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Inherited epidermolysis bullosa

4 March 2019, by BORGES A. S.

1 - ACKNOWLEDGEMENTS

Chapter written with the help of the EADV, the Fondation René Touraine and the Therapeutics in Dermatology

2 - OVERVIEW

Hereditary epidermolysis bullosa (EB) is a heterogeneous group of rare genetic diseases characterized by fragile skin and/or mucous membrane, and it may be either local or generalized.

EB is characterized by a complex genotype-phenotype correlation because mutations within the same gene may cause more or less-severe phenotypes of the disease. There may be limited moderate blistering on primarily mechanically exposed predilection sites such as hands and feet and, at times, only becomes manifest in late childhood or adolescence. On the other hand, there may be extensive, generalized, multiorgan and fatal involvement with manifestations present at birth.

3 - SIGNS AND SYMPTOMS

Clinically, there are mechanically inducible blisters and secondary erosions, ulcerations, crusts and atrophic scar.

Some specific forms are associated with other cutaneous signs (nail involvement, alopecia, hyperpigmentation, palmoplantar keratoderma) or extracutaneous involvement (muscular dystrophy or pyloric atresia).

Additionally, in generalized severe forms, the extent and chronicity of lesions, as well as mucosal involvement, can lead to systemic complications: malnutrition, pain, joint contractures, chronic inflammation, and cutaneous squamous cell carcinoma, which results in significant morbidity and mortality.

4 - WHO GETS AND CAUSES

It is caused by mutations in genes encoding different proteins involved mainly in the structural and functional integrity of intraepidermal adhesion or dermoepidermal anchoring. So far, mutations in 20 genes have been identified and they are also expressed in other epithelialized (gastrointestinal, respiratory, urogenital tract) and mesenchymal (skeletal, muscle) organs.

EB is classified by level of skin cleavage into four groups: EB simplex, junctional EB, dystrophic EB and Kindler syndrome.

EB simplex represents the most common EB type (75-85% of all cases) and most commonly results from mutations in the genes coding for keratin 5 or 14. Since the blister cleavage occurs within epidermis, lesions tend to heal without scaring. The vast majority of patients with EB simplex show autosomal dominal inheritance, although rare autosomal recessive forms have been described.

In the junctional EB, the mode of inheritance is mostly autosomal recessive. The cleavage plane occurs at the junction of epidermis and dermis and encompasses a large disease spectrum, from severe life-treating disease to relatively mild involvement.

The dystrophic EB results from mutations in the gene coding for type VII collagen and is inherited in a dominant or recessive fashion. Mutations that lead to complete protein loss are associated with generalized severe disease forms, characterized by extreme skin fragility, excessive scaring, joint contractures, pseudosyndactyly, mutilations, severe mucous membrane involvement and complications such as malnutrition, dystrophy and growth retardation. Heterozygous mutations with residual protein expression cause milder manifestations.

Kindler syndrome, a rare subtype of inherited EB, is inherited in an autosomal recessive manner and results from mutations in FERMT1, which codes for kindling-1, a component of adhesion contacts in basal keratinocytes. It is characterized not only by skin fragility and acral blister formation (beginning at birth and decreasing with age), but also by gradual poikiloderma and photosensitivity that persist.

5 - DIAGNOSIS AND TREATMENT

Clinically suspected diagnosis of EB is confirmed by immunohistochemical examination of a skin biopsy at specialized centers in order to determine the level of cleavage and the deficient protein. This first step may be followed by genetic analysis.

No curative treatment of EB is available today.

6 - TIPS FOR MANAGING

EB requires multidisciplinary medical care, nursing, psychological and social management. This is best provided by a specialized network, involving reference centers and daily caregivers. The goal of treatment is the prevention and treatment of lesions with specific non-adherent dressings and the prevention, detection and treatment of complications, such as infections and scars. It is essential not to traumatize the skin (bandaging, friction, etc.).

The patients with more severe and generalized forms are at great risk of developing squamous cell carcionoma within chronic EB wounds.

Protein, gene or cell replacement therapy, and allogeneic bone marrow, cord blood or pluripotent stem-cell transplantation are currently being assessed.

7 - REFERENCES

1. Laimer M, Prodinger C, Bauer JW. Hereditary epidermolysis bullosa. J Dtsch Dermatol Ges. 2015 Nov;13(11):1125-33. doi: 10.1111/ddg.12774.

2. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J Am Acad Dermatol. 2009 Sep;61(3):367-84; quiz 385-6. doi: 10.1016/j.jaad.2009.03.052

3. Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C,et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014 Jun;70(6):1103-26. doi: 10.1016/j.jaad.2014.01.903.

4. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs. J Am Acad Dermatol. 2009 Sep;61(3):387-402; quiz 403-4. doi: 10.1016/j.jaad.2009.03.053.

5. Kiritsi D, Nyström A. Recent advances in understanding and managing epidermolysis bullosa. F1000Res. 2018 Jul 17;7. pii: F1000 Faculty Rev-1097. doi: 10.12688/f1000research.14974.1. eCollection 2018. Review.

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