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Epidermolysis bullosa

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Abstract

Koebner used the term 'epidermolysis bullosa (EB)' for the first time in 1886 [Koebner 1886]. The term 'hereditary EB' refers to a group of rare inherited skin diseases associated with life-long trauma induced by recurring blisters of the skin and mucous membranes caused by defects in at least eleven different genes coding for components of epidermis, basement membrane and dermis [Mitsuhashi and Hashimoto 2003].
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Prevalence estimates of EB for all races combined lie between 1:50,000 - 1:500,000. Worldwide, the number of people suffering from EB is approx. 350,000. Prevalence of all forms of EB within the European population is approx. 25 in a million. In Germany, the number of people suffering from the disease lies between 2,000 and 4,700; approx. 1,000 are severely affected [Volz et al. 2007]. Symptoms of EB are manifold and vary from moderate blistering to severe forms resulting in the death of the patient. Patients suffering from severe forms usually die in their thirties. Height and weight of juvenile patients are usually significantly below that of healthy people of the same age [Bork et al. 2008]. Their prognosis mainly depends on adequate nutrition and hence on their dental status.

Classification and pathogenesis of EB

EB is classified by clinical, genetic and, above all, ultra-structural criteria. The first classification scheme was established by Pearson in 1962 [Pearson 1962. The classification that is currently used was established in 2007 at the 'Third International Consensus Meeting on Diagnosis and Classification of EB' [Fine et al. 2008]. It considers morphologically localisable splitting levels in the skin (electron-microscopic/immunofluorescence techniques), molecular-genetic, and clinical findings. (Table, #pic#).

The following four main groups are differentiated:
  • Epidermolysis bullosa simplex (EBS): intra-epidermal (epidermolytic) blister formation,
  • Junctional epidermolysis bullosa (JEB): epidermal-dermal, junctional or intra-lamina lucida (junctiolytical or lamina lucidolytical) blister formation,
  • Dystrophic epidermolysis bullosa (DEB): sub-epidermal or sub-lamina densa (dermolytical) blister formation.
  • mixed group EB (Kindler syndrome)

Morphology and molecular biology

Epidermolysis bullosa simplex (EBS)

EBS is the most common and mildest form not associated with scarring, and a mainly autosomal dominant disorder. The various clinical EBS types (Koebner, Weber-Cockayne, Dowling-Meara, EBS with mottled pigmentation) present mutations of keratine genes K5 or K14, which code for the basement cell keratines 5 and 14. Basement cells rupture, resulting in blistering. The very rare types of supra-basal EBS are associated with ruptures within the granular layer (stratum granulosum) and acantholysis. ((Table). Recessive inherited EBS with muscular dystrophy is associated with a disorder of the hemi-desmosomal protein plectin, and EBS without muscular dystrophy with a K14 mutation [Mitsuhashi and Hashimoto, 2003; Fine et al. 2008].

Junctional epidermolysis bullosa (JEB)

JEB is always an autosomal recessively inherited disease.
The electron microscope shows rupturing between the basal cells and the basement membrane in the lamina lucida.
JEB is divided into two extensive subtypes:
  • Herlitz-type lethal junctional epidermolysis bullosa (H-JEB)
    Herlitz JEB is associated with premature death and is based on mutations of the laminin-5 gene (Laminin 332 - new nomenclature).
  • Non-Herlitz junctional epidermolysis bullosa (non-Herlitz JEB) and other forms
    Non-Herlitz JEB and other forms enclose benign EB types with a good prognosis that are differentiated in their clinical course. JEB is caused by mutations in the laminin-5 gene and type XVII collagen gene, JEB with pylorus atresia in the a6ß4 integrin gene [Mitsuhashi and Hashimoto 2003; Fine et al. 2008].

Dystrophic epidermolysis bullosa (DEB)

In the DEB group, autosomal dominant forms (Cockayne-Touraine type, Pasini type), autosomal recessive forms with generalised mutilating lesions (Hallopeau-Siemens type) and types with localised changes are differentiated. Ultrastructurally, anchoring fibrillae with type-VII collagen as their main protein are changed, or they are missing entirely due to COL7A1 gene mutations [Mitsuhashi and Hashimoto 2003; Fine et al. 2008].

Morphological and molecular diagnosis

Early clinical differentiation of EB types is difficult as babies are born covered with blisters while the typical secondary characteristics and symptoms are yet to develop. If wound healing is undisturbed, a diagnostic skin biopsy is possible even in the newborn. Cryo-cut samples are examined using an immunofluorescence microscope (antigen mapping) to determine the level of blister formation and the affected protein or the distribution of specific marker proteins, respectively. From this, the EB subtype can be determined, e.g. based on the absence of laminin 5 (as with Herlitz JEB), or because of a lack of collagen VII (as with Hallopeau-Siemens DEB). Electron-microscopic examination reveals conspicuous ultra-structures such as changed keratin filaments, hemi-desmosomes and anchoring fibrillae. Molecular-genetic mutation analysis leads to the exact diagnosis and permits the exact typing in newborn babies and even as early as in prenatal screenings. Medical family history is essential to determine the type of inheritance, particularly the minimal manifestations (tooth or nail anomalies without blistering) in other members of the family [Schumann et al. 2001; Mitsuhashi and Hashimoto 2003; Fine et al. 2008].

