Epidermolysis Bullosa

Synonym: EB

This is a group of inherited disorders with blister formation in response to mechanical trauma. For the future, new treatments, based on a better understanding of the basement membrane zone and the genes responsible for its components, may include gene or protein therapy to counter the skin fragility.¹
Epidermolysis bullosa is a wide spectrum of inherited diseases and a search of OMIM for that title gives 80 results.²

The structure of normal skin³

In order to understand the pathophysiology of EB, it is necessary to have some knowledge of the anatomy of the dermis.The lowest layer is called the basement membrane zone (BMZ). It is a specialised structure that forms the junction of epithelial cells and the connective tissue adjacent to them, and it forms an anchor for various skin elements such as sweat glands. The junction between the dermis and the epidermis is conventionally divided into four layers:

1. The cytoskeleton consisting of two elements; basal keratocytes stuck firmly to the dermis by hemidesmosomes
2. The lamina lucida, an electron-lucent region that lies beneath basal keratocytes
3. The lamina densa, an electron-dense plate situated below the lamina lucida and above the papillary dermis
4. The sub-lamina densa seated immediately below the lamina densa and consisting of the uppermost portion of the papillary dermis

EBS varies from mild to very severe and even lethal. Traditionally it is classified according to skin morphology to give 3 major categories although a 4th has also been proposed:¹

• Epidermolysis bullosa simplex (EBS) involves intraepidermal skin separation.
• Junctional epidermolysis bullosa (JEB) involves skin separation in the lamina lucida or central basement membrane zone.
• Dystrophic epidermolysis bullosa (DEB) involves separation of the basement membrane zone at the sublamina densa.
• A fourth category has been proposed called hemidesmosomal epidermolysis bullosa (HEB), which produces blistering at the hemidesmosomal level in the most superior aspect of the basement membrane zone.¹ EBS usually has little or no extracutaneous involvement, while the more severe hemidesmosomal, junctional, and dystrophic forms of EB may produce significant multiorgan system involvement.

Population studies are complicated by the fact that this is not a uniform disease but a wide number of diseases of varying severity. Since 1992 there has been an epidermolysis bullosa register in the UK although it is likely that the mildest cases are omitted. It is thought to affect 1 in 17,000 births with around 5,000 sufferers in the UK. Within the Scottish population, inheritance was dominant in 88 individuals (68%), uncertain inheritance in 24 (19%) and recessive in 16 patients (13%). Within this latter group, 9 (7%) had the mutilating Hallopeau-Siemens subtype, 5 (4%) had localised (EB-loc) and 2 (2%) had a predominantly flexural (inverse) form of EB.⁴ As a general rule with inherited conditions, the more severe ones tend to be recessive and the milder ones dominant as severe dominant conditions would die out because the carriers would not live to reproduce.

Risk factors

A positive family history increases the risk depending upon the type of inheritance and the closeness of affected relatives. The mild forms are all of autosomal dominant inheritance.

History

• Presentation is usually at or shortly after birth although it may be delayed in milder cases.
• Note the age of onset, the site of blisters and the degree of trauma required to initiate them.
• Note mucous membranes including oral, respiratory, genito-urinary, naso-pharyngeal and ocular surfaces.
• Severe EB is associated with growth retardation, oesophageal strictures and other gastrointestinal abnormalities.⁵
• Urological abnormalities have also been noted.⁶
• Ask about family history.

Examination

Inspect the skin and also conjunctival, oral, and genital mucosa. Note the size, location, and character of blisters. Try to assess the general level at which lesions split. Usually, superficial blisters produce crusted erosions, intraepidermal blisters are flaccid and may expand under pressure, and intralamina lucida blisters are tense and heal with atrophy but no scarring. Sublamina densa blisters heal with scarring. Look at nails, hair and teeth.

