Vet Dermatol 2015; 26: 3–e2 DOI: 10.1111/vde.

12176

Epidermolysis bullosa in animals: a review

Gildenor X. Medeiros and Franklin Riet-Correa
Postgraduate Program in Veterinary Medicine, Veterinary Hospital, Federal University of Campina Grande, Patos, Para
ıba, CEP 58708-110, Brazil
Correspondence: Franklin Riet-Correa, Postgraduate Program in Veterinary Medicine, Veterinary Hospital, Federal University of Campina Grande,
Patos, Para
ıba, CEP 58708-110, Brazil. E-mail: franklin.riet@pq.cnpq.br

Epidermolysis bullosa (EB) is a hereditary mechanobullous disease of animals and humans, characterized by an
extreme fragility of the skin and mucous membranes. The main feature of EB in humans and animals is the for-
mation of blisters and erosions in response to minor mechanical trauma.
Epidermolysis bullosa is caused by mutations in the genes that code for structural proteins of the cytoskeleton of
the basal keratinocytes or of the basement membrane zone. Based on the ultrastructural levels of tissue separa-
tion, EB is divided into the following three broad categories: epidermolysis bullosa simplex, junctional epidermoly-
sis bullosa and dystrophic epidermolysis bullosa. Human types of EB are divided into several subtypes based on
their ultrastructural changes and the mode of inheritance; subtypes are not fully established in animals. In
humans, it is estimated that EB affects one in 17,000 live births; the frequency of EB in different animals species
is not known.
In all animal species, except in buffalo with epidermolysis bullosa simplex, multifocal ulcers are observed on the
gums, hard and soft palates, mucosa of the lips, cheek mucosa and dorsum of the tongue. Dystrophic or absent
nails, a frequent sign seen in human patients with EB, corresponds to the deformities and sloughing of the
hooves in ungulates and to dystrophy or atrophy of the claws in dogs and cats.
This review covers aspects of the molecular biology, diagnosis, classification, clinical signs and pathology of EB
reported in animals.

somes and hemidesmosomes, these filaments play a

Introduction
Epidermolysis bullosa (EB) is a hereditary mechanobul-
lous disease of animals and humans, characterized by an
extreme fragility of the skin and mucous membranes.
The main feature of EB in humans and animals is the for-
mation of blisters and erosions in response to minor
mechanical trauma, especially in areas subject to fric-
tional stress, such as the oral cavity and the limbs.1,2 The
fragility of the skin and mucous membranes results from
abnormalities in the cytoskeleton of the basal keratino-
cytes or of the basement membrane zone (BMZ).3,4
Epidermolysis bullosa is caused by mutations in the
genes that code for structural proteins of the cytoskele-
ton of basal keratinocytes and of the BMZ.3–5 Advances
in analytical techniques of molecular genetics have
allowed the identification of mutations in the genes
encoding the structural proteins of the cytoskeleton of
keratinocytes and BMZ, namely, PKP1 (plakophilin 1),
DSP (desmoplakin), KRT5 (keratin 5), KRT14 (keratin 14),
PLEC1 (plectin), ITGA6, ITGB4 (a6b4-integrin), LAMA3,
LAMB3, LAMC2 (laminin 332), COL17A1 (type XVII
collagen) and COL7A1 (type VII collagen).6
The cytoskeleton comprises a cytoplasmic network of
intermediate filaments composed primarily of keratin 5
and keratin 14. Through their connections to the desmo-
Accepted 1 July 2014
Sources of Funding: This work was supported by the National
Council of Technological and Scientific Development, CNPq,
grant 471386/2010-3.
Conflict of Interest: No conflicts of interest have been declared.
© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
role in the organization of the shape of the cell and in
maintenance of the structural integrity of the epidermis.
Desmosomes are specialized complexes that form tight
intercellular junctions between adjacent epithelial cells.
The main proteins of these intercellular junctions are pla-
koglobin, plakophilin and desmoplakin and the cadherins
desmocollin and desmoglein (Figure 1).4 The BMZ is
located at the junction between the dermis and the epi-
dermis. Its function is to maintain the adhesion between
these two structurally different tissues by means of a
complex network of adhesion molecules intricately
related to one another. The BMZ is divided into three
areas (hemidesmosomes, lamina lucida and lamina
densa), which are attached to the dermis by the anchor-
ing fibrils. The hemidesmosomes are composed of an
inner and an outer plaque. The inner plaque is composed
of the cytoplasmic hemidesmosomal proteins HD1/plec-
tin and BP230 and is connected to the intermediate
filaments within the cytoplasm of the basal-layer kerati-
nocytes. The outer plaque contains the proteins a6b4-in-
tegrin and BP180. The lamina lucida is formed by the
plasma membrane, the sub-basal dense plate and the
anchoring filaments composed of BP180 (also known as
collagen XVII) and laminin 332 (formerly known as
laminin 5). The lamina densa is composed mainly of
type IV collagen. Beneath the lamina densa are
anchoring fibrils, cross-banded structures composed of
type VII collagen that extend into the papillary dermis
(Figure 1).7,8
Epidermolysis bullosa in humans was first described by
Koebner in 18866 and has since been widely studied;
recent advances have led to the identification of
3
Medeiros and Riet-Correa

Figure 1. Schematic representation of the molecular organization of the cytoskeleton of basal keratinocytes and the basement membrane zone.
Abbreviations: E, epidermis; H, hemidesmosome; LD, lamina densa; LL, lamina lucida; and SD, sublamina densa. Proteins of the desmosome and
of the intercellular junction are abbreviated as follows: C, cadherins; Dp, desmoplakin; Pg, plakoglobin; and Pp, plakophilin.

