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GENETIC EPIDERMOLYSIS      BULLOSA PRESENTER – DR.AMAL SHYAM   MODERATOR – DR.BIFI JOY
DEFINITION• Group of genetically determined skin fragility  disorders characterised by blistering of skin  and mucosae fol...
• Its current name, ‘epidermolysis bullosa  hereditaria’, was coined by Koebner in 1886.• Simplex and dystrophic EB were c...
Prevalence and Incidence• Mainly derived from National EB Registry  (USA) Project• There is no gender, racial, ethnic or  ...
LAMINAEPIDERMOLYTIC                     LUCIDO LYTIC                EB DERMOLYTIC            MIXED
EPIDERMOLYTIC BULLOSA SIMPLEX• Supra basal              • Basal• Plakophilin deficiency   •   Localised EBS• Lethal acanth...
Molecular Pathology• In all forms of EB simplex, blister formation is  intra epidermal• Most EB subtypes begin with the di...
• Most severe form of EB simplex, the Dowling–  Meara subtype - missense mutations in the  initiation or termination pepti...
• In EB simplex with mottled pigmentation is due to  mutations of the globular head domain of keratin 5,  that binds with ...
• AR EBS caused by keratin 14 knock out  mutation• Extremely rare entities, plakophilin deficiency  and lethal acantholyti...
Localised EB simplex• Weber cockayne EBS• Most common type of EB• Palms and soles mainly affected• Most have blisters only...
•   Hyperhydrosis is common.•   Blisters heal with no milia or scar formation•   25% develop intra oral lesions, palatal• ...
Dowling-Meara EBS• EB Herpetiformis• Blisters occur in groups, heals without scar• Blistering is severe and extensive – in...
• Spontaneous herpetiform, annular,  or arcuate blistering on the trunk,  limbs, neck• Healing with hyperpigmentation• Irr...
Generalized EBS, non Dowling-Meara                  variant•   Koebner EBS•   Usually mild, 60% localized scarring, 16% mi...
EBS Ogna•   AD•   Named after a village in Norway•   Seasonal blistering of hands and feet•   Generalised bruising tendenc...
EBS with mottled pigmentation• Pigmentary changes present at birth or appear  during infancy• Reticulate pattern of small,...
AR EBS with neuromuscular disease•   Muscular dystrophy, Myasthenia gravis, SMA•   Muscle weakness and wasting severe•   B...
Lethal acantholytic EB•   Mutation in gene for desmoplakin•   AR•   Present at birth, Generalized•   Presence of oozing er...
Plakophilin-1 deficiency• AR form of ectodermal dysplasia• Mutation in plakophilin-1 gene• Generalized, appears at birth.•...
Epidermolysis bullosa simplex            superficialis• Epidermal cleavage is just beneath stratum  corneum• AD• Superfici...
Junctional epidermolysis bullosa• All variants AR inheritance• Blister formation at the level of Lamina lucida• Indetermin...
• Types      Herlitz JEB      Non Herlitz JEB      JEB, with pyloric atresia      JEB, inversa      JEB, late onset      L...
Molecularpathology• Clean split at the level of Lamina lucida, with  closely apposed basal keratinocytes, and  continuous ...
• Abnormality in anchoring filament protein laminin  5 in the skin of patients with Herlitz and some non  Herlitz JEB• Her...
Herlitz Junctional Epidermolysis                 Bullosa• Epidermolysis bullosa letalis• Epidermolysis bullosa atrophicans...
• Eroded areas are often very slow to heal.  Healing result in atrophic scarring.• Involvement of the oral and pharyngeal ...
.• Infants die early in infancy with overwhelming  infection or from failure to thrive• Typical lesions occur symmetricall...
• Following blistering and erosions, the  formation of exuberant granulation tissue on  the nail folds and nail bed leads ...
.• Blisters may occur on the cornea, resulting in  pain, erosions, scarring, and, very rarely,  blindness• Urethral meatal...
Generalized non-Herlitz JEB• Epidermolysis bullosa atrophicans generalisata  mitis• Generalized atrophic benign epidermoly...
• Teeth show severe enamel defects, fail to  erupt normally• Nails are dystropic and frequently missing• Lesions heal with...
• Pigmented nevi common• Alopecia affects scalp, eye brows, eyelashes.  Body hairs sparse or absent• Oesophageal stricture...
Localised JEB• Clinical manifestations include nail dystrophy,  dental enamel changes and blistering  involving the lower ...
Junctional EB with pyloric atresia• Level of blistering - cytoplasm of basal  keratinocytes, just above the plasma  membra...
• The teeth are hypoplastic, lacking normal  enamel, and the nails are dystrophic.• Early attempts at feeding result in no...
Late onset JEB• Epidermolysis bullosa progressiva• The onset is delayed until childhood or  adolescence, and nail dystroph...
• Condition was originally named EB  dystrophica–neurotrophica by Gedde-Dahl  because of the association of partial deafne...
Cicatricial JEB• Bistering heal with scarring and result in loss  of nails, alopecia, syndactyly and contractures.• Involv...
LOC syndrome• Laryngo-onycho-cutaneous syndrome• Shabbir’s syndrome• Chronic erosive lesions affect the face, mainly  arou...
Dystrophic Epidermolysis Bullosa• Characterized by skin fragility, blistering,  scarring, nail changes and milia formation...
Molecular pathology• Both autosomal dominant and recessive forms  of dystrophic EB are caused by mutations in a  single ge...
Severe Generalized recessive DEB• Hallopeau Siemens variant• Bullae present at birth or appear in early  infancy• Clinical...
