EB TYPES

Classification of EB into four main types is based on where splitting occurs in the different layers of skin. Reclassification of the condition takes place when new genes and clinical subtypes have been identified.

The information on this page has been sourced from Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility published in February 2020.

 
Skin layers.PNG

In EB simplex (EBS), splitting occurs within the upper layer of the skin, the epidermis. In junctional EB (JEB), splitting occurs within the structure that keeps the epidermis and the underlying dermis together, the basement membrane. In dystrophic EB (DEB), splitting occurs below the basement membrane within the superficial dermis. In Kindler EB (KEB), blistering can occur at multiple and different levels within the skin.

 

EB SIMPLEX

EBS is the most common EB type consisting of three main subtypes

JUNCTIONAL EB

Less common than EBS or DEB, there are two main subtypes for JEB

DYSTROPHIC EB

DEB can be dominant or recessive with two major subtypes for each

KINDLER EB

The rarest form of inherited EB, KEB does not have subtypes

 
 

EB SIMPLEX (EBS)

EBS is the most common EB type comprising three main subtypes:

Localized EBS (previously known as Weber-Cockayne)

Intermediate EBS (previously known as EBS generalized severe, EBS Köbner)

Severe EBS (previously known as EBS generalized severe, EBS Dowling-Meara)

What are the common clinical symptoms of these EBS subtypes?

Blistering happens in the upper layer of the skin causing erosions and crusts. Blisters can heal with hyperpigmentation (darkening of the skin). Blistering is made worse by heat, humidity, and sweating. Blistering tends to decrease during adolescence when it may only appear on the hands and feet. Milia (small, hard, pale nodules) may appear in the first weeks of life and EB naevi (birthmarks or moles) are common. Plantar keratoderma (the thickening of the skin on the soles of the feet) develops gradually, which can be painful and reduce mobility. Nails may be thick and dystrophic (appear damaged, misshapen, discoloured, and curvy), particularly in EBS severe. Hair is not affected.


Which genes are affected?

The main EBS subtypes are caused by variants in the genes containing information needed to make keratin 5 and 14.

How is it inherited?

In most cases, EBS is inherited in an autosomal dominant manner (de novo inheritance is also possible). Although autosomal recessive inheritance is possible, it is rarer.

Rare subtypes of EBS

There are a number of rare subtypes of EBS. Click on Rare subtypes of EBS below to find out more about the symptoms and affected genes of each.

 

LOCALIZED EBS

Blistering starts at birth or in early infancy and mainly appears on the hands and feet.

INTERMEDIATE EBS

Blistering starts at birth and is generalised but less severe.

 

SEVERE EBS

Ulcerated areas on the hands, feet, and nails, as well as blistering, are common at birth and the skin is noticeably fragile. Large tense blisters can appear after minimal trauma or spontaneously in the neonatal period. In infants, the oral mucosa (the mucous membrane lining the inside of the mouth) is also usually affected, reflux can occur, and stunted growth is common. Confluent palmoplantar keratoderma (widespread thickening of the skin on the palms of the hands and soles of the feet) is mostly seen in severe EBS. Neonatal complications associated with severe EBS can be life threatening in the first year of life.

 
 
JEB.PNG
 

JUNCTIONAL EB (JEB)

JEB is considered less common than simplex or dystrophic EB and comprises two main subtypes:

Intermediate JEB (previously known as JEB generalized intermediate, non-Herlitz JEB)

Severe JEB (previously known as JEB generalized severe, Herlitz JEB)


What are the common clinical symptoms of these JEB subtypes?

Blistering starts at birth or shortly afterwards and occurs within the basement membrane structure that keeps the upper and lower levels of skin together. Blisters tend to rupture leaving erosions, which can become extensive. Areas of ulcerated skin may be present at birth, most commonly on the lower limbs or top of the feet and ankles. Blisters and ulcers may heal with atrophic (indented or pitted) scarring and variable hypopigmentation (lightening of the skin) or hyperpigmentation (darkening of the skin). The oral mucosa (the mucous membrane lining the inside of the mouth) and eyes are usually affected. Corneal blistering and erosions are common; pannus formation (growth of fine blood vessels onto the clear corneal surface), scarring, and symblepharon (adhesion of the inner eyelid to the outer surface of the eyeball) may follow episodes of blistering. Scarring and non-scarring alopecia (hair loss) and thinning of the hair can also occur. Anaemia is common in severe JEB and, to a lesser extent, in intermediate JEB. Dental enamel is also affected.