mutations in different genes, which account for the clini-
cal heterogeneity of EB.2,5,6 The term ‘epidermolysis bull-
osa’ was first used in veterinary medicine in 1974,9
although it was also suggested for other similar diseases
reported in animals, including red foot disease in sheep,10
hereditary mechanobullous diseases in horses11,12 and
cattle13 and epitheliogenesis imperfecta in horses.14 It is
estimated that in humans the disease affects one in
17,000 live births in the world population.15 In animals,
the frequency of EB in different species is not known. In
our diagnostic laboratory, in the Brazilian semi-arid region,
one of 861 goat specimens for postmortem examination
received between 1983 and 2012 was diagnosed with
EB. During the same period, in a total of 1144 cattle speci-
mens, two Gir calves from different farms were diag-
nosed with EB. Genetically modified mice have been
used as animal models for understanding the pathogene-
sis of EB in humans. Molecular studies are rarely reported
in domestic animals; however, some mutations have
been identified (Table 1).1,16–28
Given the rarity of the disease and the growing volume
of literature we assembled this review, which covers the
molecular biology, diagnosis, classification, clinical signs
and pathology of EB; it is hoped that this review will assist
in the diagnosis and future research of the disease in
animals.
Diagnosis and classification
Epidermolysis bullosa is suspected when newborn ani-
mals have blisters and erosions in the skin and mucous
membranes. These typically manifest in response to
4 © 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
minor trauma or they can be identified by applying the
Nikolskiy test,29 performed by gently twisting a finger or
an object back and forth on the surrounding normal-
appearing skin (marginal Nikolskiy test) and on the nor-
mal-appearing skin distant from the lesions (direct Nikol-
skiy test; Figure 2a). In a positive test, the epidermis will
be detached easily from the skin. It is important to con-
duct a complete anamnesis, to determine whether the
disease could be hereditary, and a thorough physical
examination, including an assessment of the type and dis-
tribution of the lesions. Laboratory diagnosis is suggested
by typical histological lesions of detachment of the epider-
mis from the dermis (Figure 2b). Confirmation requires
transmission electron microscopy (Figure 3), immunoflu-
orescence mapping and mutation analysis. Electron
microscopy and immunofluorescence mapping allow the
determination of the level of skin cleavage, which may be
intraepidermal, intralamina lucida or sublamina densa.
Electron microscopy permits visualization and semi-quan-
titative assessment of the specific structures (keratin fila-
ments, desmosomes, hemidesmosomes, sub-basal
dense plates, anchoring filaments and anchoring fibrils),
which can be altered in number and/or appearance in
selected EB subtypes.30,31 Immunofluorescence map-
ping, when coupled with the use of specific monoclonal
antibodies, can provide considerable insight into the
major type of EB present and also the structural protein
most likely to be altered. Immunofluorescence mapping
has relied traditionally on the staining of cryopreserved
EB skin specimens with antibodies to bullous pemphigoid
antigen, laminin-1, type IV collagen and keratin 14, in
order to determine the level of blistering.31,32 Genetic
 Epidermolysis bullosa in animals

Table 1. Summary of epidermolysis bullosa in animals

Epidermolysis bullosa Ultrastructural site
type and animal species Mode of inheritance of separation Target gene (protein) Types of mutation known References
Epidermolysis bullosa simplex (EBS)
Cattle Autosomal dominant Basal layer KRT5 (keratin 5) Missense, G?A at 4164 23
Cattle Autosomal dominant Basal layer Undetermined Undetermined 40,44,45
Cattle Autosomal recessive Basal layer Undetermined Undetermined 43
Buffalo Autosomal recessive Suprabasal Undetermined Undetermined 39
Dogs Autosomal recessive Suprabasal PKP1 (plakophilin 1) Splice site, IVS1 + G?C 28
Herlitz junctional epidermolysis bullosa (JEB)
Cattle Undetermined Lamina lucida Undetermined Undetermined 60
Horses Autosomal recessive Lamina lucida LAMA3 (laminin 332) 6589 bp deletion, 24
exons 24–27
Horses Autosomal recessive Lamina lucida LAMC2 (laminin 332) Nonsense, insertion 18,19,21
of C after 1368
Horses Autosomal recessive Lamina lucida Undetermined Undetermined 11,12,14,69,70
Sheep Autosomal recessive Lamina lucida LAMC2 (laminin 332) Frameshift, deletion 26
of CA after 2746
Sheep Autosomal recessive Lamina lucida Undetermined Undetermined 66
Dogs Autosomal recessive Lamina lucida LAMA3 (laminin 332) Nonsense, insertion 22
of 227 bp at 4818
Dogs Undetermined Lamina lucida Undetermined Undetermined 62
Rats Autosomal recessive Lamina lucida Undetermined Undetermined 64
Mice Autosomal recessive Lamina lucida Undetermined Undetermined 65
Non-Herlitz JEB
Dogs Autosomal recessive Lamina lucida Undetermined Undetermined 61,74–79
Cats Undetermined Lamina lucida Undetermined Undetermined 63
Dystrophic epidermolysis bullosa (DEB)
Cattle Autosomal recessive Sublamina densa COL7A1 (type VII collagen) Nonsense, C?T at 4756 27
Cattle Autosomal recessive Sublamina densa Undetermined Undetermined 13,92
Sheep Autosomal recessive Sublamina densa Undetermined Undetermined 84,85
Goats Autosomal recessive Sublamina densa Undetermined Undetermined 80
Dogs Autosomal recessive Sublamina densa COL7A1 (type VII collagen) Missense, G?A at 5716 20,25
Dogs Autosomal recessive Sublamina densa Undetermined Undetermined 90,91
Cats Autosomal recessive Sublamina densa Undetermined Undetermined 88
Ostriches Undetermined Sublamina densa Undetermined Undetermined 93

