Inherited epidermolysis bullosa: update on the clinical and genetic aspects

Abstract

Inherited epidermolysis bullosa is a group of genetic diseases characterized 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), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is 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. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.

Keywords: Epidermolysis bullosa; Inheritance patterns; Skin diseases,; genetic.

Figure 1

Schematic representation of the skin layers associated with the different types of epidermolysis bullosa (EB). In the epidermis, keratinocytes are depicted. The epidermis is attached to the dermis by the basement membrane, formed by the lamina lucida and lamina densa. On the left side of the figure, each type of EB is presented next to the respective skin layer in which the formation of blisters occurs. Cleavage in EB simplex (EBS) occurs within the basal keratinocytes; in junctional EB (JEB), within the lamina lucida; and in dystrophic EB (DEB) occurs in the sublamina densa, in the upper portion of the dermis (papillary dermis). In Kindler's EB (KEB), cleavage can occur in the basal keratinocytes, in the lamina lucida, or below the lamina densa. On the right side of the figure, the main adhesion complexes of the skin layers that are associated with the EB subtypes are shown. Highlighted are hemidesmosomes, anchoring filaments, and anchoring fibrils, which play an essential role in the stable adhesion of the basal keratinocytes of the epidermis to the basement membrane area and for the connection of the lamina densa to the upper portion of the dermis.

Figure 2

Clinical aspects of epidermolysis bullosa simplex (EBS). (A‒C) Plantar keratoderma, dystrophic and thick nails on the hands and feet of patients with localized EBS. (D‒F) Blisters and erosions distributed in a generalized way in patients with intermediate EBS. The presence of epidermolysis bullosa nevi is common in all subtypes of EBS.

Figure 3

Schematic representation of the complexes and proteins associated with the different subtypes of epidermolysis bullosa simplex (EBS). Changes in structural components of hemidesmosomes, intermediate keratin filaments, and cell vesicle transport support the spectrum of EBS phenotypes. Only proteins associated with EBS are shown in the figure.

Figure 4

(A) Schematic representation of the keratin intermediate filament network. The keratin filaments connect to the hemidesmosomes to ensure attachment to the underlying basement membrane and to the desmosomes to ensure cell-cell contact in the keratinocytes. A representation of the molecular configuration of the K5/K14 heterodimer, the smallest subunit that forms the intermediate filaments, is shown at the bottom of figure A. (B) Organization of keratin domains. Keratins have a central α-helix rod domain containing four segments (1A ‒ B, 2A ‒ B), which are interrupted by three binding domains (L1, L12, and L2). The rod domain has highly conserved motifs (HIP and HTP) at its ends, often associated with the most severe cases of severe EBS. Variants in the binding domains are generally associated with localized EBS, while in the intermediate form of the disease the variants involved tend to be distributed across segments of the rod domain.

Figure 5

Clinical aspects of junctional epidermolysis bullosa (JEB). Dental enamel anomalies, chronic wounds, and absence of nails in a patient with severe JEB.

Figure 6

Schematic representation of the main structures involved in the adhesion of the skin layers. The main proteins associated with junctional epidermolysis bullosa ( to the right of the figure) interact in order to allow the connection of the keratin intermediate filaments to the anchoring fibrils (formed by type VII collagen) in the dermis.

Figure 7

Clinical aspects of dystrophic epidermolysis bullosa (DEB). (A) Patient with dominant DEB, pre-tibial. (B‒C) Dystrophy of the toenails and hands of patients with dominant DEB, localized. (D‒E) Pseudosyndactyly (fusion of the fingers) and generalized distribution of blisters and extensive scarring in a patient with recessive DEB, severe. (G‒H) Blisters and generalized scarring, especially on knees, legs, feet, and hands in a patient with recessive DEB, intermediate; hyperkeratosis of the hands and feet leads to flexion contractures. (F, I) Blisters and lesions restricted to hands and feet and nail dystrophy in patients with recessive DEB, localized.

Figure 8

Schematic representation of the assembly of the anchoring fibrils from pro-a1 (VII) collagen polypeptides. Three formed polypeptides are associated through their C-terminal ends, while their collagenous domains fold into a triple helix conformation. Thereafter, type VII collagen monomers in triple helix form antiparallel dimers, which unite after part of the C-terminal end is removed. The different dimer molecules join laterally to form anchoring fibrils. The N-terminal domains of the anchoring fibrils are bound by homology to the macromolecules in the lamina densa, stabilizing its adhesion with the underlying dermis.