1. GENETIC EPIDERMOLYSIS
BULLOSA
PRESENTER – DR.AMAL SHYAM
MODERATOR – DR.BIFI JOY

2. DEFINITION
• Group of genetically determined skin fragility
disorders characterised by blistering of skin
and mucosae following mild mechanical
trauma.
• Alternative term – mechanobullous diseases
• Epidermolysis bullosa was first described in
1870 by von Hebra under the name ‘erblichen
pemphigus’.

3. • Its current name, ‘epidermolysis bullosa
hereditaria’, was coined by Koebner in 1886.
• Simplex and dystrophic EB were clinically
separated in 1898 by Hallopeau.
• Junctional EB was first identified in 1935 by
Herlitz, and termed ‘EB letalis’.
• Precise characterization of these three major
EB types, via the application of transmission
electron microscopy, was first performed by
Pearson in 1962

4. Prevalence and Incidence
• Mainly derived from National EB Registry
(USA) Project
• There is no gender, racial, ethnic or
geographical predilection for EB.

5. LAMINA
EPIDERMOLYTIC
LUCIDO LYTIC
EB
DERMOLYTIC MIXED

6. EPIDERMOLYTIC BULLOSA SIMPLEX
• Supra basal • Basal
• Plakophilin deficiency • Localised EBS
• Lethal acantholytic • EBS, Dowling-Meara
EBS • EBS, Generalized other
• EBS superficialis • EBS,AR
• EBS-Mottled hyperpig
• EBS, Muscular dystrophy
• EBS, Ogna
• EBS, Migratory circinate
• EBS, Pyloric atresia

9. Molecular Pathology
• In all forms of EB simplex, blister formation is
intra epidermal
• Most EB subtypes begin with the disruption of
basal keratinocytes
• Mutations in the basal keratin pair, k5 and k14
• Correlation exist between the position of the
mutation on the KRT5 or KRT14 genes

11. • Most severe form of EB simplex, the Dowling–
Meara subtype - missense mutations in the
initiation or termination peptides of the rod
domains
• Weber–Cockayne EBS -, mutations occur
outside the highly conserved boundary motifs,
and chiefly in other parts of rod domain or the
L12 linker region

12. • In EB simplex with mottled pigmentation is due to
mutations of the globular head domain of keratin 5,
that binds with desmosomes & melanosomes
• Ogna form of EB simplex has also been found to be
caused by a PLEC1 mutation.
• EBS with muscular dystrophy – genetic defects in
plectin gene (PLEC1)

13. • AR EBS caused by keratin 14 knock out
mutation
• Extremely rare entities, plakophilin deficiency
and lethal acantholytic EB simplex - result
from mutations in the genes encoding for
plakophilin-1 and desmoplakin, respectively

15. Localised EB simplex
• Weber cockayne EBS
• Most common type of EB
• Palms and soles mainly affected
• Most have blisters only on the foot, in a
minority at waist or neck.
• Blisters start in childhood, rarely in adulthood.
• Aggravated by strenuous physical activity, hot
weather, friction from clothing.

16. • Hyperhydrosis is common.
• Blisters heal with no milia or scar formation
• 25% develop intra oral lesions, palatal
• Hair and teeth normal

17. Dowling-Meara EBS
• EB Herpetiformis
• Blisters occur in groups, heals without scar
• Blistering is severe and extensive – invt of
mucous membrane, shedding of nails, milia
formation
• D/d – Junctional and generalized
recessive dystrophic EB
• Skin biopsy mandatory

18. • Spontaneous herpetiform, annular,
or arcuate blistering on the trunk,
limbs, neck
• Healing with hyperpigmentation
• Irregular hyperkeratosis of palms
and soles – keratoderma, flexion
deformity of hand.
• General conditions improve with age

19. Generalized EBS, non Dowling-Meara
variant
• Koebner EBS
• Usually mild, 60% localized scarring, 16% milia
• Blisters appear within first year
• Infants- occiput, back, legs
• Childhood- hands & feet
• Blistering worse in warm weather

