2/25 Bullous Disorders Flashcards
What is the function of desmosomes?
What are they comprised of?
Where can you find them?
- provides resistance to mechanical stress and strong adhesion by anchoring intracellular keratins (intermediate filaments) to cell membrane, and by linking cells to each other (see diagram)
- comprised of cell adhesion proteins and linking proteins
- seen as “spines” or prickles” in IHC, particularly in the stratum spinosum
What are cadherins?
Where can you find them (in relation to derm…)?
Give examples!
Mutations in this particular protein results in what kind of bullous disorder?
Cadherins = Calcium-dependent cell-cell adhesion molecule
- present in desmosomes that connect cells together in the dermis
- restricted to stratified squamous epithelia
- example: Desmogleins 1, 3
Results in** Pemphigus Vulgaris **
What causes acantholysis?
What do you see histologically with acantholysis?
example?
disruption of desmosomes between keratinocytes
Histology: rounded, free floating keratinocytes and in intraepidermal bullae
ex: Pemphigus vulgaris
What is the function of hemi-desmosomes?
Where can you find them?
Give examples!
What happens if you have destruction of these proteins?
- functions to complex epithelial cells with the lamina lucida
- ex: Bullous pemphigoid antigens (BPAg1, BPAg2)
results in Bullous pemphigoid
What is the role of the basement membrane?
What are the 4 layers? What are these layers made of?
Which part is the weakest?
1) Basal Keratinocyte (cytoskeleton) - contains keratins (intermediate filaments)
2) Lamina Lucida - weakest part of the basement membrane zone; composed of various anchoring filaments
3) Lamina Densa - is actually the basement membrane “proper”, made of Type IV collagen
4) Sublamina Densa - contains anchoring fibrils (type VII collagen) and anchoring plaques (red fibers on the diagram)
There are 3 diagnostic techniques used to diagnose bullous skin d/o.
What are they and how are they done?
What specimens do they use?
- *SKIN BIOPSY**: used for
- histopathology - usually of blister edge; (routine fixative)
- direct immunofluorescence (DIF) - usually of perilesional (special fixative required)
- *SKIN BIOPSY for SALT-SPLIT SKIN prep**: used for
- Immunoflourescence on salt split skin to assess cleavage plane - determines the localization of immune reactants (ie pathogenic sIg)
SERUM for indirect immunofluorescence (IIF)
- patient’s serum is used against another tissue substrate (ie monkey’s esophagus)
- Electron microscopy (rarely done)
What’s the difference between DIF and IIF?
(direct and indirect immunofluorescence)
Direct: use of patient’s tissue for IHC preparations
Indirect: use of patient’s serum on a tissue substrate (ie monkey’s esophagus)
What is the Nikolsky sign?
What skin d/o would you see it in?
slight rubbing of the skin results in exfoliation of the outermost layer, forming a blister within minutes, or a blister extends by external pressure
Pemphigus Vulgaris
What is an Asbhoe Hansen sign?
Pressure on intact bulla extends the bulla
What are two main autoimmune bullous d/o? (2)
What is a main form of hereditary bullous d/o? (1)
Autoimmune:
Pemphigus Vulgaris
Bullous pemphigoid
Hereditary:
Epidermolysis Bullosa
What is the pathophysiology of pemphigus vulgaris?
How does it present? (4 key)
(characteristics, locations)
Who does it mostly affect?
What does it look like histologically, DIF, IIF?
What is the treatment? (3)
What is the prognosis if it’s not treated?
(you must get all 6 in order to give yourself a “5” on on Brainscape..)
Autoimmune IgG antibodies directed against** Desmogleins 1, 3 present in desmosomes** (connects epithelial cells to each other)
Results in acantholysis (loss of intracellular cohesion and intraepidermal blisters) with sparing of the dermis
Presentation:
- flaccid bullae against a non-erythematous, base; ruptures easily
- (+) Nikolsky’s sign*
- affect skin and oral mucous membranes
- blisters heal without scaring but the skin may sometimes be hyperpigmented
Who does it affect:
- Middle age people
- Ashkenazi Jews and Mediterranean descents
Histologically
- intraepidermal blister
- “tombstoning” of basal keratinocytes
- **acantholysis **
- DIF - “chicken-wire” due to deposition of IgG, C3
Treatment:
- prednisone
- Rituximab
- Immunosuppressives (mycophenolate mofetil, azathioprine, cyclophosphamide)
Mortality: 80-90% mortality rate if untreated due to fluid loss, 2˚ bacterial infections, and poor nutrition if oral mucosa is involved
What are 2 variants of pemphigus vulgaris?
What is the etiology/associations of these variants?
Where do they normally affect?
- *Pemphigus Foliaceus**
- Etiology: anti-desmoglein 1 autoantibodies
- superficial variant of pemphigus that enlarges to produce extensive areas of moist-red, edematous, exfoliated, heaped up skin
- affects upper chest, scalp
- oral mucosa is rarely involved
- *Pemphigus Paraneoplastic**
- associated with NHL, CLL
- affects mucosa and** trunk**
How does pemphigus vulgaris compare to pemphigus foliaceus in terms of the areas they affect?
In your answer, state the specific auto-antibodies.
What will y ou see histologically?
