Epidermolysis bullosa Flashcards
Major types of EB
- EB simplex - intra-epidermal
- Junctional EB- intra-lamina lucida
- Dystrophic EB - sublamina densa
- Kindler syndrome - mixed
Which is the most common EB
EBS
Major target protein in EBS
KRT 5 and KRT 14
Major target protein in DEB
Type VII collagen
Major target protein in JEB
Laminin 322
What are the different distributions of EB
- Inversa subtypes of JEB and RDEB: intertriginous
- Localized JEB: acral
- Pretibial DEB: exclusively to shins
- RDEB centripetalis: rare, features acral blistering followed by slow progression of disease activity toward the trunk over the years
Risk of skin cancers in EB?
- Risk of SCC: well diff in sites of chronic wounds, very difficult to treat and often recur locally, frequently metastasize –> leading cause of death after mid-adolescence
- Primarily in RDEB
- Risk of melanoma:
- cumulative risk of 2.5% by age of 12 years
- EB naevi: large, irregularly shaped, darkly pigmented melanocytic naevi –> look like melanoma but histologically fine, large sign from onset a good clue
EBS localized - which areas
Palmoplantar
What subtypes can have inversa
JEB and DEB
Which subtype has reticulated hyperpigmentation
EBS with mottle hyperpigmenration
Which organs are involved for extracutaneous manifestation
Ocular Oral GIT GU Respiratory Cardiac
Clinical of localized EBS
Infancy and third decade of life with trauma or friction induced blistering - palms and soles. Associated palmoplantar hyperhidrosis. Infants can get blistering or ulceration from trauma which resolves with age.
EB Naevi common, variable pigmentation and irregular borders (activation of melanocytes due to tissue damage)
No scarring
Can have localized with nephropathy
EBS localized with nephropathy target protein
CD151
EBS intermediate clinical and subtypes
Blistering starts at birth Mild hands, feet and extremities Worse in heat Plantar keratoderma EB naevi common Hyperpigmentation, atrophy and milia Thick or dystrophic nails
Can get with cardiomyopathy, and muscular dystrophy
EBS cardiomyopathy target protein
Kelch like member 24
EBS muscular dystrophy target protein
Plectin
EBS severe clinical
Generalized, common on hands and feet Herpetiform pattern of blisters PPK --> confluent EB naevi Atrophic scarring, milia Nails thick and dystrophic Hair not affected Mouth involved Risk in first year: infection, malnutrition, resp failure GORD Growth retardation
Can get with pyloric atresia –> really severe
EBS with mottled pigmentation clinical
Generalized skin blistering of intermediate severity
Development of mottled/reticulate pigmentation not related to sites of blistering
Focal keratoses of palms and soles
Dystrophic, thickened nails
Junctional EB intermediate genes
LAMA3, LAMB3, LAMC2 etc
Junctional EB intermediate clinical
Generalized blistering from birth, no chronic granulation tissue Ulcerated skin may be present at birth Risk of SCC in adulthood EB naevi Atrophic scarring, milia formation, dyspigmentation Oral involvement Nails dystrophic or lost Scarring or nonscarring alopecia Extra-c: Eyes: corneal blistering, erosions, pannus, scarring GIT and GU involvement Anaemia Growth retardation Protein-losing enteropathy Diarrhoea Dental enamel defects
Severe junctional EB clinical
Blistering from birth, may initially be mild then become generalized. Almost all of body surface
Blisters rupture with extensive erosions
Chronic wounds with bed of friable granulation tissue - perioroficial, face, ears, distal digits, gluteal
Areas of ulcerated skin may be present at birth
Atrophic scarring, dyspigmentation
Onychodystrophy
Friable granulation tissue and soft tissue swelling of distal digits
Alopecia
Oral and laryngeal involvement: airway obstruction, etc
Ocular: scarring, etc
GIT: protein losing enteropathy, failure to thrive, anaemia
Dental enamel defects
Death in first 24 months due to FTT, sepsis or airway involvement
Osteoporosis
JEB with pyloric atresia target protein
Integrin alpha 6 beta 4
