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Journal of Equine Veterinary Science 57 (2017) 95–99
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Journal of Equine Veterinary Science

journal homepage: www.j -evs.com
Case Report
Ehlers-Danlos Syndrome in a Mangalarga–Campolina
Crossbreed Mare
Jose P. Oliveira-Filho a,*, Peres R. Badial b, Robson M. Liboreiro c, Lissandro G. Conceição d,
Nena J. Winand e, Alexandre S. Borges a

a School of Veterinary Medicine and Animal Science, São Paulo State University (Unesp), Botucatu, São Paulo, Brazil
bDepartment of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Starkville, MS
cVeterinary Practitioners, Minas Gerais, Brazil
dDepartamento de Veterinária, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
eDepartment of Molecular Medicine, Cornell University, Ithaca, NY
a r t i c l e i n f o

Article history:
Received 3 February 2017
Received in revised form 16 July 2017
Accepted 16 July 2017
Available online 28 July 2017

Keywords:
Ehlers-Danlos syndrome
Horse
PPIB
Animal Care and Welfare/Ethical Approval Statem
performed were previously approved by the Ethics C
Use of the São Paulo State University (Unesp), S
Medicine and Animal Science (70/2008 CEEA).
Conflict of interest statement: The authors declar
conflict of interests.
* Corresponding author at: Jose P. Oliveira-Fi

Veterinary Clinical Science, School of Veterinary M
Science, São Paulo State University (Unesp), Prof. Do
Correa Street, Unesp Campus de Botucatu, Botucatu
Brazil.

E-mail address: zefilho@fmvz.unesp.br (J.P. Olive

0737-0806/$ – see front matter � 2017 Elsevier Inc
http://dx.doi.org/10.1016/j.jevs.2017.07.010
a b s t r a c t

The Ehlers-Danlos syndrome in horses is a group of genetic connective tissue disorders
clinically characterized by skin fragility and hyperextensibility. To date, only two of those
conditions (Hereditary Equine Regional Dermal Asthenia and Warmblood Fragile
Foal Syndrome [WFFS]) have been characterized based on the causative genetic
mutations. This report describes the dermatological and histological findings observed in
a 3.5-year-old Mangalarga and Campolina crossbreed mare with recurrent skin wounds.
Upon dermatological examination, the mare presented with hyperextensible, fragile, and
thin skin areas, and scars distributed mainly along the dorsal regions. Histopathological
evaluation of affected skin biopsies revealed collagen fibers abnormalities within the
deep dermis. The complete PPIB coding region was amplified, but no mutations were
observed. Moreover, the PLOD1 gene mutation responsible for WFFS was not present in
this animal. To our knowledge, this is the first report describing a Brazilian non-Quarter
horse mare with dermatological and histopathological findings of Ehlers-Danlos
syndrome.

� 2017 Elsevier Inc. All rights reserved.
ent: The procedures
ommittee on Animal
chool of Veterinary

e that they have no

lho, Department of
edicine and Animal
utor Walter Mauricio
, São Paulo 18618681,

ira-Filho).

. All rights reserved.
1. Introduction

In humans, the Ehlers-Danlos syndrome is a hetero-
geneous group of heritable connective tissue disorders
characterized by skin hyperextensibility, articular hyper-
mobility, easy bruising, and connective tissue fragility
[1,2]. These disorders occur due to abnormal collagen
biosynthesis as a result of mutations in several genes [3].
In horses, the Ehlers-Danlos syndrome also includes
different inherited connective tissue disorders based on
the clinical presentation, preferentially affected breed,
and causative genetic mutation. Two distinct disorders
(i.e., Hereditary Equine Regional Dermal Asthenia
[HERDA] and Warmblood Fragile Foal Syndrome [WFFS])
have been characterized based on the causative genetic
mutations [4,5].