analysis of an animal’s ascendents and decendents by
mutational analysis through DNA sequencing is the ulti-
mate means of determining the mode of inheritance and
the precise site(s) and type(s) of molecular mutation pres-
ent in an animal with EB. This also plays a key role in iden-
tification of EB carriers and provides an excellent
research tool.5–7,33 In addition, the eventual application of
gene therapy to EB cases will be dependent on the deter-
mination of the specific mutation(s) present.20,25,34
The classification of the types of EB in animals has tra-
ditionally been based on the human classification, which
is based on the ultrastructural level of the tissue separa-
tion. Thus, EB can be divided into the following three
broad categories: epidermolysis bullosa simplex (EBS),
characterized by basal or suprabasal intercellular clefting
with or without cytolysis of basal keratinocytes; junctional
epidermolysis bullosa (JEB), in which separation occurs in
the lamina lucida; and dystrophic epidermolysis bullosa
(DEB), with a cleavage within or below the lamina densa.
Other human disorders, such as Kindler’s syndrome,
which show clinical and biological aspects similar to EB
but differ in the presence of other systemic symptoms
and usually resolve with age, can be included within the
EB group.6,7 Based on the ultrastructural changes and the
mode of inheritance, human types of EB are divided into
several subtypes (Table 2).6
There is also an acquired form of EB called epidermoly-
sis bullosa acquisita, which is a rare, autoimmune, blister-
© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
ing skin disease, first reported in humans in 1895.
Epidermolysis bullosa acquisita was classified as an EB
because clinically, it resembles hereditary DEB.35 It is
caused by the production of immunoglobulin G autoanti-
bodies to collagen VII, the major component of anchoring
fibrils.36 Epidermolysis bullosa acquisita was reported in
dogs in 1998,37 but because it can mimic the clinical,
histological and immunohistological features of bullous
pemphigoid, it is likely that it was misdiagnosed before
1998.38 Epidermolysis bullosa acquisita is included in the
group of autoimmune subepidermal bullous diseases
(including bullous pemphigoid and mucous membrane
pemphigoid) and will therefore not be discussed further
in this review.
The clinical and pathological findings are similar in all
types of EB, varying only in severity. Given that the
descriptions are based on findings observed in a small
number of animals, the complete range of clinical signs
may be more diverse (Table 3). It is interesting to note
that skin fragility resulting in the formation of blisters is
common in humans, whereas in animals, especially in
dogs and cats, the integument is less prone to such
lesions. One possible explanation for this phenomenon is
that in animals hair prevents the detachment of the epi-
thelium, not only by acting as a mechanical barrier but
also by deeply anchoring the epidermis into the dermis at
the level of the invagination of the hair follicles. It can be
speculated that in animals the severity of lesions is
5
Medeiros and Riet-Correa
(a)
(b)
Figure 2. (a) Skin of the inner face of the pinna of a calf affected by
junctional epidermolysis bullosa, showing friction-induced detach-
ment of the epidermis after the Nikolskiy test. (b) Photomicrograph
of histopathology of the skin of a calf affected with junctional epi-
dermolysis bullosa. The epidermis is detached from the dermis,
forming a subepidermal cleft containing erythrocytes and neutrophils.
Haematoxylin and eosin stain. The scale bar represents 50 lm.
directly proportional to the risk of trauma associated with
the mode of life of each species. In farm animals, lesions
are more severe because they live in herds and in envi-
ronments more often favourable to trauma. In EB-
affected animals, sloughing of the hooves is also
common. In dogs and cats, the lesions are milder than in
farm animals and are most predominant in hairless areas,
such as the muzzle and footpads. Oral lesions in herbi-
vores are more extensive than in other species, possibly
because of their fibrous food, except in buffalo with EBS.
Most cases of EB in humans lead to death in infancy.
Likewise, animals are euthanized or die during the first
months of life. Reports of survival for months or years in
animals with EB are rare.
Epidermolysis bullosa simplex
Epidermolysis bullosa simplex is characterized by supra-
basal separation without cytolysis of basal cells, as it
occurs in dogs28 and buffalo,39 or by basal separation with
cytolysis of basal cells (cytolytic), as seen in cattle.23,40,41
6 © 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
Clinical signs occur immediately after birth, with superfi-
cial epidermal layers sloughing upon pressure. The signs
tend to be less severe than in JEB and DEB (Figure 4).
Dystrophic or absent nails are frequently seen in human
patients,42 and this corresponds to the deformities and
sloughing of the hooves in buffalo (Figure 4c)39 and cat-
tle23,40,41,43–45 and to dystrophic or atrophic claws in
dogs.28 Multifocal ulcers on the gums, hard and soft pal-
ates, mucosa of the lips, buccal mucosa and dorsum of
the tongue are observed in cattle with cytolytic basal layer
separation23,40,41 and dogs with noncytolytic suprabasal
separation.28 In contrast, lesions of the oral cavity are not
observed in buffalo with noncytolytic suprabasal separa-
tion.39 Generally, cattle affected by EBS with basal layer
separation die at 1–4 weeks old,23,40,41 whereas dogs28
and buffalo39 with suprabasal separation have been
reported to die at 1 and 4 years of age, respectively.
Histopathological findings in the skin and oral mucosa
are similar, but they vary in degree depending on the clini-
cal manifestation period, the distribution of the lesions
and the presence of secondary complications, such as
bacterial infections. The initial lesion is the subepidermal
separation with a minimal neutrophilic inflammation. In
more advanced skin lesions, extensive areas of intact full-
thickness epidermis are separated from the dermis, form-
ing large clefts containing eosinophilic fluid, extravasated
erythrocytes and occasional neutrophils.23,41 Periodic acid
Schiff staining of histological skin sections from calves
demonstrated cleft formation involving the epidermis,
with the basement membrane attached to the floor of the
cleft.41 An apparent loss of the intercellular junction and
acantholysis are observed in EBS with suprabasal separa-
tion (Figure 3a).28,39,43 Detachment of the corneal epithe-
lium with minimal inflammation was observed in cattle.23
In humans46,47 and in cattle,23 EBS is generally caused
by mutations in the genes encoding keratins 5 and 14
(KRT5 and KRT14) and is transmitted by autosomal domi-
nant inheritance. In cattle, suprabasal clefts arise from
lysis of the basal keratinocytes and the clumping of the
intermediate filaments.23,41 The clumping of the interme-
diate filaments has been described in the Dowling–Meara
form of EBS in humans.47,48 In cattle, a missense muta-
tion was identified in the KRT5 gene that revealed a one
base change (G-to-A substitution at position 4164 of the
genomic sequence). This resulted in a codon change from
GAG (glutamic acid, E, acidic) to AAG (lysine, K, basic) at
position 478. It is possible that this amino acid change
(acidic to basic) altered the formation of the keratin hete-
rodimers and the intermediate filaments, leading to kerati-
nocyte fragility and a separation of the epidermis. In
these cattle with EBS, only one mutant allele was identi-
fied, present at a frequency of ~20% in the sire’s blood
and semen samples. This suggested a mosaic distribution
in these tissues and a dominant mode of inheritance;
however, the sire was unaffected.23 In some human EBS
cases, the disease presents revertant mosaicism, which
refers to a situation in which a second mutation attenu-
ates or abolishes the deleterious effect of the original
mutation in certain areas of the skin.49 Revertant mosai-
cism was also demonstrated in humans patients with
mutations in the JEB genes COL17A1 and LAMB3,50 in
DEB51,52 and in Kindler’s syndrome.53,54
 Epidermolysis bullosa in animals