Which genes are affected?

The main JEB subtypes are caused by variants in the genes containing information needed to make laminin 332. Variants of the type XVII collagen gene (COL17A1) can also result in intermediate and rarely in severe JEB phenotypes.


How is it inherited?

JEB is inherited in an autosomal recessive manner.

Rare subtypes of JEB

There are a number of rare subtypes of JEB. Click on Rare subtypes of JEB below to find out more about the symptoms and affected genes of each.

 

INTERMEDIATE JEB

Blistering is generalised but less severe and does not usually tend to develop chronic granulation tissue (although this can occur in chronic wounds). EB naevi (birthmarks or moles) may occur. Development of cutaneous squamous cell carcinoma (SCC) can happen in adulthood. Nails are usually lost or thick and dystrophic (appear damaged, misshapen, discoloured, and curvy), or with ridging of the nail plate.

SEVERE JEB

There may be few blisters during the first couple weeks of life tending to occur on the buttocks, elbows, and around the nails. From a few weeks to months of age, wounds may become chronic with a bed of friable (highly delicate) granulation tissue, which commonly affects the face, ears, and tips of the fingers and toes. Persistent large wounds on the region of the buttocks are common.
Laryngeal mucosa (the mucous membranes of the voice box) is affected with blistering, erosions, granulation tissue, and scarring leading to hoarseness, stridor (high-pitched wheezing), and potentially life-threatening airway obstruction. All nails are lost in the first few months of life with the development of friable granulation tissue and soft tissue swelling of the tips of the fingers and toes. Sadly, severe JEB usually results in death in the first 24 months of life due to failure to thrive, affected airway, or sepsis.

 
 
 

DYSTROPHIC EB (DEB)

DEB may be inherited as a dominant (DDEB) or recessive (RDEB) trait. Major subtypes of DEB include:

Localized DDEB (previously encompassing nails only, pretibial, and acral DDEB)

Intermediate DDEB (previously known as generalized DDEB)

Intermediate RDEB (previously known as RDEB generalized intermediate, non-Hallopeau–Siemens RDEB)

Severe RDEB (previously RDEB generalized severe, Hallopeau–Siemens RDEB)

What are the common clinical symptoms of these DEB subtypes?

EB naevi (birthmarks or moles) may appear. The oral mucosa (the mucous membrane lining the inside of the mouth) may be affected with blistering, erosions, and scarring but changes are most extensive and marked in severe RDEB. Constipation and recurrent blistering and fissuring (cracking/splitting) around the anal margin (the area at the opening at the end of the bowel) are common in all forms of DEB, particularly the more severe types.


Which genes are affected?

All subtypes of DEB are caused by variants in the genes containing information needed to make collagen VII (COL7A1).


How is it inherited?

DDEB is inherited in an autosomal dominant manner (de novo inheritance is also possible).

RDEB is inherited in an autosomal recessive manner.


Rare subtypes of DEB

There are a number of rare subtypes of DEB. Click on Rare subtypes of DEB below to find out more about the symptoms and affected genes of each.

 

LOCALIZED DDEB

Skin is usually fragile from birth or early childhood but limited to certain areas, mainly the fingers, toes, and nails. Sometimes only the nails are affected with progressive dystrophy (appearing thickened, damaged, misshapen, discoloured, and curvy) and loss, mainly of the toenails. Some people have blistering and scarring that mainly appears on skin covering the shinbone; these symptoms may not develop until later childhood or adulthood. The risk of developing squamous cell carcinoma (SCC) is also increased (albeit it to a lesser extent) and is less common than in severe RDEB and occurs later in adulthood.