• Healing lesions produce atrophic scars like  cigarette paper.• Milia formation is a constant feature• Sites of predilect...
• Hair gowth on scalp and body impared• Scarring digits undergo progressive  contractures• Scarring Alopecia• Pseudosyndac...
• Higher incidence of caries tooth• Oesophageal involvement – Pain, dysphagia,  scarring, fibrosis, GERD, perforation• Per...
• General physical development is retarded• Can develop SCC• Delay in development of secondary   sexual changes• Patients ...
Generalized dominant DEB• Hyperplastic (Cockayne-Touraine) and  albopapuloid (Pasini) variant• AD• Skin is less fragile• B...
• Bistering in mouth is mild and teeth normal• Perianal lesions – intense pain• Clinically often impossible to distinguish...
Bullous dermolysis of newborn• AD• Blistering over limbs• Improves during childhood and remits  completely• Blisters heal ...
others• Pretibial dystrophic epidermolysis bullosa    AD , late onset    Itching, bullae, atrophy & scarring of shin• Epid...
Kindler Syndrome• AR• Mutations in FERMT1 (KIND1)• generalized blistering at birth, with some  amount of scarring.• Kerato...
• 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...
• Genetic councilling   Gold standard is identification of genetic mutation    25% recurrence rate in AR    50% recurrence...
Skin Infection• Water or air mattress to reduce friction• Loose fitting clothing, Soft leather shoes• Cool environment• Ad...
Treatment•   Amityptilline, Phenytoin therapy•   Vitamin E, Tetracyclines, Retinoids,•   Cyclosporin•   No much role for s...
Prevention & Treatment of             complications• Digital fusion & contractures• Dysphagia-        Liquid foods, IV adm...
• Anaemia correction• Constipation• Proper nutrition• Teeth – Cleaning, mouth washes, regular  examination• Eyes – lubrica...
•   IADVL Textbook of dermatology•   Rooks Textbook of dermatology•   Fitzpatrick dermatology in General Medicine•   Fine ...
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
Genetic epidermolysis bullosa
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Genetic epidermolysis bullosa

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Transcript of "Genetic epidermolysis bullosa "

  1. 1. GENETIC EPIDERMOLYSIS BULLOSA PRESENTER – DR.AMAL SHYAM MODERATOR – DR.BIFI JOY
  2. 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. 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. 4. Prevalence and Incidence• Mainly derived from National EB Registry (USA) Project• There is no gender, racial, ethnic or geographical predilection for EB.
  5. 5. LAMINAEPIDERMOLYTIC LUCIDO LYTIC EB DERMOLYTIC MIXED
  6. 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
  7. 7. 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
  8. 8. • 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
  9. 9. • 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)
  10. 10. • 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
  11. 11. 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.
  12. 12. • Hyperhydrosis is common.• Blisters heal with no milia or scar formation• 25% develop intra oral lesions, palatal• Hair and teeth normal
  13. 13. 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
  14. 14. • 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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.
  20. 20. 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.
  21. 21. 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.
  22. 22. Junctional epidermolysis bullosa• All variants AR inheritance• Blister formation at the level of Lamina lucida• Indeterminate JEB
  23. 23. • Types Herlitz JEB Non Herlitz JEB JEB, with pyloric atresia JEB, inversa JEB, late onset LOC Syndrome
  24. 24. Molecularpathology• Clean split at the level of Lamina lucida, with closely apposed basal keratinocytes, and continuous lamina densa in lower part.
  25. 25. • 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
  26. 26. 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.
  27. 27. • 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
  28. 28. .• 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.
  29. 29. • 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
  30. 30. .• 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.
  31. 31. 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
  32. 32. • 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
  33. 33. • 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
  34. 34. 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.
  35. 35. 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
  36. 36. • 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.
  37. 37. 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
  38. 38. • 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
  39. 39. 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
  40. 40. 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
  41. 41. 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
  42. 42. 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,
  43. 43. 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
  44. 44. • 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
  45. 45. • 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
  46. 46. • 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
  47. 47. • General physical development is retarded• Can develop SCC• Delay in development of secondary sexual changes• Patients die by 3rd or 4th decade.
  48. 48. 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
  49. 49. • Bistering in mouth is mild and teeth normal• Perianal lesions – intense pain• Clinically often impossible to distinguish from Dominant DEB• Good long term prognosis
  50. 50. Bullous dermolysis of newborn• AD• Blistering over limbs• Improves during childhood and remits completely• Blisters heal without atrophic scarring
  51. 51. 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
  52. 52. 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
  53. 53. • Gingival hyperplasia, colitis,• esophagitis, ectropion,• and urethral strictures
  54. 54. DIAGNOSIS• Skin biopsy• Electron microscopy• Antigen mapping• Use of specific antibody probes• Molecular diagnosis
  55. 55. 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
  56. 56. • Genetic councilling Gold standard is identification of genetic mutation 25% recurrence rate in AR 50% recurrence in AD• Prenatal Diagnosis• Fetoscopy• CVS• Amniocentesis
  57. 57. 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
  58. 58. Treatment• Amityptilline, Phenytoin therapy• Vitamin E, Tetracyclines, Retinoids,• Cyclosporin• No much role for steroids• PUVA therapy• Thalidomide• Cryotherapy• Surgical treatment – Split thickness graft
  59. 59. 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
  60. 60. • Anaemia correction• Constipation• Proper nutrition• Teeth – Cleaning, mouth washes, regular examination• Eyes – lubricants• Gene therapy
  61. 61. • 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
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