Veterinary Dermatology 2006, 16, 69 73

Case report

Blackwell Publishing, Ltd.

Junctional epidermolysis bullosa in two domestic shorthair kittens

ZEINEB ALHAIDARI*, THIERRY OLIVRY, ANNE SPADAFORA,
RANDALL C. THOMAS, CHRISTOPHE PERRIN, GUERRINO MENEGUZZI and
JEAN PAUL ORTONNE
*Clinique Vtrinaire, Cidex 248, RN 85, 06330 Roquefort les Pins, France
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC 27606, USA
INSERM Unit 385, Facult de Mdecine, 27 Avenue de Valombrose, 06107 Nice Cedex 02, France
12117 Statesville Road, Carolina Vet Specialists, Huntersville, NC 28078, USA
Service dAnatomie Pathologique, Hpital Pasteur, 30 voie Romaine, 06002 Nice Cedex 1, France
(Received 26 March 2004; accepted 30 June 2004)

Abstract This article describes two cases of junctional epidermolysis bullosa in nonrelated kittens. Both cats
exhibited pinnal erosions, oral ulcerations and severe onychomadesis. Histopathology, electron microscopy and/
or indirect immunoperoxidase revealed subepidermal clefting, with the lamina densa remaining attached to the
floor of the vesicles. Indirect immunofluorescence revealed reduced staining for laminin-5 2 subunit in case 1
and 3 subunit in case 2.

IN TRO D U CT I ON

C A SE R E P O RT S

Junctional epidermolysis bullosa (JEB) is a clinically

and genetically heterogenous blistering skin disease
that has been described in both humans and animals.
It is caused by a loss of adhesion of keratinocytes to the
underlying basement membrane. Among the different
molecules of the basement membrane, laminin-5
appears to be the primary adhesion ligand of epithelial
cells.1 Mutations in any of the three genes (LAMA3,
LAMB3, LAMC2) encoding the laminin-5 chains
induce JEB in humans. More recently, genetic defects
underlying JEB have been determined in several
domestic animal species. A homozygote mutation of
LAMC2 leading to absence of laminin-5 assembly causes
lethal JEB (Herlitz form; H-JEB)2 in Belgian draft
horses3,4 and in two French draft horse breeds, the
Trait Breton and Trait Comtois.5 Non lethal JEB (non
Herlitz form; nH-JEB)2 in German shorthaired pointers
is due to a mutation in the LAMA3 gene, which results
in reduced secretion of laminin-5.6,7 Non lethal JEB
has been sporadically described previously in cats;8,9
however, the nature of the genetic defect remains
unknown. In this article we present two cases of feline
JEB in which defective expression of laminin-5 chains
was investigated by antigen immunomapping.

Case 1

Correspondence: Z. Alhaidari, Clinique Vtrinaire, Cidex 248,

RN 85, 06330 Roquefort les Pins, France. E-mail: z.alhaidari@
wanadoo.fr
2005 European Society of Veterinary Dermatology

A 4-month-old, male domestic shorthaired kitten was

referred for onychomadesis suspected to be of fungal
origin. The kitten had been adopted 2 months previously into a multicat household. Lesions were not seen
in the patients mother or in any of the littermates.
According to the owner, the kitten was slightly undersized when compared to his siblings. Since adoption,
this cat had been affected with a stomatitis that
responded partially to antibiotic therapy (clindamycin,
marbofloxacin). One month before presentation, painful feet and onychomadesis were reported.
Clinical examination revealed a superficial ulcer on
the anterior aspect of the left ear pinna (Fig. 1), onychomadesis and paronychia affecting all four feet, with
only one single malformed claw remaining on the left
front paw. Severe stomatitis affecting mainly the gingiva
and associated with locoregional adenomegaly was also
observed. Because of the subjects age and location of
skin lesions, the diagnosis of hereditary EB was suspected.
Microscopic examination of lesional skin samples
revealed subepidermal cleavage with the epidermis
remaining attached to the underlying dermis by hair
follicles (Fig. 2). Vacuolation of basal keratinocytes
was not seen. Staining with PAS highlighted the lamina
densa attached to the floor of the bulla, suggesting the
diagnosis of junctional EB.
Because of worsening skin lesions, the cat was euthanized for ethical reasons at the age of 6 months. At the
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Figure 1. Feline JEB, case 1: superficial ulcer on the anterior aspect

of the left ear pinna at initial presentation.