Clinical courses

Epidermolysis bullosa simplex

EBS may be present at birth or develop in early childhood. The palms of the hands or the soles of the feet are commonly affected. Elevated ambient temperatures stimulate blistering (also referred to as 'summer blistering'). There are no other symptoms.
Occasionally, oral tissue changes occur in subtypes. Tooth development is normal. Only the subtype with mottled pigmentation may be associated with erosion of oral tissue, hypodontia or anodontia [Bork et al. 2008; Fine et al. 2008; Voigtländer V 1998].

Herlitz-type lethal junctional epidermolysis bullosa (H-JEB)

Massive blistering of skin and mucous membranes occurs at birth, followed by extensive and poorly healing erosions; granulation tissue develops on the fingertips and the buttocks as well as around the mouth. Dystrophic nails and enamel defects are further characteristics. Affected children rarely survive their first years of life due to fluid and protein loss and systemic infection [Bork et al. 2008; Fine et al. 2008; Voigtländer V 1998].

Non-Herlitz junctional epidermolysis bullosa and other forms

These groups of JEB include forms without a fatal outcome despite the occurrence of blisters already present at birth and their pronounced symptoms. Generalised forms of non-Herlitz JEB frequently involve the mucous membranes and the gastro-intestinal tract, minor atrophic skin, dystrophic nails, dental enamel defects and alopecia. These symptoms can also occur in the local forms though typically with a later onset. JEB with pylorus atresia involves the formation of blisters on mucous membrane and skin. Atresia can be managed surgically [Bork et al. 2008; Fine et al. 2008; Voigtländer V 1998].

Hereditary generalised Hallopeau-Siemens dystrophic epidermolysis bullosa

Hallopeau-Siemens DEB (estimated incidence of 1:200,000) is considered the most severe form of DEB with a particular prevalence in regions with high consanguinity and is characterised by early blister exacerbation, extensive erosion and ulcers that heal developing extensive scarring with skin atrophy and milia #pic#. Fingers and toes grow together (synechia) and remain in flexion contractures #pic#. Nail dystrophy or early loss of nails is observed in all cases #pic#. Mucous membranes are frequently affected, particularly the oral mucosa. Stenosis of the larynx or oesophagus is a frightening complication. Symptoms appear immediately following birth, as soon as the oral mucosa becomes subject to mechanical strain due to sucking of the infant. Scars will then develop on the buccal mucosa (obliterated vestibule), the lips (peri-oral strictures with restricted mouth opening) and the tongue with ankyloglossia (tongue-tie) and atrophic lingual mucosa #pic#. Dentition is delayed, sometimes teeth are impacted. The teeth are dysplastic with massive enamel defects and are highly susceptible to caries. Malnutrition (carbohydrate- and acid-rich diet) favours the development of caries resulting in eating difficulties. Retarded growth and development are a consequence of the malnutrition. Intellectual development is good. Due to flexion contractures of the fingers, syndactylies and adduction contractions of the thumb, the patients have difficulties performing oral hygiene measures (fig. 3). Normal brushing of the teeth may result in blistering. Periodontitis and subsequent loss of teeth may result in an atrophic jaw.
#pic# #pic# #pic#

The scar areas are pre-cancerous lesions that may lead to squamous cell carcinoma. Due to numerous complications (secondary infection, amyloidosis, sepsis, bleeding from erosions), life expectancy is reduced [Bork et al. 2008; Fine et al. 2008; Voigtländer V 1998].

Non-Hallopeau-Siemens dystrophic epidermolysis bullosa

Non-Hallopeau-Siemens variants of dystrophic epidermolysis bullosa occur as generalised, localised and inverse forms. The generalised form is characterised by blisters that are present immediately after birth and heal with scarring. Milia are visible. The clinical picture varies but it is milder than in Hallopeau-Siemens patients because of the absence of syndactily and mutilation. The oral mucosa is also affected by blisters and erosions resulting in distressing stenoses. Further symptoms are nail dystrophy and enamel hypoplasia. Development of atrophy and scars may have a delayed onset at an older age. The inverse form is associated with poorly healing extensive blister formation and erosions on the trunk, axilla, inguinal and genito-anal regions. Acral parts are usually not affected [Bork et al. 2008; Fine et al. 2008; Voigtländer 1998].