- *Pemphigus Vulgaris (L)**
- IgG antibodies against desmogleins 1, 3 in cadherin complex
- more deep: see tombstoming of basal keratinocytes
- *Pemphigus Foliaceus (R)**
- IgG antibodies against desmoglein 1 in cadherin complex; more superfiical bullae
What form of blister is this?
How can you tell?
What is it caused by?
Pemphigus Foliaceus
superficial variant of pemphigus - note how there is still epithelium attached to the BM.
anti-desmoglein 1 autoantibodies
What form of blister is this?
How can you tell?
What is it caused by?
Pemphigus vulgaris
- intraepidermal blister that is closer to the BM
- “tombstoning” of basal keratinocytes
- acantholysis - see free- floating epithelial cells
What does this person have?
How can you tell?
Pemphigus vulgaris
- flaccid bullae against a non-erythematous base; ruptures easily
- (+) Nikolsky’s sign*
- affect skin and mucous membranes
What does this person have?
How do you know?
pemphigus vulgaris
- flaccid bullae against a non-erythematous base; ruptures easily
- (+) Nikolsky’s sign*
- affect skin and mucous membranes
What does this person have?
How do you know?
Bullous pemphigoid
- large, tense bullae on erythematous OR non-erythematous base
- IF stain: IgG LINEAR staining in the BM zone
(intact epithelial layer is separated from dermis layer due to autoantibodies against BPAg1 and BPAg2 antigens in lamina lucida of BM)
- no acantholysis
What does this person have?
How do you know?
Bullous pemphigoid
- large, tense bullae on erythematous OR non-erythematous base
- bx shows: subepidermal bulla with eosinophils
(intact epithelial layer is separated from dermis layer due to autoantibodies against BPAg1 and BPAg2 antigens in lamina lucida of BM)
- no acantholysis
What does this person have?
How do you know?
Bullous pemphigoid
-
large, tense bullae on erythematous OR non-erythematous base
(intact epithelial layer is separated from dermis layer due to autoantibodies against BPAg1 and BPAg2 antigens in lamina lucida of BM) - predilection for groin, axilla, trunk, thigh, flexor forearms
(oral lesions only in 20% of cases) - no acantholysis
What does this person have?
How do you know?
Bullous pemphigoid
-
large, tense bullae on erythematous OR non-erythematous base
(intact epithelial layer is separated from dermis layer due to autoantibodies against BPAg1 and BPAg2 antigens in lamina lucida of BM) - predilection for groin, axilla, trunk, thigh, flexor forearms
(oral lesions only in 20% of cases) - no acantholysis
What is the typical presentation of Bullous pemphigoid?
Who does this usually affect?
What is the pathophysiology of it?
What does the histology and immunofluorescence show?
How do you treat these nasty bullae?
(features of bulla? location?)
- large, tense bullae on erythematous OR non-erythematous base
- predilection for groin, axilla, trunk, thigh, flexore forearms, but oral mucosa is generally spared
- very itchy
- elderly >60yo
autoimmune antibodies against BPAg1 and BPAg2 (hemidesmosomes that connect the epidermis to the BM) results in separation of the epidermis from the dermis
Bx: subepidermal bullae with eosinophils
IF: linear IgG staining on the BM
Treatment: (same as vulgaris)
- prednisone
- rituximab
- immunosuppressants (mycophenolate motefil, azathioprine, cyclophosphamide)
What does this baby have?
What are the 3 forms of this disorder?
Which one is the most severe form?
Which one predisposes the patient to squamous cell carcinoma?
Epidermolysis Bullosa
genetic disorder that results in blistering at sites of incidental trauma (even a very light touch can cause a bullous!!!) or increased ambient temperature
-
Simplex (intradermal separation)
* dominant inheritance - Junctional (dermal-epidermal separation)
- esophageal or tracheal involvement
- dominant inheritance
- Dystrophica: (sub-lamina densa of BM separation)
- dominant or recessive inheritance
- most severe form; can result in digital fusion “mitten” hand deformity with flexural contratures
- predisposition to squamous cell carcinoma and early death
What does this baby have?
What is the life expectancy of patients with this d/o?
What are the 3 variants of this disease?
Which one predisposes the patient to squamous cell carcinoma?
Epidermolysis Bullosa
- genetic disorder that results in blistering at sites of incidental trauma (even a very light touch can cause a bullous!!!) or increased ambient temperature
- mild disease = normal life expectancy
- severe disease = significant morbidity/mortality; death during infancy
- Simplex:
- intradermal separation
- dominant inheritance
- Junctional:
- separation at the dermal-epidermal junction
- esophageal or tracheal involvement
- dominant inheritance; begins at birth
- Dystrophica:
- separation within the sub-lamina densa of BM
- dominant or recessive inheritance
- most severe form; can result in digital fusion “mitten” hand deformity with flexural contratures
- predisposition to squamous cell carcinoma and early death
What is the most severe form of Epidermolysis Bullosa?
What is it’s pattern inheritance?
What areas of the skin does it affect?
What is its presentation?
What is the prognosis?
Dystrophica:
- separation within the sub-lamina densa of BM
- extremities, but may generalize
- dominant or recessive inheritance
- can result in digital fusion “mitten” hand deformity with flexural contratures
- predisposition to squamous cell carcinoma and early death