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J.P. Oliveira-Filho et al. / Journal of Equine Veterinary Science 57 (2017) 95–9996
Hereditary Equine Regional Dermal Asthenia is an
autosomal recessive disease frequently described in the
Quarter Horses and related breeds [6–9]. Clinical signs
of the disease are usually associated with the beginning
of saddle training [8]. Hereditary Equine Regional
Dermal Asthenia is caused by a missense mutation
(c.115G>A) in the peptidylprolyl isomerase B (PPIB)
gene [4]. Warmblood Fragile Foal Syndrome is also an
autosomal recessive disease, but it affects Warmblood
breeds [10–14]. The disease is caused by a missense
mutation (c.2032G>A) in the equine procollagen-lysine,
2-oxoglutarate 5-dioxygenase 1 (PLOD1) gene [5].
Although the PLOD1 mutation has been identified in
only one case report [14], there are four other case
reports [10–13] published before the identification of the
causative mutation where the animals were suspected to
be affected by the same condition [14].

In addition, Ehlers-Danlos syndromes in horses were
described in a few previous reports [15–17]. In those
reports, a 2-year-old Arabian cross filly [15], a 6-year-old
Thoroughbred gelding [16], and a 7-year-old Quarter
Horse gelding [17] developed open wounds and atrophic
scars as a result of skin fragility. Furthermore, those
horses presented hyperextensible skin, which was most
evident over the shoulders and dorsum. Although the
clinical signs of the disease reported in those case
reports resembled both HERDA and WFFS, the disorder’s
cause (genetic or otherwise) was not determined.
Besides HERDA [9], other Ehlers-Danlos syndromes
affecting horses have not been previously identified in
Fig. 1. (A) Mangalarga and Campolina crossbreed mare with Ehlers-Danlos syndrom
presenting leukotrichia. (C) Marked cutaneous hyperextensible (stretched 10 cm abo
returned to its original position.
Brazil. This report describes the dermatological and
histological findings and the molecular characterization
of the complete PPIB coding region in a Mangalarga and
Campolina crossbreed mare affected with Ehlers-Danlos
syndrome.

2. Case Presentation

A 3.5-year-old Mangalarga and Campolina crossbreed
mare was referred for evaluation of recurrent skin wounds
over the back that had been present for over 1 year. The
owner also reported fragile and elastic skin along the body.
The owner was unaware of any traumatic incident that
could have caused the wounds. The mare had been
purchased as a foal at an auction with no apparent skin
abnormalities.

At presentation, the mare was in good body condition.
Physical examination revealed bilateral asymmetric skin
lesions distributed mainly on the neck and along the dorsal
regions. The abnormalities consisted of fragile and thin
skin, scarring, and tumor-like masses. The abnormal skin
was also hyperextensible when pinched up (stretching
about 10 cm above the skin surface), slowly returning to its
normal position upon release. Marked leukotrichia was
observed over the right shoulder on an area that had been
previously wounded (Fig. 1). Besides the dermatological
findings, no evident ocular and musculoskeletal abnor-
malities were observed.

Incisional biopsies were performed on the affected
areas of the neck and dorsal loin region after local
e. (A) Right side view of the whole body. (B) Healed lesion at the right side
ve the skin surface) on the left dorsum area. (D) Hyperextensible skin slowly



Fig. 2. Histological appearance (H&E) of the skin in mare affected with Ehlers-Danlos syndrome. (A) Control Quarter Horse. (B) Affected mare. Note the loosely
arranged thin, small, and fragmented collagen bundles within the superficial and perifollicular dermis in the affected skin.

J.P. Oliveira-Filho et al. / Journal of Equine Veterinary Science 57 (2017) 95–99 97
anesthesia with lidocaine 2% (Xylestesin, Cristália, Itapira,
São Paulo, Brazil). The skin samples were routinely pro-
cessed. Histopathological evaluation of the skin speci-
mens revealed thin, small, and fragmented collagen fibrils
that created a mild loose arrangement of the collagen fi-
bers within the superficial and perifollicular dermis
(Fig. 2). Mild perivascular mononuclear infiltrate was
found in the superficial dermis. The epidermis and
epidermal adnexa were unaffected. The presumptive
diagnosis of Ehlers-Danlos syndrome was made based on
the history, dermatological signs, and histopathological
examination.

