epidermolysis bullosa 2.pdf for derma resident

epidermolysis bullosa 2.pdf for derma resident

1. EPIDERMOLYSIS BULLOSA

2. DERMOEPIDERMAL JUNCTION
Anchoring fibrils

3. INTRODUCTION
•Heterogeneous group of inherited mechanobullous disorders, which is clinically
characterized by the development of blisters over the skin and mucous
membranes following minor frictional trauma.
•Based on the level of cleavage at the dermoepidermal basement membrane
zone.
•Four major forms of EB—simplex, junctional, dystrophic, and mixed

4. CLASSIFICATION - Stepwise "onion skin" approach
•Level of blister formation
•Clinical presentation – distribution (localised/ generalised) and severity
(severe, mild, intermediate)
•Mode of inheritance, genetic mutation/ defect

5. •Based upon the level of skin cleavage, EB is classified into four major groups:
•Epidermolysis bullosa simplex (EBS)– Intraepidermal cleavage plane within
the basal layer of keratinocytes (basal EBS)
•Junctional epidermolysis bullosa (JEB)– Cleavage plane within the lamina
lucida of the dermoepidermal junction
•Dystrophic epidermolysis bullosa (DEB)– Cleavage plane below the lamina
densa, within the upper papillary dermis at level of anchoring fibrils
•Kindler epidermolysis bullosa (KEB)– Multiple cleavage planes
(intraepidermal, intralamina lucida, or sublamina densa)

6. EPIDERMOLYSIS BULLOSA SIMPLEX
•Major – autosomal dominant, few autosomal recessive
•Clinical features not very severe except
•EBS, Dowling–Meara (EBS-DM) - can sometimes be fatal
























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9. Localized EB simplex
•Most common type of EB
•Inheritance is autosomal dominant.
•The soles and palms mainly affected, with
the exception of the sides of the toes
•Blistering may be particularly painful
•Typically worse in warm weather
•The hair and teeth are normal
•Nail dystrophy is infrequent
•25% oral erosion

10. EBS with mottled pigmentation
•Reticulated hyperpigmented macules
•Punctate keratoses on the palms and
soles sometimes progressing to
keratoderma
•Mild localized skin atrophy and nail
dystrophy

11. •EBS – Dowling Meara
•Grouped (“herpetiform”) blisters, often in
an arcuate or polycyclic array are highly
characteristic.
•Heal without scarring.
•Involvement of the oral mucosa is common.
•Hyperkeratosis of the palms and soles
appears during infancy and can progress
over time to confluent keratoderma.
•Additional clinical features include nail
dystrophy and nail shedding.

12. JUNCTIONAL EPIDERMOLYSIS BULLOSA
•In 1935, Herlitz described a nonscarring variant of EB, which was lethal in infancy -
variant was called JEB-Herlitz (JEB-H)/ JEB generalized severe.
•JEB compatible with survival to adulthood was termed JEB-non-Herlitz (JEB-nH) / JEB
generalized intermediate.
•JEB associated with pyloric atresia
•JEB inversa
•Late onset manifesting at older age
•Laryngo-onycho-cutaneous (LOC) syndrome.
























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14. •JEB-H - Premature termination codons in both alleles of anyone of the three
genes—LAMA3, LAMB3, and LAMC2, encoding, respectively, the three
constituent polypeptide chains (α3, β3, γ2) of Laminin 332 gene.

15. •JEB-H – generalized, often extensive,
mucocutaneous blistering
•Characteristic perioral and occipital granulation
tissue, nonscarring hair loss
•Nail dystrophy, and loss with granulation tissue
of the nail beds
•Dental enamel hypoplasia with pitting.
•Conjunctival involvement with corneal
ulceration, pannus and symblepharon,
•Hoarse cry due to laryngeal involvement.
•Involvement of GIT & GUT.
•Anemia, and failure to thrive and death is often
due to septicemia.

17. Dystrophic Epidermolysis Bullosa
•DEB may be inherited either dominantly or recessively.
•Dominant forms are milder than recessive forms of DEB.
•Autosomal dominant
•DDEB, generalized (DDEB-
gen)
•DDEB, acral (DDEB–ac)
•DDEB, pretibial (DDEB-Pt)
•DDEB, pruriginosa (DDEB-Pr)
•DDEB, nails only (DDEB-na)
•DDEB, bullous dermolysis of
newborn (DDEB-BDN)
•Autosomal recessive
•RDEB, severe generalized (RDEB-
sev gen)
•RDEB, generalized other (RDEB-O)
•RDEB, inversa (RDEB-I)
•RDEB, pretibial (RDEB-Pt)
•RDEB, pruriginosa (RDEB-Pr)
•RDEB, centripetalis (RDEB-Ce)
•RDEB, bullous dermolysis of
newborn (RDEB-BDN)
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19. •Pathogenesis
•Severe generalized RDEB - Premature termination codons in both alleles, either
homozygous or compound heterozygous
•RDEB generalized, other - compound heterozygosity for a premature
termination codon in one allele and a different missense or splice site mutation
resulting in less disruption of structural integrity.
•DDEB is caused mainly by mutations resulting in glycine substitution or splice
site mutations. This destabilizes the triple helix but the presence of wild type
allele allows for a small percentage of normal collagen 7.