(a) (b)

(c) (d)

Figure 3. Transmission electron photomicrographs. (a) Skin of a buffalo affected with epidermolysis bullosa simplex. The floor of the suprabasal
blister (star) is formed by basal cells attached to the dermis (D). Note acantholytic cells (arrows) within the blister. The scale bar represents 2 lm.
(b) Skin of a calf affected with junctional epidermolysis bullosa. Basal cells form the roof of the blister (star) after separation from the dermis at the
level of the lamina lucida. Note the small hemidesmosomes (box). The scale bar represents 1 lm. (c) Higher magnification of the box in (b). Note
the cell plasma membrane (arrow) and small and ill-defined hemidesmosomes within the boxes. The scale bar represents 200 nm. (d) Skin of a
goat affected with dystrophic epidermolysis bullosa. The lamina densa (arrows) forms the roof of the bulla (star). The basal lamina, hemidesmo-
somes and anchoring filaments are well preserved. The scale bar represents 500 nm.

In humans, recessively inherited EBS is caused by
mutations in the plectin,55,56 desmoplakin57 and plakophi-
lin-1 (PKP1) genes.46,58 In Chesapeake Bay retriever
dogs, an autosomal recessive acantholytic dermatosis
with deficiency of plakophilin-1 was reported.28 Electron
microscopy demonstrated a reduced number of partly
formed desmosomes with detached and aggregated ker-
atin intermediate filaments. Immunostaining for desmo-
somal adhesion molecules revealed a complete lack of
staining for plakophilin-1 and anomalies in the distribution
of desmoplakin and keratins 10 and 14. Nucleotide
sequencing revealed a G-to-C conversion at the IVS1
splice donor site within the first intron of PKP1, resulting
in a premature stop codon. As a consequence, the
mutated protein is predicted to be truncated and com-
posed of 75 instead of 749 amino acids.28 These changes
resemble EBS with a suprabasal separation, associated
with a deficiency of plakophilin-1, known as ectodermal
dysplasia/skin fragility syndrome in humans.46,58
In buffalo, a hereditary mechanobullous disease called
hereditary suprabasilar mechanobullous acantholytic der-
© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
matosis was not classified as EB because the ultrastruc-
tural site of the separation is suprabasal and oral lesions
are not observed.39 However, following the current clas-
sification of EB in humans (Table 2), this buffalo disease
can be defined as epidermolysis bullosa simplex with a
suprabasal separation. The disease is similar to EBS,
which also has minimal or absent oral lesions, in its defi-
ciency of plakophilin-1.6 Epidermolysis bullosa simplex in
buffalo is inherited through an autosomal recessive mech-
anism, characterized by a suprabasal separation between
the stratum basale and stratum spinosum, with a loss of
the desmosomal attachment (Figure 3a).39 Further stud-
ies suggested that it is likely the disease in buffalo occurs
due to defects in the stability, structure or function of the
desmosomal cadherins and not to alterations in the des-
mosomal plaque proteins.59
Junctional epidermolysis bullosa
In JEB, the clinical signs are due to defects and changes
in the hemidesmosomes, the plasma membrane, the
7
Medeiros and Riet-Correa