time of death, clinical examination revealed a large

corneal ulcer on the right eye, a residual linear crusted
ulcer underlying the left ear fold, and a severe stomatitis affecting the gingiva, pharynx, base of the tongue
and distal hard palate (Fig. 3). Rubbing of perilesional
skin did not result in iatrogenic blistering.
Skin biopsy specimens fixed in glutaraldehyde were
processed for ultrastructural studies and snap frozen in
liquid nitrogen for immunostaining. Similar areas were
biopsied in a normal cat for comparison. Transmission
electron microscopy examination revealed that the
lamina densa remained on the floor of the cleavage,
and that the hemidesmosomes were present but morphologically altered on the roof of the bullae.
Indirect immunofluorescence (IF) staining for the
three chains of laminin-5 was reduced in the subjects
skin samples when compared to those of the normal
cat. Staining with the polyclonal antibody SE83p, specific for human laminin 3, revealed a slightly reduced
intensity. A similar reduction in labelling was observed
with polyclonal antibodies directed against human
laminin 3, while the intensity of staining was strongly
decreased with the polyclonal antiserum (L628) specific for human laminin 2 (Fig. 4). The use of monoclonal antibody 1A8C, specific for the intracellular
portion of collagen type XVII demonstrated a granular
staining at the roof of the bullae. In addition, staining
for keratins 10 and 14, bullous pemphigoid antigen
230, plectin, laminin 1, collagen type IV and collagen
type VII was identical in normal and affected cats. The

Figure 2. Feline JEB, case 1: biopsy demonstrating the attachment

of the epidermis to the underlying dermis by the follicles (H&E,
100; bar = 50 microns).

Figure 3. Feline JEB, case 1: severe stomatitis at 6 months of age.

Figure 4. Feline JEB, case 1: comparative immunostaining of

laminin-5 components in the control (a, c, e) and affected (b, d, f)
cats. Immune reactivity for the laminin 3 (a, b), 3 (c, d) and
2 (e, f ) chains was assessed using polyclonal antibodies SE85p,
antihuman 3 and L628, respectively. Immunoreactivity for the
laminin 2 chain was strongly reduced and that of 3 and 3 was
weaker compared to the wild type control skin. The localization
of the staining at the floor of the blister is suggestive of the diagnosis
of JEB (bar = 50 microns).

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reduced immunostaining for laminin 3 and 3 chains

was believed to be caused by a defective synthesis of the
2 chain, because the stability of these two chains
depends on expression of 2 and incorporation into
laminin-5 heterotrimers.10
Altogether, clinical, histological and ultrastructural
findings, along with markedly reduced staining for
laminin 2, were felt to be consistent with the diagnosis
of nH-JEB secondary to defective laminin-5 synthesis.

Case 2
A 31/ 2-month-old, female domestic shorthaired cat was
referred with a history of nonhealing ulcerations of the
skin and onychomadesis. The kitten was from a litter
found by the owner at approximately 3 weeks of age. At
about 5 weeks of age, the owner noted onychomadesis
of multiple claws on different feet. Lesions were initially treated with topical antibiotic and antifungal
medicaments without improvement. Over the next
several weeks, the owner noted ulcerated lesions on the
skin and footpads. All littermates of the affected cat
and their queen were clinically normal, but historical
information was unavailable for the sire.
On presentation, the kitten exhibited multifocal
erosive to ulcerative lesions at the base of the right ear,
along the lip margins (Fig. 5a,b) and on the footpads
(Fig. 6). Multiple claws had been lost and there was
crusting around the claws of affected digits.
Biopsies of one clawfold and affected areas of skin
were submitted in formalin for routine histopathology.
Histopathological examination of perilesional skin
and clawfold region revealed subepidermal clefting
with minimal dermal inflammation (Fig. 7a,b). Immunostaining for collagen type IV confirmed that the
dermal-epidermal separation occurred above the lamina
densa of the basement membrane, thereby confirming
the diagnosis of JEB.
Indirect immunofluorescence was performed with
antibodies specific for human laminin-5 chains.
Whereas immunoreactivity for the laminin 2 and 3
chains appeared comparable to that of a control
healthy cat (Fig. 8a,b,e,f), immunostaining for laminin
3 was markedly reduced in the affected cat (Fig. 8c,d)
The results of these studies suggest that the secretion of

Figure 5. Feline JEB, case 2: ulceration and crusts are present on the
right lip commissure (a), while labial erosions and ulcers can be seen
next to the canine teeth (b).

Figure 6. Feline JEB, case 2: ulceration, scales and crusts on the footpads.

Figure 7. Feline JEB, case 2: there is dermo-epidermal separation

with subepidermal vesiculation occurring on haired skin (a) and claw
biopsy specimens (b). Hematoxylin-eosin stain.