20. EBS Ogna
• AD
• Named after a village in Norway
• Seasonal blistering of hands and feet
• Generalised bruising tendency, haemorrhagic
bullae, and onychogryphotic great toe nails

21. EBS with mottled pigmentation
• Pigmentary changes present at birth or appear
during infancy
• Reticulate pattern of small, tan coloured
macular lesions which fade with age
• Involve neck, upper trunk and extremities
• Mild localized skin atophy and nail dystrophy
seen

22. AR EBS with neuromuscular disease
• Muscular dystrophy, Myasthenia gravis, SMA
• Muscle weakness and wasting severe
• Blisters over skin and mucosa
• MR, atrohic scarring seen
• Milia, nail dystrophy, alopecia

23. Lethal acantholytic EB
• Mutation in gene for desmoplakin
• AR
• Present at birth, Generalized
• Presence of oozing erosions than frank blisters
• Abnormal nails, neonatal teeth, intraoral
erosions, alopecia of the scalp.

24. Plakophilin-1 deficiency
• AR form of ectodermal dysplasia
• Mutation in plakophilin-1 gene
• Generalized, appears at birth.
• Superficial erosions, blistering to a lesser
extent
• Abnormal nails, hypotrichosis, focal
keratoderma, perioral and tongue fissures,
constipation, oesophageal stricture,
blepharitis, absent or sparse eye lashes.

25. Epidermolysis bullosa simplex
superficialis
• Epidermal cleavage is just beneath stratum
corneum
• AD
• Superficial erosions, blisters similar to
pemphigus foliaceous.
• Mutations in type 7 collagen gene COL7A1
was found in one study.

26. Junctional epidermolysis bullosa
• All variants AR inheritance
• Blister formation at the level of Lamina lucida
• Indeterminate JEB

27. • Types
Herlitz JEB
Non Herlitz JEB
JEB, with pyloric atresia
JEB, inversa
JEB, late onset
LOC Syndrome

28. Molecular
pathology
• Clean split at the level of Lamina lucida, with
closely apposed basal keratinocytes, and
continuous lamina densa in lower part.

30. • Abnormality in anchoring filament protein laminin
5 in the skin of patients with Herlitz and some non
Herlitz JEB
• Herlitz- mutation in LAMA3, LAMB3, LAMC2
• Leads to premature termination codon mutations.
• Non Herlitz JEB – laminin 5 mutation or mutation
in COL17A1

31. Herlitz Junctional Epidermolysis
Bullosa
• Epidermolysis bullosa letalis
• Epidermolysis bullosa atrophicans
generalisata gravis
• Blistering and erosions are present at or soon
after birth and rapidly become generalized
• The whole skin is extremely fragile and lifting
or turning the baby may cause extensive
blistering or peeling away of the epidermis.

32. • Eroded areas are often very slow to heal.
Healing result in atrophic scarring.
• Involvement of the oral and pharyngeal
mucosa is frequent and may be severe
• Hoarseness and stridor may indicate laryngeal
or supraglottic involvement, most notably
potentially life-threatening stenosis or
stricture

33. .
• Infants die early in infancy with overwhelming
infection or from failure to thrive
• Typical lesions occur symmetrically around the
nose and mouth
• The teeth show abnormal enamel formation,
but normal dentine - are malformed, pitted
and lost prematurely.

34. • Following blistering and erosions, the
formation of exuberant granulation tissue on
the nail folds and nail bed leads to shedding of
the nails and bulbous changes of the fingertips

35. .
• Blisters may occur on the cornea, resulting in
pain, erosions, scarring, and, very rarely,
blindness
• Urethral meatal stenosis, urinary retention,
hydronephrosis and bladder hypertrophy,
Squamous cell carcinoma
• 40% of patients die in first year, most patients
die within first 5years
• 75% develop flexural contractions at axillae,
upper & lower limbs.