Dominant dystrophic epidermolysis bullosa:

Autosomal-dominant hereditary DEB involves the serious generalised Cockayne-Touraine type with hypertrophic lesions and the localised form where the acral parts are almost exclusively affected (Pasini type). Permanent, ivory-coloured papules of up to 15 mm develop, e.g. inside the oral cavity on the palate [Bork et al. 2008; Fine et al. 2008; Voigtländer 1998].

Interdisciplinary management and treatment

The objective of treatment of EB is a quality of life as normal as possible; causal treatment of EB including gene therapy is still not available [Ferrari et al. 2006]. Numerous treatment and prophylactic measures are effective. Besides interdisciplinary care by the family dermatologist, general practitioner, or paediatrician close to the patient's home, optimum care is delivered in a specialist centre were long-term treatment is provided by a team comprising a dermatologist, paediatrician, intensive care practitioner, surgeon, dentist, wound management team, physiotherapy, ergotherapy, and nutrition counselling.

Local treatment of the skin (and mucosa) is part of daily care. It is especially important to avoid trauma and heat; regular skin care (frequent application of a high-fat lotion or cream), early opening of blisters and local disinfection are essential. Topical antibiotics should be used only for a short period of time in case of secondary infection, as well as external steroids for the treatment of eczema. Vaseline or silicon-coated non stick lattice-structured gauze dressings, for example a Sofra-tulle dressing, as well as self-adherent bandages and tube bandages are good options for dressing skin defects. Surgical treatment may be required for stenosing and mutilating Hallopeau-Siemens EB, especially to loosen synechiae (attention: intubation general anaesthesia is contra-indicated!). Careful bougienage of oesophageal stenosis is possible. In severe cases, a percutaneous endoscopic gastrostomy (PEG) tube must be placed to ensure adequate long-term nutrition. Identification of causative mutations, a comprehensive understanding of pathological mechanisms of EB and the rapid development of molecular technologies will make new causal approaches to treatment possible in the future, e.g. transfer of ex vivo genetically repaired keratinocyte grafts [Ferrari et al. 2006].

Network structures have been established in order to optimise treatment of these patients improving co-operation and information exchange between treatment centres as well as with the patient. There is also close contact with patient support groups (IEB-DEBRA Germany, DEBRA UK) [Bruckner-Tuderman et al. 2007].

Dental surgical treatment aspects

Oral mucosa and teeth are involved in many forms of EB ((Table) so that dental medical care is an essential part of overall treatment; however, severe forms of the disease will always be managed in specialist centres [Finke et al. 1996].
The dentist's main task is reduction of caries and gingivitis in order to achieve absence of pain for the patient and make sure that they will be able to maintain an optimal diet. First and foremost, traumatic lesions in the oral mucosa caused, during treatment or when the patient eats coarse food, by fractured teeth or those destroyed by caries or with sharp edges, as well as defective dentures, must be prevented #pic# Newly developed blisters or erosions will lead to increased scarring of the oral mucosa.

Soft toothbrushes should always be used for oral hygiene so that trauma to the gingiva is minimised. Oral rinse with lukewarm water following each meal helps to remove food remnants as soon as possible and so reduce development of caries. It will also accelerate the healing of erosions.

Regular, close end thorough recall sessions are required for the prophylaxis and treatment of carious defects. Scar strictures of the oral mucosa, synechiae of the fingers and flexion contractures in patients with severe EB forms (Hallopeau-Siemens, Herlitz) limit the patient's own ability to perform their oral hygiene very much. Therefore, professional plaque removal is advisable, as well as sufficient fluoridation until adult age.

Dental medical treatment, and especially surgical procedures and the preparation of dentures must be carefully planned, particularly for patients suffering from more severe forms or phases of the disease. In addition to the greater sensitivity of the oral mucosa to trauma, microstomia (fig. 5) and reduced vestibular depth must be borne in mind by the dentist in case of lethal Hallopeau-Siemens DEB. These symptoms require very special adaptations to the normal process of dental treatment for the individual patient #pic#. The cheek should be held using only a finger, and the corners of the patient's mouth protected using vaseline. Use of paediatric instruments and smaller mirrors usually employed in otorhinolaryngology is usually advised. Impressions can be taken using a spoon manufactured individually in the laboratory, or a soft pre-fabricated commercially available spoon. Cotton rolls should be horizontally cut in half and always be soaked completely with water prior to removal.

