GENETIC EPIDERMOLYSIS BULLOSA

PRESENTER – DR.AMAL SHYAMMODERATOR – DR.BIFI JOY

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’.

• 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

Prevalence and Incidence

• Mainly derived from National EB Registry (USA) Project

• There is no gender, racial, ethnic or geographical predilection for EB.

EPIDERMOLYTIC

LAMINA LUCIDO LYTIC

DERMOLYTIC

MIXED

EB

EPIDERMOLYTIC BULLOSA SIMPLEX

• Supra basal• Plakophilin deficiency• Lethal acantholytic

EBS• EBS superficialis

• Basal• Localised EBS• EBS, Dowling-Meara• EBS, Generalized other• EBS,AR• EBS-Mottled hyperpig• EBS, Muscular dystrophy• EBS, Ogna• EBS, Migratory circinate• EBS, Pyloric atresia

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

• 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

• 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)

• 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

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.

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

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

• 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

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

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

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

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

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.

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.

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.

Junctional epidermolysis bullosa

• All variants AR inheritance• Blister formation at the level of Lamina lucida

• Indeterminate JEB

• Types Herlitz JEB

Non Herlitz JEB JEB, with pyloric atresia JEB, inversa JEB, late onset LOC Syndrome

Molecular pathology

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

.

• 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

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.

• 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

.• 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.

• 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

.• 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.

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

• 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

• 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

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.

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

• 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.

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

• 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

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

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

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

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,

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

• 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

• 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

• 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

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

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

• Bistering in mouth is mild and teeth normal• Perianal lesions – intense pain• Clinically often impossible to distinguish from

Dominant DEB• Good long term prognosis

Bullous dermolysis of newborn

• AD• Blistering over limbs• Improves during childhood and remits

completely• Blisters heal without atrophic scarring

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

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

• Gingival hyperplasia, colitis,

• esophagitis, ectropion,• and urethral strictures

DIAGNOSIS

• Skin biopsy

• Electron microscopy

• Antigen mapping

• Use of specific antibody probes

• Molecular diagnosis

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

• Genetic councilling Gold standard is identification of genetic mutation 25% recurrence rate in AR 50% recurrence in AD

• Prenatal Diagnosis• Fetoscopy• CVS• Amniocentesis

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

Treatment

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

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

• Anaemia correction• Constipation• Proper nutrition• Teeth – Cleaning, mouth washes, regular

examination• Eyes – lubricants

• Gene therapy

• 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

References

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