Table 2. Types and subtypes of epidermolysis bullosa based on the ultrastructural level of tissue separation in the basement membrane zone,
based on the classification in humans*
Epidermolysis bullosa type and subtype Ultrastructural site separation Other ultrastructural findings
Epidermolysis bullosa simplex (EBS)
Localized EBS Basal layer Split may spread to suprabasilar layer
Dowling–Meara EBS Basal layer Dense, circumscribed clumps of keratin filaments
(most commonly observed within lesional biopsy site)
EBS–muscular dystrophy Predominantly in basal layer, above Reduced integration of keratin filaments within
the hemidesmosome attachment plaque hemidesmosomes
Autosomal recessive EBS Basal keratinocytes Absent or reduced keratin filaments within basal
keratinocytes
Superficial EBS Suprabasal, usually at interface between –
granular and cornified cell layers
Lethal acantholytic EBS Suprabasal and acantholysis Perinuclear retraction of keratin filaments
Plakophilin-1 deficiency EBS† Suprabasal, mid-epidermal cell–cell separation Diminutive suprabasal desmosomes; perinuclear
retraction of keratin filaments
Junctional epidermolysis bullosa (JEB)
Herlitz JEB† Lamina lucida Markedly reduced or absent hemidesmosomes;
absent sub-basal dense plate
Non-Herlitz JEB† Lamina lucida Hemidesmosomes may be normal or reduced in size
and number
JEB–pyloric atresia Lamina lucida Small hemidesmosome plaques often with attenuated
sub-basal dense plate
Dominant dystrophic epidermolysis bullosa (DDEB)
Generalized DDEB Sublamina densa Normal or decreased numbers of anchoring fibrils
DDEB–bullous dermolysis Sublamina densa Electron-dense stellate bodies within basal layer,
of the newborn reduced anchoring fibrils
Recessive dystrophic epidermolysis bullosa (RDEB)
Severe generalized RDEB† Sublamina densa Absent or rudimentary anchoring fibrils
Other generalized RDEB Sublamina densa Reduced or rudimentary-appearing anchoring fibrils
RDEB–bullous dermolysis Sublamina densa Electron-dense stellate bodies within basal layer,
of the newborn reduced anchoring fibrils
Kindler’s syndrome Variable; intraepidermal, intralamina Reduplication of lamina densa; presence of upper
lucida or sublamina densa dermal colloid bodies and melanophages
*Adapted from Fine et al. (2008)6 and Bruckner-Tuderman and Has (2014).7
†
Subtypes described in animals.

sub-basal dense plate and the anchoring fibrils. In cattle
(Figure 5),60 horses,18 and sheep26 affected by Herlitz
type of JEB, the skin lesions are more severe than in the
other types of EB, are distributed throughout the body
with all hooves affected at the same time (Figure 5a,b),
and most animals die in the first week of life. The same
pattern is observed in dogs,61,62 cats (Figure 6),63 rats64
and mice65 with JEB, although the lesions are somewhat
less severe. In all animal species with JEB, oral multifocal
ulcers are observed (Figure 6a).18,26,60,63,66 Enamel hypo-
plasia is a common finding in humans67 with JEB; in ani-
mals, it has only been sporadically observed in
horses18,19 and dogs.22 Sporadically, ulcers are observed
elsewhere, such as on the anus, vagina14 and rumen (Fig-
ure 5c). Histopathological findings in skin (Figure 2b) and
oral mucosa are similar to those observed in EBS with
separation in the basal layer. In cattle, areas of a total loss
of the oral and lingual epithelium are observed, leading to
necrosis, extensive ulceration, infiltration by neutrophils
and haemorrhages.60 Similar changes are observed in the
vaginal and anal mucosa in horses.14
Junctional epidermolysis bullosa in humans is inherited
through autosomal dominant68 and recessive genes.2,6,46
In animals, JEB is inherited through autosomal recessive
genes.1,11,12,14,18,19,21,22,24,26,64–66,69,70 The disease is
characterized by blister formation in the lamina lucida
(Figure 3b) and defects in the proteins of the hemidesmo-
8 © 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
some-anchoring filament complex. The hemidesmo-
somes are the principal structures of adhesion at the
BMZ. Abnormalities in the hemidesmosome–anchoring
filament complex can cause extreme fragility in the
dermo-epidermal junction.4,15 In cattle,60 horses14,70 and
rats,64 abnormalities in this complex include reduced
anchoring filaments, small hemidesmosomes without
clear demarcation (Figure 3c) and an attenuated or absent
sub-basal dense plate. In contrast, dogs affected by JEB,
with severe fragility of the skin and mucosa caused by
mutations in the LAMA3 gene, do not present abnormali-
ties in hemidesmosomes.22 Most mutations causing JEB
in humans are located in one of three genes encoding the
a3, b3, or c2 laminin 332 heterotrimer chains, the
LAMA3, LAMB3 and LAMC2 genes, respectively.2 These
mutations result in a lack of expression of the respective
protein chain. The laminin 332 heterotrimer forms the
anchoring filaments that attach the a6b4-integrin of the
hemidesmosome to the collagen VII of the anchoring
fibrils.8
In Belgian horses, a nonsense mutation in the LAMC2
gene, designated 1368insC, caused a shift in the open
reading frame of the c2 messenger RNA, resulting in a
downstream premature termination codon (TGA).18,19
The same mutation was associated with JEB in trait Bre-
ton and trait Comtois horses.21 Mutations in the gene
LAMA3 due to a deletion of 6589 bp in the region that
 Epidermolysis bullosa in animals

Table 3. Summary of the clinical and pathological findings of epidermolysis bullosa in animals
Clinical and pathological
findings
Onset of the clinical signs
Skin findings
Predominant distribution
Blisters, erosions and crust
Alopecia
Atrophic scarring
Milia
Ear deformities
Hoof and claw findings
Erythema of the coronary
band
Deformities
Exungulation
Extracutaneous involvement
Growth retardation
Oral cavity lesions
Corneal ulcer
Postmortem examination
Ulcers in the oral cavity
Ulcers on the tongue
Defects in tooth enamel
Gastrointestinal tract lesions
Genitourinary tract lesions
Death
Scale: –, absent; +, sporadically present; ++, frequently present; and +++, always present.
*In buffalo and dogs, in which the separation is suprabasal without cytolysis, the lesions are less severe than in cattle, in which separation is basal
with cytolysis.
Epidermolysis bullosa
simplex Junctional epidermolysis bullosa
First week At birth
Limbs, pressure points, Generalized
glabrous areas
+++ (cattle), ++ (buffalo, dogs)* +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
+++ (cattle), ++ (buffalo, dogs) +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
– –
– –
– –
+++ (cattle), ++ (buffalo, dogs) +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
+++ (cattle), ++ (buffalo, dogs) ++ (cattle, horses, sheep),
+ (dogs, cats, rats, mice)
+++ (cattle), ++ (buffalo, dogs) +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
++ +++
+++ (cattle), ++ (dogs) +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
+ (cattle) + (cats)
+++ (cattle), ++ (dogs) +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
+++ (cattle), ++ (dogs) +++ (cattle, horses, sheep),
++ (dogs, cats, rats, mice)
– Enamel hypoplasia, +
(horses, dogs)
– Rumenal ulcers, + (cattle);
anal ulcers, + (horses)
– Vaginal ulcers, + (horses)
Third week (cattle) Herlitz: first week
First year (dogs) and fourth Non-Herlitz: first year (cats)
year (buffalo) and fourth year (dogs)
Dystrophic epidermolysis bullosa
First week
Limbs, pressure points, glabrous areas
++ (cattle, sheep, goats, ostriches),
+ (dogs, cats)
++ (cattle, sheep, goats, ostriches),
+ (dogs, cats)
++ (goats)
+ (dogs, cats)
++ (cattle)
++ (cattle, sheep, goats, ostriches),
+ (dogs, cats)
+++ (cattle, sheep, goats), + (dogs, cats)
++ (cattle, sheep, goats, ostriches),
+ (dogs, cats)
++
+++ (cattle, sheep, goats), ++ (dogs, cats)
+ (sheep, goats)
+++ (cattle, sheep, goats), ++ (dogs, cats)
+++ (cattle, sheep, goats), ++ (dogs, cats)
–
Oesophageal ulcers, + (sheep, goats, dogs)
Vulvar ulcers, + (goats)
First at third month (cattle, sheep, goats,
ostriches)
First year (dogs, cats)