In order to administer general infiltration anaesthesia, the needle must penetrate deeply to avoid separation of skin layers and thus reduce the risk of blistering. It is recommended that a small amount of the anaesthetic be delivered initially, the rest later, if required. Treatment sessions should be scheduled so as to allow possible lesions at the angles of the mouth and the oral mucosa time to heal in between. Use of chlorhexidine is advised to support wound healing and to prevent infection of the traumatised areas.
Tooth extraction should result in as little trauma as possible. Sufficient time should be made for the procedure which should proceed cautiously so as to avoid any rough manipulation of the lips and oral mucosa that would cause blistering. In principle, however, wound healing in these patients is not disturbed. Generous application of vaseline or Bepanthen® ointment to the lips is advisable. If mouth opening is restricted, local anaesthesia at an angle to the mouth will avoid painful contact if posterior extractions are necessary. If the mouth opening is severely restricted, regional block anaesthesia into the mandible is possible from outside the mouth, or La Guardia's intra-oral technique can be used. The tooth is then extracted using instruments as small as possible, such as elevators, desmotomes, root elevators, and small paediatric forceps. Frequently, only the use of elevators alone is possible as there is often inadequate room for manoeuvre of forceps within the oral cavity. If several teeth in a row are extracted, it is sensible to work from anterior to posterior in order to obtain more room and improved vision. Sedation using Midazolam is recommended so the patient will have no recollection of the procedure. However, this requires post-operative monitoring of the patient. Unlike the radical surgical approach under general anaesthesia advocated by some authors[Stavropoulos and Abramowicz 2008; Becker et al. 2004], based on our own experience in the care of EB patients, we prefer treatment under local anaesthesia and sedation using Midazolam, so as to avoid the risk of trauma to the tracheal mucosa with its potential for severe compromise of the airway.

Summary

Epidermolysis bullosa (EB) represents a group of hereditary diseases associated with blistering due to trauma. This is caused by changes of structural proteins of the epidermis and basement membrane of the skin because of gene mutation. EB is classified according to immuno-pathological, ultra-morphological, molecular-genetic, and clinical findings. The skin and mucous membrane are usually affected though tooth dysplasia, muscular dystrophy, syndactyly, oesophageal stenosis, or pylorus atresia may also occur. The clinical picture includes early lethal forms with pronounced symptoms and mild localised forms as well as minimal lesions without any blistering that are often misinterpreted. Primary diagnosis of the minimal forms is possible in different medical disciplines. Nowadays, precise diagnosis of this rare disease is possible at a very early stage. However, despite approaches in gene therapy, causal treatment is still not known. Therefore, treatment of symptoms and optimal interdisciplinary management are essential. Involvement of the mucous membranes in more severe forms, such as dystrophic epidermolysis bullosa, leads to limited options for oral hygiene and the intake of food in almost all of these patients resulting in massive destruction of teeth. Therefore, dental hygiene is very important in the course of inter-disciplinary medical care.

Table

Splitting level Main EB
group
Main EB
subgroups
EB subgroups Mucosal lesion Tooth dysplasia/caries Target protein
Intra-epidermal 'epidermolytic' EB simplex Suprabasal EBS - lethal acantholytic EBS ++   desmoplakin
- EBS deficient in plakophillin + plakophilin-1
- superficial EBS   ?
basal EBS - localised Weber-Cochayne EBS + keratin 5 and 14
Dowling Meara EBS + keratin 5 and 14
- generalised Koebner EBS +/- keratin 5 and 14
- Kallin EBS with mottled pigmentation + anodontia keratin 5
- EBS with muscular dystrophy     plectin
- EBS witj pylorus atresia ++ a6ß4 integrin
- Ogna EBS + plectin
Intra-lamina lucida
'lamina lucidolytic'
junctional EB Herlitz JEB Herlitz JEB +++ +++/+++ laminin 5 (laminin 332)
other forms of JEB - generalised JEB, non-Herlitz JEB (atrophic benign EBS) +++ +++/+++ laminin 5
collagen XVII
localised non-Herlitz JEB + +++/+++ collagen XVII
- JEB with pylorus atresia +/- + a6ß4 integrin
- inverse JEB +/- +/+ laminin 5
late onset JEB +/- + ?
Sub-lamina densa
'dermolytic'
dystrophic EB dominant DEB generalised Cockayne-Touraine DDEB +++   collagen VII
- acral (Pasini) DDEB ++  
- pre-tibial DDEB   -/+++
- pruriginous DDEB    
- nail DDEB    
- DDEB bullous dermolysis of the newborn   -/+++
recessive DEB - severe generalised Hallopeau-Siemens RDEB +++ -/+++ collagen VII
- generalised DREB +++  
- inverse DREB +++ -/+
- pre-tibial DREB    
- pruriginous DREB    
- centripetal DREB +  
- DREB bullous dermolysis of the newborn    
mixed forms Kindler syndrome     ++   kindlin-1
EB epidermolysis bullosa
EBS epidermolysis bullosa simplex
JEB junctional epidermolysis bullosa
DEB dystrophic epidermolysis bullosa
DDEB dominant dystrophic epidermolysis bullosa
DREB recessive dystrophic epidermolysis bullosa