Epidermolysis bullosa

What is epidermolysis bullosa?¹

Epidermolysis bullosa is a group of genetic diseases characterised by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs:

• Epidermolysis bullosa simplex (intraepidermal). (EBS)

• Junctional epidermolysis bullosa (within the lamina lucida of the basement membrane). (JEB)

• Dystrophic epidermolysis bullosa (below the basement membrane). (DEB)

• Kindler epidermolysis bullosa (mixed skin cleavage pattern). (KEB)

Epidermolysis bullosa is also stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs.

Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa.

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal blistering disease of the skin and mucous membranes, causing blisters, scars and milia, mainly in the areas of skin prone to trauma. EBA is rare in humans.²

How common is epidermolysis bullosa? (Epidemiology)

• Population studies are complicated by the fact that this is not a uniform disease but a wide number of diseases of varying severity. It is likely that many patients with the more mild forms of EB remain undiagnosed.

• It is thought to affect 1 in 17,000 births. Around 5,000 people are affected in the UK.^{3 4}

• Males and females are equally affected.⁵

Risk factors

A positive family history increases the risk, depending upon the type of inheritance and the closeness of affected relatives.

Symptoms of epidermolysis bullosa (Presentation)^{1 5}

• The main clinical sign is the formation of blisters on the skin in areas of mechanical trauma. Depending on the cleavage layer of the skin, the blisters can be more superficial and result in erosions, as in the case of EBS, or they can be deeper and lead to ulcerations, as in the cases of JEB, DEB, and KEB.

• The blisters may be localised in the extremities or generalised, affecting different parts of the body. Skin lesions can become chronic when mechanical trauma is permanent or recurrent.

• The oral, oesophageal, tracheal, genitourinary, and ocular mucous membranes can also be affected by erosions, ulcers, and scars.
  In specific EB subtypes, changes in nails and hair can also occur.

• Progressive healing can result in contractures and/or mutilations of the extremities, microstomy, and oesophageal stricture, common features in more severe cases of DEB and KEB.

• Specific subtypes of EB associated with severe phenotypes may involve other organs and systems, such as osteoporosis, joint contractures, cardiomyopathy, renal amyloidosis, and growth retardation.

• Epidermolysis bullosa simplex (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.

Epidermolysis bullosa simplex (EBS)
EBS is a collection of disorders of keratin that produces intra-epidermal blistering with little internal involvement. Lesions usually heal without scarring. The more severe EBS subtypes include Köbner, Dowling-Meara and Weber-Cockayne forms:

• Mild EBS of the Weber-Cockayne subtype is the most common. Blisters are usually caused by an obvious (although often mild) traumatic event. Examples may include tight-fitting underwear, writing for extended periods and using adhesive dressings or plasters. 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 Köbner EBS. Dowling-Meara EBS involves oral mucosa and produces groups of herpetiform blisters. It is sometimes called EBS herpetiformis.

Junctional epidermolysis bullosa (JEB)
JEB is divided into three subgroups or types. They are, in decreasing order of severity, Herlitz (or JEB letalis), a non-lethal 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.

• Non-lethal 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 the 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.

• 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)
DEB is a group of diseases in which blisters heal with dystrophic scarring. Milia, little white papules of 1-4 mm in diameter, result from damage to hair follicles. Inheritance may be dominant or recessive. The recessive group varies from mild to severe:

• Dominantly inherited DEB (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 (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.⁶

  • 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. 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.⁶

Hemidesmosomal epidermolysis bullosa (HEB)
The newly classified HEB includes two rare conditions:

• EB with congenital muscular dystrophy, which 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, which 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.

As knowledge about the pathophysiology of EB has become more advanced, new variants of EB have been identified based on their specific genetic mutation.⁷

Investigations⁸

The diagnosis of EB is initially clinical and subsequently confirmed by immunofluorescence antigen mapping and ultrastructural examination of skin biopsies.⁹

• 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 to check for infection.

• Monitor height and weight on centile charts.

• Albumin may be low.

• If available, DNA mutation analysis may be performed.¹⁰

• When a family has had gene mapping it is possible to make an antenatal diagnosis by chorionic villus sampling or amniocentesis.¹¹

• Gastrointestinal imaging may be required - eg, if an oesophageal web is suspected.

The exact form should be identified as well as possible and genetic counselling given. Prenatal testing is possible using fetal skin biopsy, chorionic villus sampling and pre-implantation genetic diagnosis.¹²

Differential diagnosis¹³

See also separate Bullous Dermatoses (Blisters and Bullae) article.

• Benign familial pemphigus.

• Bullous pemphigoid.

• Burns.

• Congenital syphilis.

• Ectodermal dysplasia.

• Epidermolytic hyperkeratosis.

• Intrauterine infection with herpes simplex virus.

• Kindler's syndrome (a rare autosomal recessive genodermatosis characterised by congenital acral skin blistering, photosensitivity, progressive poikiloderma, and diffuse cutaneous atrophy). This is considered by some to be an EB subtype rather than a separate condition.¹⁴

• Pemphigus vulgaris.

• Porphyria cutanea tarda.

• Shabbir's 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).¹⁵

• Staphylococcal scalded skin syndrome.

• Staphylococcal pyoderma.

• Toxic epidermal necrolysis.

Management of epidermolysis bullosa^{16 17}

Patients with possible EB should be referred to a dermatologist. In England, there are four specialist centres: Birmingham Children's Hospital, Solihull Hospital, Great Ormond Street Children's Hospital, London, and St Thomas' Hospital, London.

There is no cure for EB. Treatment is symptomatic and the primary aim is to protect the skin and stop blister formation, promote healing and prevent complications. Because EB can affect so many different parts of the body, a multidisciplinary team approach is usually required.

There is no specific therapy for epidermolysis bullosa acquisita and the response to treatment is variable, usually with complete remission in children and a worse prognosis in adults with mucosal involvement. Systemic corticosteroids and immunomodulators (colchicine and dapsone) are options for mild forms of the disease, while severe forms require the use of corticosteroid therapy along with immunosuppressants, intravenous immunoglobulin, and rituximab.²

Therefore, essential aspects of management of EB include:

• Attention must be paid to facilitating wound healing. Wound care is important. Do not let crusts and fluids build up, as they facilitate infection. Topical antibiotics may be required. Avoid adhesive tape.

• Prevention of trauma to the skin reduces blistering.

• Treatment of infections.

• 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.¹⁹

• Elective tracheostomy should be considered for infants and children with those rare subtypes where airways embarrassment is a feature.

• 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 postoperative care, with static and dynamic splinting, helps to delay the onset of recurrence.²⁰

• Because of the extensive skin damage, a diet high in calories, protein and vitamins is required. Malnutrition is especially liable in the dystrophic types.²¹ A soft diet helps to reduce oral and oesophageal erosions.

• 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.

Prognosis

The effect on the quality of life is very marked and perhaps more so than with any other skin disease, particularly for the more severe forms of the disease.

Death and disability are highly variable according to type of disease. 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.²²

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.²³

Some subtypes, especially the milder EB forms, improve with age.⁵