36. Generalized non-Herlitz JEB
• Epidermolysis bullosa atrophicans generalisata
mitis
• Generalized atrophic benign epidermolysis
bullosa (GABEB)
• Early clinical course similar to Herlitz form
• Patient usually survives till adulthood
• Gradual lessening of severity of disease with
age

37. • Teeth show severe enamel defects, fail to
erupt normally
• Nails are dystropic and frequently missing
• Lesions heal with atrophic scarring,
sometimes post inflammatory
hypopigmentation or depigmentation

38. • Pigmented nevi common
• Alopecia affects scalp, eye brows, eyelashes.
Body hairs sparse or absent
• Oesophageal stricture, laryngeal invt, oral
erosions, corneal ulcers, hypoacusis and
urethral stricture reported

39. Localised JEB
• Clinical manifestations include nail dystrophy,
dental enamel changes and blistering
involving the lower legs and feet only
• Localized forms of non-Herlitz junctional EB
• Chronic, painful erosions associated with
hyperkeratosis present on the soles.

40. Junctional EB with pyloric atresia
• Level of blistering - cytoplasm of basal
keratinocytes, just above the plasma
membrane, rather than within lamina lucida.
• Few survive beyond the first few months of
life
• Blistering is usually present at birth, following
a pregnancy complicated by polyhydramnios

41. • The teeth are hypoplastic, lacking normal
enamel, and the nails are dystrophic.
• Early attempts at feeding result in non-bilious
vomiting.
• Death occurs in first few months, unless
pyloric stenosis is surgically corrected.

42. Late onset JEB
• Epidermolysis bullosa progressiva
• The onset is delayed until childhood or
adolescence, and nail dystrophy is a common
presentation.
• Later, knees and elbows are involved.
Progressive atrophic changes lead to early loss
of fingerprint patterns and mild finger
contractures

43. • Condition was originally named EB
dystrophica–neurotrophica by Gedde-Dahl
because of the association of partial deafness
• The ultrastructural changes - widening of the
lamina lucida with deposition of amorphous
material

44. Cicatricial JEB
• Bistering heal with scarring and result in loss
of nails, alopecia, syndactyly and contractures.
• Involvement of oral mucosa with stenosis of
anterior nares

45. LOC syndrome
• Laryngo-onycho-cutaneous syndrome
• Shabbir’s syndrome
• Chronic erosive lesions affect the face, mainly
around the nose and mouth, and, to a lesser
extent, the limbs, trunk and genitalia.
• Notched teeth, hoarseness

46. Dystrophic Epidermolysis Bullosa
• Characterized by skin fragility, blistering,
scarring, nail changes and milia formation.
• Unlike junctional EB, there are both autosomal
recessive and autosomal dominant subtypes

47. Molecular pathology
• Both autosomal dominant and recessive forms
of dystrophic EB are caused by mutations in a
single gene, COL7A1, which encodes the
anchoring fibril protein, type VII collagen.
• Ultrastructurally, the level of blistering or
tissue cleavage in all dystrophic forms of EB is
immediately below the lamina densa of the
epidermal basement membrane,

49. Severe Generalized recessive DEB
• Hallopeau Siemens variant
• Bullae present at birth or appear in early
infancy
• Clinical presentation include localized absence
of skin – Bart’s syndrome
• Skin extremely fragile
• Blisters develop on mildest trauma

50. • Healing lesions produce atrophic scars like
cigarette paper.
• Milia formation is a constant feature
• Sites of predilection – knees, elbows, hands,
feet, back of neck ,shoulders, over the spine
• Ulcers over shoulders and spine heal slowly
• Can sometimes become secondarily infected
• Ocasionally lesions heal with excessive
granulation tissue