includes exons 24–27 have been identified in American

saddlebred horses with JEB.24 A 2 bp deletion within
exon 18 of LAMC2 (c.2746delCA) was identified as
responsible for Herlitz-type JEB in black-headed mutton
sheep, causing a frameshift with a premature stop codon
and an alternative splicing of exon 18.26 In German shor-
thaired pointer dogs, the mutation is due to an abnormal
mRNA transcript with an insertion of an out-of-frame 227
nucleotides in position 4818 at the junction between ex-
ons 35 and 36 of the LAMA3 gene. This 227 bp insertion
carries a nonsense (TAA) codon 33 bp downstream of
the insertion site.22 In animals, mutations located in one
of the three genes encoding laminin 33218,19,21,22,24,26
are genetically similar to mutations causing Herlitz-type
JEB in humans.71,72
In humans, JEB with less severe clinical findings,
known as non-Herlitz JEB, is caused by mutations in the
COL17A1 (encoding type XVII collagen), ITGA6 and
ITGB4 genes (encoding a6b4-integrin). In these cases,
the hemidesmosomes are either normal or reduced in
size and number.6,73 Clinical and ultrastructural findings
similar to the non-Herlitz form of JEB in humans have
been observed in dogs.74–79
© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
Dystrophic epidermolysis bullosa
In DEB, lesions of the skin and mucous membranes can
heal with scar formation, and this has been reported in
goats80 and humans.81 Healing with scar formation
occurs because blisters below the lamina densa will lead
to a mesenchymal wound-healing response in the der-
mis.81,82 As reported in humans,67,83 healing in goats with
DEB80 led to changes in the architecture of some of the
anatomical structures of the oral mucosa, including the
palatal rugae and tongue papillae, which may reduce in
length or disappear after healing, leaving a flat surface
(Figure 7a). This finding is not observed in ruminants with
EBS23,40,41,43,44 or JEB (Figure 7b).60 Ulcers in the
oesophagus,80,84,85 vulva80 and cornea80,84 are described.
Histopathological findings in the skin and oral mucosa are
similar to those found in EBS and JEB; however, periodic
acid Schiff staining of histological sections skin demon-
strated that the basement membrane was attached to
the roof of the cleft.80,85
Dystrophic epidermolysis bullosa comprises dominant
and recessive forms caused by mutations in the
COL7A1 gene that codes for type VII collagen, which
9
Medeiros and Riet-Correa
(a)
Figure 4. Buffalo with epidermolysis bullosa simplex. (a) Numerous areas of chronic lesions with alopecia, erosions, crusts and scars are
observed on the skin. Note that the buffalo is an adult and nearly 4 years old. (b) Skin with recent detachment of the epidermis caused by occa-
sional friction. (c) Palmar aspect of the digits of the thoracic limb showing loss of the hoof of a paradigit and deformities in the other hooves.
Courtesy of Cristina Ghever Fernandes.
(a)
(b) (c)
Figure 5. Calf (2 months old) with junctional epidermolysis bullosa.
(a) Large areas of erosions and crusts are observed on the skin, espe-
cially at the areas of friction, mainly on the limbs. Note exungulation
of all hooves. (b) Lateral aspect of the digits of the thoracic limb
showing skin detachment and exungulation of the hooves. (c) Rume-
nal mucosa showing several ulcers, mainly in the ruminal pillars.
10
(b)
(c)
is the major component of the anchoring fibrils of the
dermo-epidermal junction.81,86,87 Ultrastructurally, the
site of blistering is the sublamina densa zone
(Figure 3d). In humans,81,86 cats,88,89 dogs,90,91
sheep,84 cattle13,92 and goats80 with recessive DEB,
the anchoring fibrils are scarce and rudimentary. Dys-
trophic epidermolysis bullosa with similar ultrastructural
alterations has also been reported in ostriches,
although the mode of inheritance was not deter-
mined.93 These changes in the anchoring fibrils
decrease their adhesion to the collagen fibres of the
dermis, leaving the dermo-epidermal junction suscepti-
ble to separation.94 In dominant DEB, recorded in
humans but not in animals, the anchoring fibrils are
normal but decreased in number.95 Other structures of
the BMZ, such as the basal keratinocytes, the lamina
lucida, the lamina densa and the hemidesmosomes,
appear to be normal in DEB. Over 300 mutations have
been reported in humans, and DEB is strongly associ-
ated with the glycine substitution by different amino
acids in one allele of the gene encoding the collage-
nous domain of type VII collagen. Glycine substitutions
probably have a dominant negative effect on the forma-
tion of type VII collagen.95–97 A missense mutation in
the COL7A1 gene (5716G-to-A) with the substitution of
glycine by a serine has also been observed in golden
retriever dogs with recessive DEB. This mutation
results in reduced secretion of abnormal type VII colla-
© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.