20. •Clinical features :
•In general, bullae in DEB heal with scarring
and milia
•Associated with varying degrees of nail
dystrophy.
•Dominant dystrophic EB (DDEB) is the most
common subtype of DEB and usually
presents from birth to 5 years of age.
•Nails can be thickened with discoloration of
the nail plate or may be totally absent.
•Most cases improve during early adult life.

21. •Recessive DEB
•Generalized and very severe blistering
•Mucosa involved.
•Blisters appear spontaneously or may be
trauma induced.
•There is associated scarring alopecia and
flexion contracture of the fingers and
toes resulting in pseudosyndactyly -
"mitten" deformity
•Ocular involvement is common.

22. •Increased frequency of dental caries.
•Dysphagia is a common symptom due to ankyloglossia, dysmotility, and esophageal
strictures.
•Constipation is seen in most cases due to reduced intake and anal fissuring.
•Anemia resulting from inadequate dietary intake, chronic blood loss, and chronic disease
•Reduced bone mineral density due to prolonged immobility, low vitamin D levels, and a
proinflammatory state. This is associated with severe bone pain and fractures.
•Scarring alopecia is common.
•Increased risk of developing squamous cell carcinoma (SCC).

25. •Bullous dermolysis of newborn
•Rare subtype of DEB characterized by extensive blistering.
•Improves over months to years.
•Intracytoplasmic retention of Type VII collagen
























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26. DM

27. KINDLER SYNDROME
•Mixed planes of cleavage that can be within basal keratinocytes, through the
lamina lucida, and/or below the lamina densa.
•Mutations in the fermitin family homolog 1 gene (FERMT1) encoding kindlin-1, a
component of focal adhesions that connect actin filaments in basal keratinocytes
to the underlying ECM.
•Through integrin-mediated signaling, kindlin-1 affects the shape, polarity,
adhesion, proliferation, and motility of keratinocytes.

28. •Erosions at birth, most often on the forearms and shins, and blistering during infancy
is most prominent on the hands and feet.
•Skin fragility in Kindler syndrome tends to decrease considerably during childhood.
•Photosensitivity, reticulated hyperpigmentation and telangiectasias
•Poikiloderma
•Mild webbing of the digits and palmoplantar hyperkeratosis
•Eczematous dermatitis
•Erosive gingivitis and poor dentition.
•Mucosal involvement may result in intraoral and corneal scarring, ectropion, colitis,
and strictures of the esophagus, urethra, vagina and anus.
•Increased risk of SCC of the lip and oral mucosa as well as acral skin.

31. LABORATORY DIAGNOSIS of EB
•Diagnosis – mainly clinical
•Transmission electron microscopy (TEM) - direct visualization of the various
components of the DEJ and a semi qualitative assessment of these structures.
•Immunofluorescence antigen mapping (IFM) - monoclonal antibodies used
•Typically, four antibodies are used - collagen IV, Keratin 14, laminin 332 and
collagen VII.
•These four in combination determine the level of blistering and categorize into the
major types of EB.
•Biopsy must be taken from the unaffected skin after inducing a blister by rubbing
the skin with a fingertip or a pencil eraser.

32. Genetic
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33. Immunofluorescence
antigen mapping

34. Transmission electron microscopy
JEB
EBS
DEB

35. Electron Microscopy in Epidermolysis Bullosa (EB)

Specimen Collection and Processing
• Biopsy site:
o Fresh perilesional skin (at the edge of a new blister or induced blister).
o Avoid fully developed or chronic lesions as they may show secondary
changes.
o Sometimes, induced blister (by gentle rubbing for 30–60 sec, then
biopsy in a few hours) is preferred.
• Size: 2–3 mm punch biopsy.
• Handling: Must be placed immediately in 2.5% glutaraldehyde fixative
(NOT formalin, which destroys ultrastructure).
• Processing steps:
1. Fixation in glutaraldehyde.
2. Post-fixation in osmium tetroxide.
3. Dehydration in graded alcohol/acetone.
4. Embedding in resin (Epon/Araldite).
5. Ultrathin sectioning (60–90 nm).
6. Staining with uranyl acetate + lead citrate.
7. Examination under transmission EM at 50,000–100,000× magnification.
• Artifacts: Poor fixation or delay can mimic cleavage → careful
interpretation needed.

Role of EM in EB
• Provides ultrastructural details of basement membrane zone (BMZ).
• Identifies level of tissue cleavage → cornerstone for EB classification.
• Visualizes abnormalities of hemidesmosomes, anchoring filaments,
anchoring fibrils.
• Still useful when immunofluorescence antigen mapping (IFM) is
inconclusive.