51. • Hair gowth on scalp and body impared
• Scarring digits undergo progressive
contractures
• Scarring Alopecia
• Pseudosyndactyly
• Oral lesions – Ankyloglossia, microstomia.
• Gums are fragile with erosions & bleeding
• Lingual papillae are lost

52. • Higher incidence of caries tooth
• Oesophageal involvement – Pain, dysphagia,
scarring, fibrosis, GERD, perforation
• Perianal blistering, erosions and painful
fissures common in childhood
• Fecal retention, abdominal pain, bloating
• Ocular – symblepharon, limbal broadening,
corneal erosions, opacification, scarring

53. • General physical development is retarded
• Can develop SCC
• Delay in development of secondary
sexual changes
• Patients die by 3rd or 4th decade.

54. Generalized dominant DEB
• Hyperplastic (Cockayne-Touraine) and
albopapuloid (Pasini) variant
• AD
• Skin is less fragile
• Blisters usually follow sharp knocks or glancing
blows
• Blisters mainly occur over bony prominances
• Nail dystrophy- MC

56. • Bistering in mouth is mild and teeth normal
• Perianal lesions – intense pain
• Clinically often impossible to distinguish from
Dominant DEB
• Good long term prognosis

57. Bullous dermolysis of newborn
• AD
• Blistering over limbs
• Improves during childhood and remits
completely
• Blisters heal without atrophic scarring

58. others
• Pretibial dystrophic epidermolysis bullosa
AD , late onset
Itching, bullae, atrophy & scarring of shin
• Epidermolysis bullosa pruriginosa
Intractable pruritus
Violaceous lichenoid papules & plaques in
a linear arrangement in shin & forearm

59. Kindler Syndrome
• AR
• Mutations in FERMT1 (KIND1)
• generalized blistering at birth, with some
amount of scarring.
• Keratoderma, skin atrophy, poikiloderma,
photosensitivity,
• and rarely, mental retardation and bone
abnormalities

60. • Gingival hyperplasia,
colitis,
• esophagitis, ectropion,
• and urethral strictures

61. DIAGNOSIS
• Skin biopsy
• Electron microscopy
• Antigen mapping
• Use of specific antibody probes
• Molecular diagnosis

63. Management
• Blistering becomes less frequent as age
advances
• Prevention of trauma
• Prevention of infection
• Avoidance of provocating factors
• Treatment of complications
• Usually a team approach

64. • Genetic councilling
Gold standard is identification of genetic mutation
25% recurrence rate in AR
50% recurrence in AD
• Prenatal Diagnosis
• Fetoscopy
• CVS
• Amniocentesis

65. Skin Infection
• Water or air mattress to reduce friction
• Loose fitting clothing, Soft leather shoes
• Cool environment
• Adhesives are avoided, instead use paraffin
impregnates gauze for dressings
• Blisters drained by puncturing,roof left behind
• Antibiotics in severe infection

66. Treatment
• Amityptilline, Phenytoin therapy
• Vitamin E, Tetracyclines, Retinoids,
• Cyclosporin
• No much role for steroids
• PUVA therapy
• Thalidomide
• Cryotherapy
• Surgical treatment – Split thickness graft

67. Prevention & Treatment of
complications
• Digital fusion & contractures
• Dysphagia-
Liquid foods, IV administration, NG feed,
Strictures surgically corrected.
• Laryngeal invt –
• Humidification of air
• Nebulized adrenaline, steroids,
Tracheostomy

68. • Anaemia correction
• Constipation
• Proper nutrition
• Teeth – Cleaning, mouth washes, regular
examination
• Eyes – lubricants
• Gene therapy

69. • IADVL Textbook of dermatology
• Rooks Textbook of dermatology
• Fitzpatrick dermatology in General Medicine
• Fine JD, Eady RAJ, Bauer EA et al. The
classification of inherited epidermolysis
bullosa (EB): report of the Third International
Consensus meeting on Diagnosis and
Classificationof EB. J Am Acad Dermatol
2008;58:931-50