DNA was purified from whole blood using the Ilustra
blood genomic Prep Mini Spin Kit (GE Healthcare Life
Science, Little Chalfont, Buckinghamshire, UK). The mare
was tested for both HERDA and WFFS causative
mutations. The missense mutation in the PPIB gene was
evaluated as previously described [18]. PLOD1 gene
mutation was evaluated at Cornell University [5]. The
sequences were analyzed, and the mutations were not
confirmed. Then, we performed the characterization of
the complete PPIB coding region in order to observe any
mutation that could be related to the disease. Primer sets
were designed with the Primer Express software (Applied
Table 1
Primer sets used for the peptidylprolyl isomerase B coding region characterizati

Primer Set Sequence (50d30)

P1 ForwarddCCCGCGGGGGACCTACTATT
ReversedGGCTGAGGTGTCCGGGTCAT

P2 ForwarddTTCTCCCGGTGGATGCTGCGTTT
ReversedTTTGCAACAGACAGCACTGAGGC

P3 ForwarddCGTAGTCTGAAGGAGAGTGGCAAA
ReversedAACAGTTAGCTGGTACCCAGTGAG

P4 ForwarddATAATTCTGGCCAGCAGCAGTGTC
ReversedTACAAAGAAGGGTGCAGCTGGTCT

P5 ForwarddACACTTGGTCAGCATGGTTTGGCT
ReversedGAACAATGGTCTGAATCTGTGGGT

P6 ForwarddCCTCAAGGCTTGTATGCTGCTTGT
ReversedAAACTGGGCCCTGTGGAATGTGA

P7 ForwarddCACTGGGGCCTGCCTCTCTT
ReversedTGGGGAATGGGTTCAGGCCA
Biosystems, Grand Island, NY) (Table 1). The provisional
PPIB gene sequence (Gene ID: 100066834) of the equine
reference genome assembly (EquCab2.0) available in the
NCBI GenBank was used to design the primer sets. The
exon 1 forward primer and the exon 5 reverse primers
were anchored in the 50 and 30 untranslated regions of the
PPIB gene, respectively.

The 50 mL polymerase chain reaction contained 25 mL of
GoTaq Green PCR Master Mix (Promega, Madison, WI),
0.3 mM of each forward and reverse primer, 5 mL of tem-
plate DNA, and nuclease-free water to complete the final
volume. The amplification conditions were as follows:
initial denaturation at 95�C for 2 minutes; followed by 35
cycles of denaturation at 95�C for 30 seconds, annealing at
55�C for 30 seconds, and extension at 72�C for 1 minute;
followed by a final extension at 72�C for 5 minutes.
Amplicons were analyzed by 1.5% agarose gel electro-
phoresis, purified, and submitted to direct sequencing. The
obtained sequences and electropherograms were analyzed
using Sequencing Analysis 5.3.1 software (Applied Bio-
systems, Grand Island, NY) and aligned against the refer-
ence genome sequence. Homology differences were not
observed between the mare and wild-type PPIB coding
region sequences.
on.

Product (bp) Fragment Amplified

521 UTR5 and exon 1

420 Exon 1

465 Exon 2

372 Exon 3

498 Exon 4

410 Exon 5

535 Exon 5 and UTR3



J.P. Oliveira-Filho et al. / Journal of Equine Veterinary Science 57 (2017) 95–9998
3. Discussion

The clinical history, dermatological signs, histopatho-
logical examination, and the absence of the HERDA and
WFFS causativemutations are consistent with a diagnosis of
Ehlers-Danlos syndrome. To date, PPIB and PLOD1 causative
mutations allow equine practitioners to differentiate
between HERDA [4] and WFFS [5]. Cases that are not
diagnosed as one of those diseases are commonly referred
as Ehlers-Danlos syndrome or simply a disorder of collagen
[15–17]. The clinical and histopathological findings of these
disorders are quite similar [8,9,13,14,19], making the
differential diagnosis difficult with no genetic information.
However, clinical presentation, age of onset of dermato-
logical findings, and affected breed usually help to differ-
entiate between HERDA and WFFS.

