Epidermolysis Bullosa. A Rare Disturbance in Clinical Veterinary of Felines

Introduction

Epidermolysis bullosa corresponds a group of genetic diseases characterized by mechanical fragility of tissues leading to formation of mucocutaneous blisters, erosion and ulceration secondary to trauma. The blisters can be localized or generalized, affecting different parts of the body, from limbs to the oral cavity [1]. In humans, epidermolysis bullosa have worldwide occurrence, affecting both sexes in equal proportion, and its incidence varies from 3.8 to 35/1 million live births [2]. In pets, the frequency of epidermolysis bullosa is not known or estimated, and in cats it is recognized as a rare disease with few isolated cases described.

Microscopic Structure of Skin

The skin is considered the large organ in the body of humans and animals, being formed by the epidermis and dermis layers. Between the epidermis and dermis is located the basement membrane, responsible for the adhesion of epidermis to dermis [3]. The basement membrane is formed by two structures, lamina lucida and lamina densa. Above the lamina lucida are present the intermediate filaments (composed by keratin 5 and 14), and an intracellular network that links the cytoskeleton of basal cells to the hemidesmosomes (formed by the inner plate and outer plate) in the keratinocyte basement plasma membrane [4].

The anchoring filaments connect the hemidesmosomes (formed by the proteins plakoglobin, placophyllin, desmoplakin; and the cadherins desmocolin and desmogelin) the lamina densa, and anchor the fibrils across the lamina lucida [5].

The inner plate of hemidesmosomes is composed by the proteins HD1/plectin and BP230, and is connected to the intermediate filaments inside the cytoplasm of basal keratinocytes. The outer plate of hemidesmosomes is composed of integrin α6β4 and BP180. The lamina lucida is formed by the plasmatic membrane, sub-basal plate and anchoring filaments (composed of collagen XVII and laminin 332), and the lamina densa is formed by type IV collagen [6]. The type VII collagen present in anchoring fibrils extends from the lamina densa towards the papillary dermis and combines with interstitial collagen fibrils in the dermis, promoting skin support [7] (Figure 1).

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Classification of Epidermolysis Bullosa

Epidermolysis bullosa can be of genetic or autoimmune origin, being classified as hereditary epidermolysis bullosa or acquired epidermolysis bullosa [8]. The hereditary epidermolysis bullosa has different phenotypes because the different genetic mutations caused by inherance autosomal dominant or recessive that cause structural changes and fragility of the cytoskeleton of basal keratinocytes or basement membrane [9]. The acquired epidermolysis bullosa no has genetic transmission, being of an autoimmune nature, where the production of IgG autoantibodies against collagen VII that make the anchoring fibrils [10]. Current, the acquired epidermolysis bullosa is included in the group of autoimmune subepidermal bullous diseases [1].

In veterinary medicine the classification of epidermolysis bullosa is based on the human classification according to the level of ultrastructural separation of skin [11]. The according with the layer skin involved, epidermolysis bullosa is classified into simple epidermolysis bullosa, junctional epidermolysis bullosa, dystrophic epidermolysis bullosa, and Kindler’s epidermolysis bullosa [1, 8, 9].

Although skin fragility is greater in humans, it is less reported in pets, probably due to the presence of hairs that act as mechanical barrier and promote the anchoring of dermis to the epidermis because the invagination of hair follicles [11, 12].

Simplex Epidermolysis Bullosa

The simplex epidermolysis bullosa corresponds to 70% of all cases in humans and is usually as inherited in an autosomal dominant manner, with some rare autosomal recessive forms [1]. The mutations involved in simplex epidermolysis bullosa affect proteins that provide structural support and cohesion of stratified epithelium, in particular of epidermis [1, 2]. In domestic animals, this is apparently the most common form [11].

In humans, the most common mutations involve KRT5 gene (encodes keratin 5) and KRT14 gene (encodes keratin 14) involved in the formation of intermediate filaments and cytoskeleton of basal keratinocytes. Mutations of these genes lead to a reduction in the mechanical rigidity of the keratinocyte cytoplasm, increased sensitivity to mechanical stress and weakening of desmosome adhesion. Also, mutations in PLEC gene (encodes plectin) compromises the formation of intermediate filaments [1].

Genes encoding hemidesmosome proteins that anchor keratin filaments to the plasma membrane, such as DSP (desmoplakin), JUP (plakoglobin junction), PKP1 (plakophilin 1), PLEC (plectin) and DST (dystonin) are also associated with cases of simplex epidermolysis bullosa, as well the EXPH5 gene (exophilin 5) leading to disruption of intracellular vesicle trafficking along actin and tubulin networks and loss of basal keratinocyte adhesion. The mutations of KLHL24 gene cause increase of keratin degradation leading to cytoskeleton collapse, tissue cohesion and cellular resilience under stress conditions [9].

In domestic animals, clinical signs appear early after birth, with detachment of the epidermal layers under pressure, and development of deformity of hooves or claws. When occur basal separation with cytolysis of basal cells, ulcers may form on the gingiva, palate, oral mucosa and dorsum of the tongue [11].

Classically the histology of simplex epidermolysis bullosa is characterized by intraepidermal cleavage without cytolysis of basal cells. Microscopic changes are seen below epidermis with intraepidermal blister formation and vacuolar changes in the layer of epidermal basal cell [9].

Recently Dettwiler et al. described the first case report of simplex epidermolysis bullosa in a domestic cat with a history of desquamation of the paw pads and ulcerations in the oral cavity and inner surface of the ear. Clinical and histopathological findings indicated a congenital disease with the formation of blisters inside layer of basal cell of epidermis and epithelium of oral mucosa. Genetic sequencing revealed a homozygous nonsense variant in the KRT14 gene (c.979C>T, p.Gln327*) and the mapping of antigens by immunohistochemistry indicated the absence of keratin 14 staining of biopsied tissues [13].

Treatment

There is no specific treatment for epidermolysis bullosa in pets, especially in cats. Care is palliative and includes the prevention of trauma and blisters through nail clipping to protect the skin from friction, prevent infections and fluid loss. Control of ectoparasites such as fleas is essential to avoid self-trauma [14].

In the presence of small lesions, the use of antimicrobial ointments is recommended, but they do not present encouraging results [12]. In cases of extensive wounds, the application of sutures and the use of systemic antibiotics are necessary [14, 15]. In animals affected by stomatitis, antibiotic therapy has a partial effect [12].

Cats with epidermolysis bullosa have a short survival rate of a few months to years, being euthanized or dying during the first few months of life [11, 12, 14].

Conclusion

Since skin diseases are uncommon in cats and their clinical manifestations are restricted to a limited number of patterns, the diagnosis of epidermolysis bullosa is a challenge for the small animal veterinarian. In cats, three types of epidermolysis bullosa have been described, simplex, junctional and dystrophic. Unfortunately, few veterinary laboratories have the capacity and experience to perform the diagnosis of epidermolysis bullosa. Transmission electron microscopy, immunofluorescence antigen mapping and mutation analysis are usually performed at reference centers in public universities in developing countries, limiting their access. Currently, there is no specific treatment for cats affected by this disease, whose clinical management consists of protecting the skin from friction and preventing infections.