• Epidermolysis bullosa simplex (EBS) is a collection of disorders of keratin that produces intraepidermal blistering with little internal involvement. Lesions usually heal without scarring. The more severe EBS subtypes include Koebner, Dowling-Meara and Weber-Cockayne forms.
  • Mild EBS of the Weber-Cockayne subtype is the commonest type. Blisters are usually caused by an obvious traumatic event. They can be mild to severe and most often occur on the palms and soles. Hyperhidrosis may also occur.
  • Severe EBS usually has a generalised onset with blisters at or shortly after birth. Hands, feet and extremities tend to be involved. Palmoplantar hyperkeratosis and erosions are common, especially in Koebner EBS. Dowling-Meara EBS involves oral mucosa and produces groups of herpetiform blisters. It is sometimes called EBS herpetiformis.
• Junctional epidermolysis bullosa is divided into 3 subgroups or types. They are, in decreasing order of severity, Herlitz or JEB letalis, a nonlethal subtype named JEB mitis, and a milder type called generalised atrophic benign EB (GABEB).
  • The Herlitz or letalis form shows generalised blistering at birth. There are characteristic erosions around the mouth, eyes, and nostrils, often with significant hypertrophic granulation tissue. Other involvement includes the corneal, conjunctival, tracheobronchial, oral, pharyngeal, oesophageal, rectal, and genitourinary mucosa. Internal complications may produce a hoarse cry, cough, and respiratory difficulty. There is risk of death from sepsis or other complications due to epithelial dysfunction, and they usually die in infancy.
  • Nonlethal JEB or JEB mitis produces generalised blistering in those who survive infancy and clinically improves with age. They do not normally have the same hoarse cry or other respiratory symptoms as with Herlitz form. Scalp, nail, and tooth abnormalities may become apparent. Mucous membranes are often affected by erosions that can produce strictures. Some patients with JEB mitis have blistering only in the intertriginous zones.
  • Generalised atrophic benign EB or GABEB is a relatively mild form with generalised cutaneous blistering that presents at birth. It is worse in a hot environment, and blisters heal with a distinctive atrophic appearance. Extracutaneous involvement is rare, except for teeth. Hypoplastic enamel formation causes tooth decay. Nail dystrophy and alopecia are also common. They have a normal life expectancy and ability to reproduce.
• Dystrophic epidermolysis bullosa: DEB is a group of diseases in which blisters heal with dystrophic scarring. Milia, little white papules of 1 to 4mm in diameter, result from damage to hair follicles. Inheritance may be dominant or recessive. The recessive group vary from mild to severe.
  • Dominantly inherited DEB or DDEB usually appears at birth or during infancy, with generalised blistering. With increasing age, blistering becomes more local. A common variant described by Cockayne-Touraine has a peripheral distribution and minimal oral or tooth involvement. Another variant described by Pasini shows more extensive blistering, scar-like papules on the trunk called albopapuloid lesions, and involvement of the oral mucosa and teeth. Dystrophic or absent nails are common in both of the dominantly inherited variants.
  • Recessively inherited DEB or RDEB covers a range of diseases from mild to severe.
    • The localised form is called RDEB mitis. Peripheral areas and nails are often involved but there is little mucosal involvement. It is quite similar to the dominantly inherited forms.⁷
    • Severe RDEB, as described by Hallopeau-Siemens, gives generalised blistering at birth followed by extensive dystrophic scarring, especially on the extremities. This can produce pseudosyndactyly, also called mitten-hand deformity of the hands and feet. Flexion contractures of the extremities become more common with age. Nails and teeth also are affected. Involvement of internal mucosa can result in oesophageal strictures and webs, urethral and anal stenosis, phimosis, and corneal scarring. Malabsorption may produce a mixed anaemia from iron and folate deficiency and overall malnutrition may cause failure to thrive. If they survive to childhood they are at risk of developing aggressive squamous cell carcinomas in areas of chronic erosions. Recently, the genetic mutation causing RDEB has been identified. The degree of severity depends to some extent on the location of the mutation, although other familial and environmental factors are thought to play a part.⁷
• Hemidesmosomal epidermolysis bullosa: The newly classified HEB includes 2 rare conditions.
  • EB with congenital muscular dystrophy presents initially as variable blistering. The degree of blistering does not correlate with the severity of muscular dystrophy. Some patients may have dental abnormalities.
  • EB with pyloric atresia has pyloric atresia at birth and usually severe generalised blistering. Prognosis is poor despite correction of the pyloric atresia because of extensive internal involvement. It is usually fatal in infancy but a few patients with a milder disease have survived into childhood.

• Skin biopsy is required. Routine microscopy may help to exclude other causes. To make the diagnosis, immunofluoresence is required and also electron microscopy.
• FBC and iron studies may be required in dystrophic types.
• Swabs should be taken for infection.
• Monitor height and weight on centile charts.
• Albumin may be low.
• If available, DNA mutation analysis may be performed.
• When a family has had gene mapping it is possible to make an antenatal diagnosis by chorionic villus sampling or amniocentesis.
• Gastro-intestinal imaging may be required, e.g. if an oesophageal web is suspected.