Hereditary Equine Regional Dermal Asthenia–affected
horses exhibit dermatological lesions with 1.3 years of age
after the beginning of saddle training, and the lesions are
mainly distributed along their dorsum [8], which are the
area of the body most exposed to sunlight [20]. Similarly,
lesions in horses affected with Ehlers-Danlos syndrome
occur on the shoulders and dorsal areas, but the age of
onset of dermatological signs varies between 2 and 7 years
[15–17]. Typically, WFFS affects neonates and juvenile
horses up to 6 weeks of age usually presenting hematomas,
multiple lacerations, and skin fragility in the flanks, limbs,
perineum, and abdomen [10–14]. However, a previous
report described a 1.5-year-old Swiss Warmblood filly with
lesions distributed in the flank and along the back, which
was tested negative for the PPIB mutation causative of
HERDA [12] and the PLOD1mutation causative of WFFS [5].
The clinical presentation and age of onset of dermatological
signs in the present case report were very similar to
those observed in HERDA [8], the case of the Swiss
Warmblood filly [12], and previous cases of Ehlers-Danlos
syndrome [15–17].

Horses affected with HERDA exhibit increased incidence
of corneal ulcers, mild corneal opacity, decreased corneal
thickness, increased curvature diameter of the cornea, and
multifocal corneal collagen fibers disorganization [21,22].
Moreover, HERDA-affected horses show profoundly artic-
ular hypermobility and weaker tendinoligamentous tissues
[23,24]. The mare reported here did not exhibit articular
hypermobility or ocular abnormalities such as opacity, ulcer,
and evident scar of the cornea. This animal was a single case
diagnosed in a rural areawith no interest of a more detailed
examination by the owner. Hence, we did not measure the
thickness, curvature, or diameter of the cornea, did not
evaluate ocular tissue histological sections, and did not
perform ultrastructural and biomechanical evaluations of
the tendons or ligaments. Therefore, we cannot rule out the
possibility of clinically nonevident ocular findings or
abnormal physical weakness in collagen-rich tissues.

Unlike HERDA and WFFS, which are described in the
Quarter Horse and Warmblood breeds [6,8,13,14], the mare
described here was a crossbreed of the Mangalarga and
Campolina breeds. In the 18th century, those breeds were
originated in Brazil from breeding Portuguese Alter real
and the Spanish Andalusian horses with native horses [25].
The Mangalarga and Campolina breeds have no known
Quarter Horse or Warmblood ancestors [25], which could
segregate the causative allele mutations. Therefore, it is not
surprising that PPIB and PLOD1 mutations tested negative
in the mare reported here. In addition, the probable
inheritance pattern of the condition could not be
performed in this case report because the owner did not
have any information besides the breeds of origin.

In humans, distinct mutations in the same gene may
cause similar clinical phenotypes of Ehlers-Danlos syn-
drome [2]. Despite the negative results for PPIB and PLOD1
causative mutations, the case described in the present
report resembled HERDA regarding the age of onset,
dermatological signs, and localization of the lesions.
Therefore, we decided to perform the entire characteriza-
tion of the equine PPIB coding region. Although nomutation
was observed in the characterized PPIB coding region, other
candidate genes were not investigated because the case
reportedwas an isolated diagnosis. It is possible that, similar
to the disease in humans, the Ehlers-Danlos syndrome in
horses is a group of several diseases caused by mutations in
several genes and/or distinct mutations in the same gene
[17]. Therefore, despite being clinically distinct from WFFS,
we cannot rule out another mutation in PLOD1 as the
causative of the phenotype described. It is also possible that
the present case might be the result of novel and sponta-
neous mutation as previously suggested [17].

In summary, this is the first report in Brazil describing a
horse affected with Ehlers-Danlos syndrome which
clinically resembled HERDA, but without a PPIB mutation.
The disease might be associated with novel mutations in
the PLOD1 coding region or in another gene involved in the
collagen biosynthesis rather than PPIB.
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	Ehlers-Danlos Syndrome in a Mangalarga–Campolina Crossbreed Mare
	1. Introduction
	2. Case Presentation
	3. Discussion
	References