Figure 8. Feline JEB, case 2: indirect immunofluorescence using

normal (wild type) feline salt-split lip (a, c, e) and lip biopsies from
JEB case 2 (b, d, f ). Antibodies tested are antilaminin 3 polyclonal
antiserum SE85 (a, b), anti3 monoclonal antibody K140 (c, d) and
anti 2 polyclonal antiserum SE144 (e, f ). While the intensity of the
fluorescence staining appeared comparable between control and
patient for the laminin 3 and 2 chains (a and b; e and f ), it was
reduced for the 3 laminin chain in case 2 (d) compared to the
normal cat (c).

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Z Alhaidari et al.

the laminin 3 chain was impaired in this cat with

nonlethal JEB.
This cat was re-examined at approximately 11 months
of age, along with a nonaffected littermate. Both cats
were of comparable size and stature. The affected cat
was declawed to prevent further onychomadesis and
the surgical sites healed without incident. The cat has
continued to thrive in a multicat household. Minor
ulcerated lesions have intermittently arisen, and have
been treated with topical antibacterial ointment.

DISCU SSIO N
The various hereditary forms of EB have rarely been
reported in cats. The most superficial form, EB simplex, resulting from a deficiency in the synthesis of keratin 5 or keratin 14, has to our knowledge not yet been
described in the cat. Dystrophic EB has been described
in a domestic shorthaired cat11 and in a Persian cat.12
The clinical presentation in those cases appeared very
similar to our cases, with a juvenile onset of ulcerations
in the oral cavity and on the footpads, and onychomadesis. However, epithelial sloughing at sites of mechanical
trauma is more prominent in dystrophic EB, probably
as a consequence of a deeper cleavage that occurs
beneath the lamina densa. Ultrastructural examination
in the Persian cat12 demonstrated a reduced number of
anchoring fibrils, and immunostaining revealed a
decreased expression of type VII collagen.
Both cats in this report presented with a junctional
form of EB. According to the revised classification system for inherited epidermolysis bullosa,2 subdivision
of JEB mainly recognizes two clinical subtypes: Herlitz
(e.g. lethal) and non-Herlitz variants of the condition.
Classically, human patients with H-JEB exhibit extensive detachment of the integument and mucosae with
early death of the affected individuals, while patients
with nH-JEB suffer from a milder phenotype, with
generalized lifelong blistering, yet a normal lifespan.13
Both subtypes of JEB are inherited as autosomal recessive conditions, and both can exhibit a generalized
distribution.2
Both variants of JEB have been reported in several
animal species including horses and dogs. It is interesting to note that skin fragility resulting in blister formation is common in humans, while in animals the
integument is less prone to lesions. Indeed, we were not
able to induce blistering in case 1 despite rubbing of
umbilical skin. One possible explanation for this phenomenon is that hair prevents detachment of the epithelium, 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 follicles as histologically demonstrated in case 1 (Fig. 2). Dystrophic or
absent nails is another frequent sign seen in human
patients with JEB, and this corresponds to sloughing
of hooves in horses with H-JEB, and to onychomadesis
in dogs and our two cats with nH-JEB. In all animal
subjects reported as affected with JEB, oral blistering

is a major clinical sign that impairs quality of life. Oral

involvement was severe in case 1. This cat also demonstrated a slight growth retardation, which was probably
due to a poor ability to nurse or ingest food. However,
none of our cats presented with enamel hypoplasia, a
classical finding of humans, dogs and horses with
JEB.3,7,14 Our first feline patient developed severe corneal ulceration, a sign observed in 40% of human subjects with JEB.15 To our knowledge, corneal ulceration
has not been reported previously in animals with this
disease.
The two cases of feline JEB reported herein illustrate
the genetic heterogeneity of this entity in cats. In our
patients, JEB was suspected to be caused by mutations
of the genes LAMC2 in case 1 and LAMB3 in case 2,
because of reduced immunostaining of skin biopsy
samples for the 2 and 3 laminin chains, respectively.
In conclusion, feline JEB appears to be clinically
heterogeneous, as shown by the relative mildness of
symptoms compatible with life-long maintenance with
conservative treatment in case 2 that contrasted with
the severity of ocular and oral involvement leading to
euthanasia in case 1. Unfortunately, the genetic mode
of inheritance of the condition could not be determined because of a lack of an informative family
pedigree, and the sporadic presentation of the disease.
However, the lack of skin lesions in all siblings and
mothers of these two kittens suggest a recessive mode
of inheritance, despite the possible implication of multiple sires. Unfortunately, studies that would elucidate
the genetic basis of JEB in cats would only be feasible
when cases occur in a restricted pedigree, as shown for
German shorthair pointer dogs with nH-JEB and
horses with H-JEB.