(a)
(b)
Figure 6. Cat with junctional epidermolysis bullosa. (a) Oral lesions
at 6 months of age. (b) Superficial ulcer on the anterior aspect of the
left pinna at initial presentation. Reproduced with permission from Al-
haidari et al.9 Copyright © 2005, John Wiley and Sons.
(a) (b)
Figure 7. Oral vestibule. (a) Goat with dystrophic epidermolysis bull-
osa. (b) Calf with junctional epidermolysis bullosa. In the goat, there
are ulcers and scars on the cheek mucosa with a loss of papillae
(arrow). In the calf, an ulcer is observed on the cheek mucosa (arrow)
but without scarring and loss of cheek papillae.
gen and assembly of anomalous anchoring fibrils abut-
€henvieh cat-
ting the lamina densa.20,25,91 In Rotes Ho
tle, DNA sequencing revealed a nonsense mutation in
© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
Epidermolysis bullosa in animals
the COL7A1 gene (c.4756C.T), resulting in a stop
codon at amino acid residue 1586 in the bovine
COL7A1 protein sequence, which probably prevents
anchoring fibril formation in the homozygous animals.27
Conclusion
Knowledge about EB in animals has increased in recent
years; however, more extensive use of molecular tech-
niques is needed to identify further gene mutations
responsible for the different clinical and pathological pic-
tures of the diseases. In animals, the three basic types of
EB have been reported; subtypes remain poorly defined.
In animals, the severity of oral, cutaneous and hoof
lesions may be related to the type of EB and to the mode
of life of each species. At present, there is no specific
treatment for EB. Clinical management is mainly support-
ive, aiming at protection of the skin from friction, preven-
tion of infections and loss of body fluids, analgesia and
optimal nutritional status. Progress in understanding the
molecular basis of recessive DEB will provide the basis
for development of novel genetic and cellular therapies
targeted at restoring the defective anchoring fibrils. The
availability of animal models to study human EB may pro-
vide a basis for gene therapy approaches as a potential
definitive treatment for this devastating disease.
Acknowledgements
We would like to thank Severo Sales de Barros and Cristi-
na Gevher from the Federal University of Pelotas, Brazil
and Zeneib Alhaidari from Clinique Ve
te

rinaire Roquefort
les Pins, France, for providing photographs.
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pidermolyse bulleuse
jonctionelle du Braque Allemand: un mode le canin spontane

de
Re
sume
– L’e

pidermolyse bulleuse (EB) est une maladie he
re

ditaire bulleuse des animaux et des humains,
qui se caracte
rise par une extre
^me fragilite

de la peau et des muqueuses. La principale caracte
ristique de
l’EB animale et humaine est la formation de cloques et d’e
rosions en re
ponse a un traumatisme me
canique
mineur.L’e
pidermolyse bulleuse est cause
e par des mutations des ge

ratinocytes basaux ou de la membrane basale. Compte tenu des nive-
structurales du cytosquelette des ke
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nes codant pour les prote
ines
13
Medeiros and Riet-Correa

aux de se
paration ultrastrcturale tissulaire, l’EB est divise
e en trois grandes cate
gories : l’e

pidermolyse bul-

pidermolyse billeuse jonctionnelle et l’e
leuse simple, l’e
pidermolyse bulleuse dystrophique. Les types hu-
mains d’EB sont divise
s en plusieurs sous-types base
s sur les modifications ultrastructurales et le mode
de transmission ; les sous-types ne sont pas totalement e
tablis chez les animaux. Chez l’homme, on es-
time que l’EB touche 1 individu sur 17 000 naissances ; on ne conna^ıt pas la fre
quence de l’EB dans les

rentes espe
diffe ces animales.Pour toutes les espe ces animales,  a l’exception du bison atteint d’e
pidermo-
lyse bulleuse simplex, les ulce res multifocaux sont observe
s sur les gencives, les palais mous et durs, les
muqueuses labiales, et les muqueuses des joues et la face dorsale de la langue. Les ongles absents ou dy-
strophiques, un signe fre
quent chez l’homme atteint d’EB, correspond 
formation et 
a la de
des
a la friabilite
sabots chez les ongule
s et a de la dystrophie a l’atrophie des griffes chez le chien et le chat.Cette revue
couvre les aspects de la biologie mole
culaire, du diagnostic, de la classification, des signes cliniques et de
la pathologie de l’EB de
crite chez l’animal.

Resumen – La epidermolisis bullosa (EB) es una enfermedad hereditaria mecanovesicular de animales y

humanos, caracterizada por una extrema fragilidad de la piel y de las membranas mucosas. La principal car-
acter
ıstica de EB en humanos y animales es la formacio
n de ampollas y erosiones en respuesta a traumas
mec
anicos menores.La epidermis bullosa se caracteriza por mutaciones en los genes que codifican para
prote
ınas estructurales del esqueleto de los queratinocitos basales o de la zona de la membrana basal. Ba-
sado en los niveles de separacio
n del tejido a nivel ultraestructural, la epidermis bullosa se divide en las tres
siguientes amplias categor
ıas: epidermolisis bullosa simplex, epidermolisis bullosa de la unio
n, y epidermal
bullosa distro
fica. Los tipos humanos de epidermolisis se dividen en varios subtipos basados en sus cambi-
os estructurales y el modo de herencia; Los subtipos no est
an totalmente establecidos en animales. En
humanos, se estima que la epidermolisis bullosa a uno en 17.000 nacimientos; la frecuencia de epidermoli-
sis bullosa en diferentes especies animales no se conoce.En todas las especies animales, excepto el bis-
onte con epidermolisis bullosa simplex, se observan u
lceras multifocales en las enc
ıas, paladares duro y
blando, mucosa de los labios, mucosa de los carrillos, y superficie dorsal de la lengua. Las un ~as est
an dis-


plasicas o ausentes, un signo frecuente en pacientes humanos con epidermaolisis bullosa, que corre-
sponde con la deformacio
n y la pe

rdida de pezun ~as de ungulados y la distrofia o atrofia de las un ~as en
perros y en gatos.Esta revisio
n cubre aspectos de la biolog
ıa molecular, diagno
stico, clasificacio

n, signos
cl
ınicos y patolog
ıa de la epidermolisis bullosa descritos en animales.

