDx: Other disorders with congenital localized absence of skin – eg. aplasia cutis congenita

But these d/o’s do NOT have blisters present

Front 46

Ectodermal Dysplasia w/ skin fragility:
Inheritance & gene defect
Clinical Picture

Back 46

AR
Plakophilin-1 gene defect (desmosomal component)

At birth, generalized erythroderma with blistering

Improves with age

Trauma-induced skin fragility
Soles are the worst
PPK w/ painful fissuring
Ectodermal dysplasia
Short, sparse hair
Thick, dystrophic nails
Hypo-hidrosis

Front 47

Kindler Syndrome
Defect?
Clinical picture?

Back 47

KIND-1 gene defect
-- Encodes a protein linking actin with the extracellular matrix

Generalized progressive poikiloderma – worsens w/ age

Atrophic scarring – worsens w/ age
Congenital acral skin blistering – blister formation improves w/ age
Photosensitivity – improves w/ age
Diffuse cutaneous atrophy – increased with age
Skin fragility
Webbing of fingers/toes
Nail dystrophy
Oral mucosal lesions
Others
-- PPK, leukokeratosis
-- red friable gums, GU/GI stenosis