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Epidermolysis bullosa

Abstract

Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality. Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. The study of EB has led to seminal advances in our understanding of cutaneous biology. To date, pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion. Precise diagnosis is reliant on correlating clinical, electron microscopic and immunohistological features with mutational analyses. In the absence of curative treatment, multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which — and also the leading cause of mortality — is squamous cell carcinoma. Preclinical advances in cell-based, protein replacement and gene therapies are paving the way for clinical successes with gene correction, raising hopes amongst patients and clinicians worldwide.

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Fig. 1: The cutaneous dermal–epidermal junction.
Fig. 2: Tumorigenesis in recurrently blistered and chronically inflamed EB skin.
Fig. 3: Clinical images of EB.
Fig. 4: Diagnostic algorithm for EB.
Fig. 5: TEM of EB biopsy specimens.
Fig. 6: Immunofluorescence microscopy and genetic analysis in EB.
Fig. 7: Extracutaneous manifestations in EB.

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Contributions

Introduction (A.B., N.H. and A.H.H.); Epidemiology (J.-D.F.); Mechanisms/pathophysiology (L.B.-T., C.H., T.M.M., M.P.M. and J.F.M.); Diagnosis, screening and prevention (A.B., N.H. and A.H.H.); Management (L.B.-T., M.P.M. and J.E.M.); Quality of life (I.L.C.C., J.E.M. and R.P.); Outlook (J.A.M.); Overview of the Primer (A.B. and A.H.H.).

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Correspondence to Ajoy Bardhan or Adrian H. Heagerty.

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Glossary

Mechanobullous disorder

A group of inherited disorders characterized by skin fragility and blister formation secondary to trauma.

Poikiloderma

A cutaneous change showing concurrent atrophy (thinning), telangiectasia (visible blood vessels), hypopigmentation and hyperpigmentation.

Hemidesmosome

A structure at the lower surface of basal keratinocytes, extending from the intracellular compartment to the lamina lucida, with a critical role in adhesion and implicated in keratinocyte migration.

Desmosome

A specialized junctional complex in the lateral surface of plasma membranes enabling cell–cell adhesion.

Thermolability

The susceptibility of a substance to change (or destruction) in response to heat.

Null mutations

Genetic mutations that result in a complete lack of functional protein product or no protein production at all.

Hyperkeratosis

Abnormal thickening of the stratum corneum, the outermost layer of the skin.

Shave biopsy

A surgical procedure whereby a thin layer of skin is removed with a sharp blade for the purpose of microscopic examination.

Germline mosaicism

Occurs when more than one set of genetic information is present in the gamete cells, arising owing to mutations that occur post-conception.

Uniparental isodisomy

The inheritance of both copies of a chromosome, or part of a chromosome, from a single parent, with no copies received from the other parent.

Chorionic villus sampling

Prenatal sampling of placental tissue during early pregnancy, undertaken via the cervix or through the abdomen to screen for chromosomal or genetic abnormalities in the developing fetus.

Amniocentesis

The sampling of amniotic fluid during pregnancy via insertion of a needle into the uterus to screen for abnormalities in the developing fetus.

Oesophageal webs

Thin mucosal membrane webs that project into the oesophageal lumen causing constriction, making swallowing difficult.

Erythropoietin

A glycoprotein hormone secreted by the kidney in response to hypoxia to stimulate erythrocyte (red blood cell) production or erythropoiesis in the bone marrow.

Blepharitis

Inflammation of the eyelid.

Pannus

An abnormal growth of granulation or fibrovascular tissue.

Symblepharon

Adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva.

Revertant mosaicism

Spontaneous abolition of pathogenetic mutations within somatic cells of an affected individual; in epidermolysis bullosa, this results in localized areas of unaffected skin due to expression of functional protein.

CRISPR–Cas9

Adapted from a naturally occurring bacterial immune mechanism, CRISPR-associated protein 9 (Cas9) is an enzyme that uses clustered regularly interspaced short palindromic repeats (CRISPR) sequences as a guide to perform cleavage of specific DNA strands, enabling precise genome editing.

Holoclone

Colony-forming keratinocyte stem cells with the greatest replicative capacity in which <5% of the cells in a clone abort and undergo terminal differentiation.

Meroclones

Colony-forming keratinocytes with a mix of reproductive capacity between that of holoclones and paraclones.

Paraclones

Colony-forming keratinocytes characterized exclusively by cells of limited reproductive lifespans, not more than 15 generations, following which they abort and undergo terminal differentiation.

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Bardhan, A., Bruckner-Tuderman, L., Chapple, I.L.C. et al. Epidermolysis bullosa. Nat Rev Dis Primers 6, 78 (2020). https://doi.org/10.1038/s41572-020-0210-0

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