JEB with pyloric atresia linical
Gestational hydramnios
Full thickness skin loss
Pyloric atresia
Lethal within first few weeks
JEB inversa clinical
Flexural blistering
Atrophic scarring, milia, dyspigmentation
Nail involvement
Dental abnormalities
JEB with ILD and nephrotic syndrome target protein
Integrin alpha 3
ILD - soon after birth
Nephrotic syndrome: early death
Target protein for DEB
Type 7 collagen
Localized DDEB clinical
Acral and pretibial skin fragility
Increased risk SCC
EB naevi
Progressive nail dystrophy
DDEB mutation
COLD7A1
Intermediate DDEB clinical
Generalized scar fragility, scarring and milia from birth or early childhood Bony prominences: elbows,knees, ankles Risk of SCC May have EB naevi Mucosal involvement Nail dystrophy and loss due to trauma
Mucosal: oeosphageal, blistering and fissuring around anal margin
Ocular: conjunctival involvement and corneal scarring
Nutritional impairment from oesophageal involvement + metabolic demand from wounds
Constipation
Intermediate RDEB
Again bony prominences Mutilating deformities Keratoderma striate pattern SCC EB naevi
Mucosal: oeosphageal, blistering and fissuring around anal margin
Ocular: conjunctival involvement and corneal scarring
Nutritional impairment from oesophageal involvement + metabolic demand from wounds
Constipation
Severe RDEB clinical
Widespread, bony prominences Congenital skin ulcerations High risk of SCC EB naevi Extensive scarring and flexion contractures of large joints --> mitten deformities Distal resorption of digits Oral mucosa: microstomia, dental overcrowding Nail dystrophy and loss Scarring alopecia
Oesophgeal: strictures, protein losing enteropathy, anal involvement, corneal, urethral
Nutritional impairment
Anaemia
Osteopenia
Renal impairment: 10% risk of death by age 35 –> from outflow obstruction, FN, systemic amyloidosis, IgA nephropathy
Cardiomyopathy
DDEB, pruriginosa clinical
tarts like localized or intermediate but becomes intensely pruritic - excoirated violaceous papules or linear plaques
Milia common
Nail dystrophy
JEB generalized intermediate target antigen
Type XVII collagen
Kindler syndrome target antigen
Kindlin-1
What is the recommended diagnosis for EB now
genetic testing + IFM
What are the methods for genetic testing
- NGS - Next generation sequence targeting
- Relatively rapid and effective
- Allows for prenatal diagnosis
- Can provide incidental information which may not be wanted
- WES - Whole exome sequencing
- May identify new variants of EB
- Can cause incidental findings
- SS - Sanger sequencing
- Straightfoward approach if candidate genes are obvious or have been identified by IFM or TEM
- Will miss variations in other EB genes
- May be more time consuming
- Requires pre-selction
What is IFM?
Immunofluourescence antigen mapping
- recommended to obtain a rapid diagnosis and prognosis, and to prioritize genetic testing
- High specificity and sensitivity can be reached at relatively low costs
- 4-6 mm punch or shave from an area not exposed to the sun (may create nonspecific background fluorescent, interfering with interpretation). Should include peri-lesional skin as well as a small part of a fresh blister
- Can induce a blister before taking the biopsy or after with a suction syringe
- Often a blister is created from the trauma alone
- Put in Michels medium or liquid nitrogen, and ship ASAP as cell cytolysis can occur after just 48 hours
- Then compared to normal human skin
- Recommend doing with at least one antibody for each main type of EB, as well as for antibody type 4 collagen
- Staining of the type 4 collagen to the floor of the blister is indicative of junctional or intraepidermal blister, whereas staining to the roof defined a dermal blister
- If lack of blistering –> do a TEM
- If genetic testing indicates something but no blistering –> keratinocytes/fibroblasts for expression and functional studies
- Pros: easy, rapid, may indicate protein, prognostic helpful, but may be uninformative, doesn’t give a genetic test
What is TEM?