Zusammenfassung – Die Epidermolysis bullosa (EB) ist eine heredita €re mechanobullo €se Erkrankung von
Tieren und Menschen, die charakterisiert wird durch extreme Fragilit€ at der Haut und der Schleimh€ aute.
Das Hauptcharakteristikum der EB des Menschen und der Tiere ist die Blasenbildung und die Entstehung
von Erosionen als Reaktion auf geringes mechanisches Trauma.Die Epidermolysis bullosa wird durch Mu-
tationen von Genen verursacht, die die Strukturproteine des Zytoskeletts der basalen Keratinozyten oder
der Basalmembran kodieren. Basierend auf den ultrastrukturellen Levels der Gewebstrennung, wird die
EB in die folgenden drei breiten Kategorien eingeteilt: Epidermolysis bullosa simplex, junktionale Epiderm-
olysis bullosa und dystrophische Epidermolysis bullosa. Die Typen der humanen EB werden basierend auf
den ultrastrukturellen Ver€anderungen und der Art der Vererbung in verschiedene Subtypen eingeteilt; bei
den Tieren sind die Subtypen nicht g€anzlich bekannt. Beim Menschen wird gesch€ atzt, dass EB eine von
17000 Lebendgeburten betrifft, w€ahrend die Frequenz von EB bei den verschiedenen Tierspezies nicht
bekannt ist.Bei allen Tierspezies, außer beim Bu €ffel mit Epidermolysis bullosa simplex, kommen multifok-
ale Ulzera am Zahnfleisch, sowie am harten und weichen Gaumen, an den Schleimh€ auten der Lippen, der
Wangenmukosa und dem Zungenru €cken, vor. Dystrophische oder fehlende N€ agel, ein h€
aufig auftretendes
Symptom beim menschlichen Patienten mit EB, korrespondiert mit Deformit€ aten und dem Ausschuhen
von Hufen bei Einhufern und mit Dystrophie oder Atrophie der Krallen bei Hunden und Katzen.Diese
Review befasst sich mit Aspekten der Molekularbiologie, der Diagnose, Einteilung, den klinischen Sympto-
men und der Pathologie der EB, die bei Tieren beschrieben sind.

要約 – 表皮水疱症(EB)は皮膚と粘膜の極度の脆弱性を特徴とする、イヌおよびヒトの遺伝性水疱性疾患
である。ヒトと動物におけるEBの主な特徴は水疱の形成と軽度の機械的な外傷による糜爛形成である。
表皮水疱症は基底部ケラチノサイトの細胞骨格あるいは基底膜領域の構造タンパク質をコードする遺伝
子の変異により生じる。微細構造的なレベルの組織分離に基づくと、EBは以下の3つの広いカテゴリー、
単純型表皮水疱症、接合部表皮水疱症、栄養障害型表皮水疱症に分類される。ヒトのEBのタイプはそれ
らの微細構造的な変化と遺伝形式に基づいて複数の亜型に分類されている。しかし、亜型は動物では十
分に確立されていない。ヒトでは、EBは17,000人に1人が罹患すると推定されているが、他の動物種にお
けるEBの頻度は知られていない。バッファローにおける単純型表皮水疱症以外で、すべての動物種にお
いて、歯肉、硬口蓋、軟口蓋、口唇部粘膜、頬粘膜ならびに舌の背側に多病巣性の潰瘍が認められた。
異栄養性あるいは爪の欠損はヒトのEB患者では頻繁に認められるが、有蹄動物における蹄の変形や脱落
およびイヌやネコにおける爪の変形あるいは萎縮と合致する。このレビューは動物で報告されたEBの分
子生物学、診断、分類、臨床症状、および病理的な側面を網羅している。
e1 © 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2.
 Epidermolysis bullosa in animals

摘要 – 大疱性表皮松懈症(EB)是一种人和动物的遗传性机械性大疱性疾病,以皮肤和黏膜极端脆弱为特
点。人和动物EB的主要特征是形成水疱和溃疡,主要源于轻微的机械损伤。大疱性表皮松懈症是基因突变引
起,导致基底膜区的基底角质形成细胞的细胞骨架结构蛋白编码改变。根据组织分离的超微结构等级不同,
EB被分为以下三个类别:单纯大疱性表皮松懈症、交接处大疱性表皮松懈症、发育不良性大疱性表皮松懈
症。根据超微结构和遗传类型的不同,人EB类型分为多个亚型;亚型不全适用于动物。人类每17,000人就有
一人患有EB;然而其他物种EB发病率没有统计。单纯大疱性表皮松懈症,所有动物,除了水牛,均表现为牙
龈、硬软颚、唇部黏膜、颊黏膜和舌背部多处溃疡。人EB也会出现指甲发育不良或缺失,对应有蹄动物则是
蹄部畸形和脱落,犬猫则是甲发育不良或萎缩。本综述包含了动物EB分子生物学、诊断、分类、临床症状和
发病机理等方面。

© 2014 ESVD and ACVD, Veterinary Dermatology, 26, 3–e2. e2