REFERENCES
1. Castiglia D, Posteraro P, Spirito F et al. Novel mutations
in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion,
and deposition. Journal of Investigative Dermatology
2001; 117: 7319.
2. Fine JD, Eady RAJ, Bauer EA et al. Revised classification
system for inherited epidermolysis bullosa: Report of the
Second International Consensus Meeting on diagnosis and
classification of epidermolysis bullosa. Journal of the
American Academy of Dermatology 2000; 42: 105166.
3. Linder KE, Olivry T, Yager JA et al. Mechanobullous
disease of Belgian foals resembles lethal (Herlitz) junctional epidermolysis bullosa of humans and is associated
with failure of laminin-5 assembly. Veterinary Dermatology 2000; 11 (Suppl.1): 24 (abstract).
4. Spirito F, Charlesworth A, Linder K et al. Animal
models for skin blistering conditions: absence of laminin5 causes hereditary junctional mechanobullous disease in
the Belgian horse. Journal of Investigative Dermatology
2002; 119: 68491.
5. Milenkovic D, Chaffaux S, Taourit S et al. A mutation in
the LAMC2 gene causes the Herlitz junctional epidermolysis bullosa (H-JEB) in two French draft horse
breeds. Genetic Selective Evolution 2003; 35: 24956.

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Feline epidermolysis bullosa

6. Spirito F, Capt A, Ortonne JP et al. Genetic bases of
canine junctional epidermolysis bullosa. Journal of
Investigative Dermatology 1999; 113: 1139 (abstract).
7. Guagure E, Spirito F, Capt A et al. Hereditary junctional
epidermolysis bullosa in the German Shorthaired
pointer: an epidemiological and clinical prospective
study of 21 cases. Veterinary Dermatology 2003; 14: 1037
(abstract).
8. ODair HA, Henderson JP. Suspected mechanobullous
skin disease in a cat. Journal of Small Animal Practice
1994; 35: 24 7.
9. Johnstone I, Mason K, Sutton R. A hereditary junctional mechanobullous disease in the cat. Proceedings of
the Second World Congress of Veterinary Dermatology.
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Montral, 1992: 1112.
10. Baudoin C, Miquel C, Blanchet-Bardon C et al.
Herlitz junctional epidermolysis bullosa keratinocytes
display heterogeneous defects of nicein/kalinin gene

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anchoring fibril formation and collagen VII immunoreactivity in feline dystrophic epidermolysis bullosa.
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Nakano A, Chao SC, Pulkinnen L et al. Laminin-5
mutations in junctional epidermolysis bullosa: molecular
basis of Herlitz vs. non-Herlitz phenotypes. Human
Genetics 2002; 110: 4151.
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Rsum Cet article rapporte deux cas dpidermolyse bulleuse jonctionnelle chez deux chatons.Les deux
animaux prsentaient des rosions des pavillons auriculaires, des ulcrations de la cavit buccale, et une
onychomadse. Lexamen histopathologique, la microscopie lectronique et/ou une immunoperoxydase indirecte
ont montr une fissuration sous-pidermique, la lamina densa restant au plancher des vsicules. Une
immunofluorescence indirecte a montr un marquage diminu pour la la laminine 5 (sous-unit 2 dans un cas
et 3 dans lautre).
Resumen Este artculo describe dos casos de epidermolisis bullosa de la unin en dos cachorros felinos no
relacionados. Ambos gatos mostraban erosiones en pabellones auriculares, ulceraciones orales y onicomadesis
grave. La histopatologa, la microscopa electrnica y/o la inmunoperoxidasa indirecta revelaron separaciones
subepidrmicas con persistencia de unin de la lamina densa al suelo de las vesculas. La inmunofluorescencia
indirecta revel una disminucin de la tincin para la subunidad 2 de la laminina-5 en el caso 1 y la subunidad
3 en el caso 2.

Zusammenfassung Dieser Artikel beschreibt zwei Flle von Epidermolysis bullosa junctionalis bei zwei nicht
miteinander verwandten jungen Katzen. Beide Katzen zeigten Erosionen an den Ohrmuscheln, orale
Ulcerationen und schwere Onychomadese. Histopathologie, Elektronenmikroskopie und/oder indirekte
Immunperoxidase zeigten subepidermale Spaltenbildung, bei der die Lamina densa an der Basis der Vesikel
angeheftet blieb. Indirekte Immunfluoreszenz zeigte verminderte Anfrbung der Laminin-5 2-Untereinheit in
Fall 1 und 3-Untereinheit in Fall 2.

2005 European Society of Veterinary Dermatology, Veterinary Dermatology, 16, 6973