Transmission electron microscopy
- then cut into small pieces 0.5-1 mm thick, then further processing
- Ligh microscopy examination of sections
- Allows definition of blister level
- Requires someone who knows a lot about it
- Can also see clumping of tonofilaments etc which may be seen in EBS
- Pros: identified ultrastructural stuff
- Cons: uninformative can occur, time consuming, no genetic defect
DDx for EB
- pretty minimal ddx for chronic mechanobullous diseases
- Acrodermatitis enteropathica
- IP stage 1
- Pachyonychia congenita
- Early lipoid proteinosis
- Acute blistering
- Bart syndrome: EB and congenital locazlied absence of skin
- Genoderms:
- EBS skin fragility syndromes such as Woolly hair
- Acantholytic EBS
- Acral peeling skin syndrome (transglutaminase 5)
- EBS superficialist
- Superficial epidermolytic icthysosi
- Epidermolytic ichthyosis
- Gunther
- Mendes da Costa
- AEC
EB management principles
- Prevention of mechanical trauma
- Wound care
- Soft silicone dressings are wildly used
- Silver-impregnated dressing good –> but don’t use long term due to silver absorption
- Infection avoidance
- Bathing or soaking with 0.005% sodium hypochlorite in a full standard or 0.25% acetic acid
- Antibiotics - only use when needed
- Hyperhidrosis treatment: aluminium chloride hexahydrate, botox
EB dressing recommendations
Soft silicone: mepilex, mepitel, for primary or secondary
Non-adherent lipido-colloid dressings
Hydrogel dressings - provide moisture to drier wounds
Foam dressings - absorb moderate amounts of wounds - Mepilex, Allevyn
Absorptive dressings - for heavy exudate
Silver containing dressings - for colonized or infected - Mepilex
Systemic agents for EB management
- Phenytoin: for JEB and RDEB, not effective in RCTR
- Tetracyclines or erythromycin for EBS
- Thalidomide and cyclosporin in DEB pruriginosa
- Systemic retinoids: jury is out as to whether prevents SCCs in this group
Excessive caries management
Oral hygiene
Antiseptic and fluoride
Dentist
Microstomia management
Physical therapy
Mouth expanding devices
Oral ulceration management
Topical antiseptics
NSAIDs
barriers
GIT management
Dietary modification
PPI
H2 blocker
Gastro
Nutritional management
Check growth and vitamins and minerals
Refer to dietician
Anaemia management
Monitor Iron EPO Transfusion gen paeds
Urinary outflow obstruction
Annual USS of UT
urology
Renal disease mgmt
Monitor every 6 months - U/A, UEC, BP
Osteopaenia management
Annual DEXA scan at age 5 on for RDEB and JEB, calcium and vitamin D
Consider bisphosphonate
Pseudosyndactyly of hands/feet management
Splints
Wrapping of fingers in RDEB
Surgeons
SCC monitoring
Skin exams for RDEB every 3-6 months starting from age 10, and every 3 months after 16 years
Serial photos
Ocular management
Ophthal –> can do amniotic membrane transplantation
When to monitor for cardiac
Annual TTE in late childhood for RDEB
Pathogenesis of Kindler syndrome
- Basement membrane reduplication and mixed planes of cleavage: can be in stratum basale, lamina lucida, lamina densa
- FERMT1 mutation: involved in actin filaments in basal keratinocytes to underlying ECM
- Kindlin-1: affects keratinocyte normality, and also regulates stem cell homeostasis –> increased risk of skin cancer if gone
Kindler clinical
- At birth - forearms, shins
- Blistering - hands and feet
- Skin fragility - decreases with age
- Photosensitivity - increased burning, reticulated hyperpigmentation, telangiectasias in sun exposed sites –> moves to sun protected sites
- Poikiloderma: persists throughout life
- Mild webbing
- Palmoplantar hyperkeratosis
- Eczema –> resolves by early childhood
- Extracutaneous:
- Erosive gingivitis and poor dentition
- Intraoral and corneal scarring, ectropian, colitis
- Strictures of oesophagus, urethra, vagina, anus
- Increased risk of SCC