36. Findings by EB Subtype

1.
EB Simplex (EBS)
• Cleavage: Intraepidermal (basal keratinocyte cytolysis).
• Features:
o Vacuolization, cytolysis of basal keratinocytes.
o Collapse and clumping of tonofilaments.
o BMZ (hemidesmosomes, lamina lucida, lamina densa) preserved.

2.
Junctional EB (JEB)
• Cleavage: Within lamina lucida.
• Features:
o Blister cavity passes through lamina lucida.
o Hemidesmosomes: small, hypoplastic, or absent.
o Anchoring filaments: reduced or abnormal.
o Basal plasma membrane remnants within blister floor.

3.
Dystrophic EB (DEB)
• Cleavage: Below lamina densa (sublamina densa).
• Features:
o Lamina densa separates from dermis.
o Anchoring fibrils (type VII collagen) → absent, reduced, rudimentary, or fragmented.
o Dermal microvesicles in severe recessive forms.

4.
Kindler Syndrome
• Cleavage: Variable / multiple levels (basal keratinocyte, lamina lucida, sublamina densa).
• Features:
o Mixed cleavage planes in same biopsy.
o Reduplication/multilayering of lamina densa.

Advantages
• Direct localization of cleavage plane.
• Visualization of abnormal BMZ structures.
• Still a reference standard and useful for novel or atypical EB variants.

Limitations
• Requires fresh biopsy + special fixatives.
• Expensive, time-consuming, requires expertise.
• IFM is easier and faster, so EM is now used mostly for research/complex cases.

37. TREATMENT
•Supportive management
•Multidisciplinary team headed by a dermatologist.
•Prevention of new blisters;
•Keeping the soles and palms cool and dry particularly in summer, well-fitting
footwear, soft clothing, cotton mittens, adequate moisturization.
•Preventing and treating infections and enhancing wound healing;
•Nutritional support;
•Management of extracutaneous complications and preserving function;
•Providing psychological support to patients and family members.

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38. •Management of neonates:
•Handled with extreme care, placed on a thick foam pad and the pad should be
used for transporting the infant.
•They should not have heel prick tests performed at birth, as this carries the risk
of degloving of the heel.
•Soft suction catheter should be chosen.
•Disposable diapers can be used but should be lined with a soft material.
•Clothes should be turned inside out to prevent skin damage from the seams.

39. •Wound care:
•Ensure good nutritional status of the child
•Antibiotic usage based on culture and sensitivity
•Non-adhesive dressings - vaseline gauze dressings
•Wounds on fingers and toes should be covered separately to prevent fusion.
1.Dressing materials: hydrocolloids, lipidocolloids, silicon foam and mesh, hydrogels,
hydrofibers, silver and honey, or honey-impregnated dressings;
2. Collagen based;
3.Artificial skin substitutes: dermal allograft
4. Bioengineered skin products: dermagraft, a fibroblast derived skin substitute harvested
from neonatal foreskin; and
5. Biological dressings: amniotic membrane.

40. •Pain and itch management:
•For mild to moderate pain, analgesics (eg, paracetamol,acetaminophen) can be
used alone or in conjunction with a nonsteroidal anti-inflammatory drug.
•For more severe pain, opioids (eg,codeine, morphine) or anxiolytics
(eg,diazepam,lorazepam,midazolam) may be required.
•Gabapentinandpregabalinmay be used as adjuvant therapy for severe chronic
pain.
•Chronic pruritus – antihistamines, moisturisers

41. •Management of extracutaneous complications:
•Ocular : regular use of preservative-free ocular lubricants, corneal erosions treated with
antibiotic ointments.
•Oral and dental- Gentle tooth brushing with a soft, small brush, Lubrication of lips, oral
mucosa, enamel hypoplasia may require staged restoration of dentition with full crowns
with or without dental implants to improve appearance and feeding ability.
•Delayed puberty - Hormonal treatment for puberty induction should be evaluated on a
case-by-case basis in collaboration with a pediatric endocrinologist.
•Esophageal strictures are managed by esophageal dilation using endoscopic balloon
dilators.

42. GENERAL MEASURES EXTRACUTANEOUS
•Laxatives , faecal softners
•iron supplements
•Calcium supplements
•Pain- amitriptyline/ BZP/ Cognitive behaviour therapy
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43. •Mitten deformity –
•Providing simple pinch grip and grasp, by releasing the first web space and flexion
contractures
•Allowing independent finger movement, by releasing pseudosyndactyly
•Improving the appearance of the hand
•Postoperative use of custom-made splints and hand therapy are important to maintain
the benefits of surgery
•Squamous cell carcinoma arising in chronic wounds is the most serious complication and
a major cause of death for patients with RDEB.
•Wide local excision with 2 cm margins is considered the treatment of choice for SCCs
confirmed by histopathologic examination.
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44. NEWER THERAPIES

45. THANK YOU