• Benign familial pemphigus
• Bullous pemphigoid
• Burns
• Congenital syphilis
• Ectodermal dysplasia
• Epidermolysis bullosa acquisita (this is much rarer than the congenital forms)⁹
• Epidermolytic hyperkeratosis
• Intrauterine infection with herpes simplex virus
• Incontinentia pigmenti
• Kindler syndrome (a rare autosomal recessive genodermatosis characterised by congenital acral skin blistering, photosensitivity, progressive poikiloderma, and diffuse cutaneous atrophy)
• Pachonychia congenital
• Pemphigus vulgaris
• Porphyria cutanea tarda
• Shabbir syndrome (an autosomal recessive epithelial disorder confined to the Punjabi Muslim population, characterised by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx)¹⁰
• Staphylococcal scalded-skin syndrome
• Staphylococcal pyoderma
• Toxic epidermal necrolysis

• There is not yet any specific cure for the disease but attention must be paid to facilitating wound healing. Steroids must be avoided and infections treated.
• Wound care is important. Do not let crusts and fluids build up as they facilitate infection. Topical antibiotics may be required. Avoid adhesive tape.
• Surveillance of chronic lesions is important as they are susceptible to undergoing malignant change to squamous cell carcinoma. Such change often occurs at multiple sites. Surgical excision is required. These lesions tend to be aggressive.
• Oesophageal lesions can be most troublesome. They are found in Hallopeau-Siemens and inverse RDEB subtypes, Dowling-Meara, letalis EBS subtypes, and all JEB forms except localised and progressiva or neurotropica. One possible approach is to use phenytoin and oral steroid elixirs to reduce the symptoms of dysphagia although generally steroids are avoided. If there is oral candidiasis, appropriate antifungal medication is helpful. Oesophageal dilatation may be required.
• Ophthalmic complications may occur in EBS, especially the Weber-Cockayne and Dowling-Meara subtypes, there may be recurrent blepharitis in one or both eyes along with bullous lesions of the conjunctivae.¹¹ In JEB and Hallopeau-Siemens DEB there may be corneal ulcerations, corneal scarring, obliteration of tear ducts, and eyelid lesions. Corneal erosions require antibiotic ointment and cycloplegic agents to reduce ciliary spasm and provide comfort. Avoid using tape to patch the eye as it may cause blistering of the skin under the adhesive.
• Elective tracheostomy should be considered for infants and children suffering from those rare sub-types where airways embarrassment is a feature.¹²
• Good dental hygiene and regular dental checks are recommended. Many patients with JEB and DEB develop dental caries because of enamel defects. Oral mucosal involvement can accompany severe forms of JEB and DEB. Avoid harsh mouthwashes containing alcohol. Normal saline rinses can help to clean the mucosal surfaces.
• Mitten-hand deformity may require surgical correction. Diligent post-operative care, with static and dynamic splinting, helps to delay the onset of recurrence.¹³
• Because of the extensive skin damage, a diet high in calories, protein and vitamins is required. Malnutrition is especially liable in the dystrophic types.^14,15
• The exact form should be identified as well as possible and genetic counselling given. Pre-natal testing is possible using fetal skin biopsy, chorionic villus sampling and preimplantation genetic diagnosis.¹⁶

• Particularly for the more severe forms of the disease, the effect on the quality of life is very marked and perhaps more so than with any other skin disease.¹⁷ A study of data collected throughout the continental United States between 1986 and 2002 by the National EB Registry showed that the risk of death during infancy and childhood was greatest in junctional EB , with cumulative and conditional risks of 40% to 44.7% by age 1 in both JEB subtypes, rising to 61.8% in children with JEB, Herlitz subtype and 48.2% in those with JEB, non-Herlitz subtype (JEB-nH) by age 15.
  
  
• Death in infancy can occur from infection. In the more severe recessive types death from skin cancer is common between the ages of 15 and 35 but in the milder, dominant forms, life expectancy is unaffected. With the Herlitz or letalis form of JEB, nearly 90% die in the first year of life. Sepsis, respiratory failure and failure to thrive are the main causes.¹⁸ Death and disability are highly variable according to type of disease.
  
  
• Some subtypes, especially the milder EB forms, improve with age.¹