INTERMEDIATE DDEB & RDEB

Although the recessive form tends to be more severe, it is usually not possible to tell the difference between these two types based on symptom appearance alone. Skin fragility, scarring, and milia (small, hard, pale nodules) are more generalized from birth or early childhood and tend to appear on bony areas like elbows, knees, ankles, and tops of the hands and feet. Mild flexion contractures (joints that cannot be straightened) or a striated-pattern of keratoderma (thickening of the skin) of the fingers, and limited fusion of the spacing between the fingers may occur, particularly in intermediate RDEB. The risk of developing squamous cell carcinoma (SCC) is also increased but less common than in severe RDEB and occurs later in adulthood. Oesophageal blistering and scarring are common. The eyes are usual affected leading to corneal erosions, pannus formation (growth of fine blood vessels onto the clear corneal surface), scarring, symblepharon (adhesion of the inner eyelid to the outer surface of the eyeball), and reduced clarity of vision. There may be a lack of sufficient nutrition owing to factors affecting eating, including oesophageal blistering, and increased metabolic demands due to chronic wounds, infection, and inflammation.

 

SEVERE RDEB

Skin blistering is widespread from birth with significant fragility from minor skin trauma. Chronic wounds are frequent in areas of repeated blistering. From infancy, blistering is more marked on bony areas causing extensive scarring that can lead to flexion contractures of the large joints (joints that cannot be straightened). Progressive pseudosyndactyly (fusion of the fingers and toes), flexion contractures, and resorption of the bone of the end of the fingers and toes lead to mitten deformities of the hands and feet. Areas of ulcerated skin is common and can appear on one or both sides of body, but in particular on the inner lower leg, and the tops of the feet and ankles. The development of aggressive squamous cell carcinoma (SCC) is very common and a frequent cause of death increasing in incidence from the teen years onwards, arising in areas of repeated trauma, wounds, and scarring. Progressive scarring leads to microstomia (contracture of the mouth) and ankyloglossia (reduced movement of the tongue), which can result in dental overcrowding and malalignment, and the development of secondary caries (cavities). Oesophageal blistering and scarring are common and urethral strictures may occur. Scarring alopecia (hair loss) and crusting are common with increasing age. Nails are usually lost progressively during the first several years of life. Anaemia due to iron deficiency and inflammation is common as is osteopenia, osteoporosis, and vertebral fractures possibly due to reduced mobility, chronic inflammation, vitamin D and calcium deficiency, and pubertal delay. Cardiomyopathy may rarely arise. Renal impairment and failure may occur as a result of acute kidney injury, post-streptococcal glomerulonephritis), renal amyloid, or IgA nephropathy. Lack of sufficient nutrition is common owing to factors affecting eating, including oesophageal blistering, microstomia, and dental caries, in combination with increased metabolic demands due to chronic wounds, infection, and inflammation.

 
 
 

KINDLER EB (KEB)

Kindler EB (previously known as Kindler Syndrome) is a rare form of EB.


What are the clinical symptoms?

Skin blistering can occur at multiple and different levels within the skin, which begins at birth and is generalised with a tendency to affect the extremities. The tendency to blister decreases with age. Skin atrophy and poikiloderma (skin becomes discoloured) start on the top of the hands and on the neck during childhood and extends throughout the skin. There is widespread palmoplantar keratoderma (thickening of the skin on the palms of the hands and soles of the feet) and loss of dermatoglyphs (ridges and lines of the skin on the hands, such as fingerprints). Photosensitivity is of variable severity. Squamous cell carcinoma (SCC) SCC on extremities, lips, or oral cavity develop in young adulthood, have a severe course and cause premature death. Gingivitis (inflammation of the gums) with tooth loss, gingival hyperplasia (overgrowth of gum tissue around the teeth), oesophageal strictures, and colitis (inflammation of the large intestine) have been seen in a few cases. Urogenital strictures, ectropion (eyelid turns outwards), corneal erosions, and nail dystrophy (appearing thickened, damaged, misshapen, discoloured, and curvy) can occur. Scalp hair is not affected.

Which genes are affected?

KEB is caused by variants in the gene containing information needed to make Fermitin family homolog 1.


How is it inherited?

KEB is inherited in an autosomal recessive manner.

 
 

Find out about what causes EB and the three different ways it can be inherited

Find out about the two main methods that are used in the laboratory to diagnose EB

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