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Persistent right aortic arch and associated axial skeletal malformations in cats

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 Journal of Feline Medicine and Surgery
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Persistent right aortic arch and associated axial skeletal malformations in cats
Giovanni Tremolada, Maria Longeri, Michele Polli, Pietro Parma and Fabio Acocella
Journal of Feline Medicine and Surgery 2013 15: 68 originally published online 18 September 2012
DOI: 10.1177/1098612X12459736

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59736 JFM15210.1177/1098612X12459736Journal of Feline Medicine and SurgeryTremolada et al

Original Article

Journal of Feline Medicine and Surgery

Persistent right aortic arch 15(2) 68­–73

© ISFM and AAFP 2012
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and associated axial skeletal sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1098612X12459736

malformations in cats jfms.com

Giovanni Tremolada1, Maria Longeri2, Michele Polli2,

Pietro Parma3 and Fabio Acocella1

Abstract
Persistent right aortic arch (PRAA) in cats is an uncommon vascular anomaly with clinical signs referable to
oesophageal obstruction. To our knowledge no reports of axial skeletal malformations concomitant to PRAA
have been reported in cats. The aim of this study is to depict a new clinical feature in cats affected by PRAA. In
the study six cats with a diagnosis of vascular ring anomaly were enrolled. A complete physical examination, a
neurological examination and a total body radiograph were performed on each animal. Four of the six cats showed
contemporary PRAA and skeletal malformations. Additionally, for the first time, a genetic test was performed on
one subject to detect DNA alterations in the homologous DiGeorge region of cat. The percentage of skeletal
malformations reported in the normal population was compared with animals with PRAA and showed a higher
frequency. Genetic testing failed to demonstrate a correlation between PRAA and DiGeorge genomic deletion. A
review of veterinary and human diseases that presented both conditions was assessed. The few animals enrolled
do not allow definitive conclusions. Further studies are required to corroborate the correlation between PRAA and
axial skeletal malformations in cats.

Accepted: 7 August 2012

Introduction
During embryogenesis mammals develop six pairs of
aortic arches. From the left aortic arch normally develop
the aorta, ligamentum arteriosum and left subclavian
artery; from the right one develops the right subclavian
artery. All vascular ring anomalies result from abnormal
development of arches III, IV or VI.1 These anomalies
have been reported in a wide variety of animal species,
including the domestic cat,2,3 cougars,4 dogs,5 horses,6,7
elephant seals,8 cattle,9 lamas and alpacas.10 The most
common anomaly in dog is the persistent right aortic
arch (PRAA) with a left ligamentun arteriosum (95%).11
No comparable data exist for PRAA in cat.
Clinical findings of vascular ring anomalies are usu-
ally referable to oesophageal obstruction. Dilation of the
oesophagus cranial to the base of the heart and left dis-
placement of the trachea are common radiographic
signs.11 Definitive diagnosis often requires exploratory
PRAA seems to be hereditary both in dogs and
humans.15,16 Heritability of heart defects in dogs, based
on epidemiological studies, indicates that purebred
dogs are more prone to develop heart defects than
mongrels. Breeding studies involving dogs with similar
heart defects showed a high frequency of congenital
heart disease in offspring. The type of heart defect
detected in those puppies was identical or closely
related to the one of the parents.15 In humans 80% of
conotruncal heart defects, including aortic arch abnor-
malities, have been associated with deletion of the
1Department of Veterinary Medical Science, University of Milan,
Milan, Italy
2Department of Veterinary Science and Public Health, University
of Milan, Milan, Italy
3Department of Animal Science, Agronomy Faculty, University of

surgery1 and prognostic factors are not completely clear. Milan, Milan, Italy
Some authors suggest that early surgical correction and
Corresponding author:
the presence of mild dilation of the oesophagus are Fabio Acocella DVM, PhD, University of Milan, Department of
indicative of a better prognosis,12 but more recent studies Veterinary Medical Science, Via Celoria 10, 20100, Milan, Italy
do not confirm this.13,14 Email: acocella@unimi.it
Tremolada et al 69

Figure 2  Presence of a thoracic block vertebra (T8-T9), a

butterfly vertebra (T12) and 6 lumbar vertebrae

Figure 1  X-ray showing 15 ribs in the left hemithorax. The

arrowhead shows the two ribs articulated within the same vertebra

chromosome 22q11 region,17 also known as the DiGeorge

region. DiGeorge syndrome is caused mainly by genomic
deletions: 90% are 3 Mb deletion, and 7% are 1.5 Mb
genomic deletions. The other 3% are represented by
other caused as TBX1 gene mutations.18 Deletion on this
region in humans can lead to concomitant skeletal and
vascular malformations. Comparative mapping of this
region failed to demonstrate its linkage to conotruncal
heart defects in dogs,19 but a more recent study on inher-
itance of a specific form of PRAA in German Pinschers
showed a chromosome-wide significantly-linked
genomic region on CFA26, which corresponds to the
human DiGeorge critical region (DGCR). However,
despite linkage and association between this form of
PRAA and the canine DGCR, none of the 13 genes and
their 36 polymorphisms appear responsible for it, sug-
gesting that chromosomal aberrations might be causal.20
Reports of multiple malformations in dogs21–23 and
cats24–27 have been published, but no skeletal malforma-
tions in animals affected by PRAA have been reported
with the exception of one case of cribriform plate aplasia
in an elephant seal.8 Additionally, no searching for dele-
tions in the DiGeorge region in cats has been performed.
Our aim is to describe the presence of a new clinical fea- Figure 3  Malformation of a caudal vertebra
ture in cats affected by PRAA and to attempt to correlate
this malformation with gross genomic alteration involv-
ing the DGCR.

Materials and methods haematological and biochemical analysis. Diagnosis was

All cats with a diagnosis of PRAA presented to the
Department of Veterinary Clinical Sciences, Section of
Surgery of the Università degli Studi di Milano from
November 2006 to December 2009 were included.
Informed client consent was obtained from each owner.
Each animal underwent a complete physical and neuro-
logical examination. Blood samples were collected for
based on clinical signs and on the presence of a dilation
of the oesophagus cranial to the base of the heart on con-
trast oesophagram. Given the finding of a malformed
thoracic vertebra in the first cat a total body radiograph
of each patient was assessed.
A lithium–heparin blood sample was collected from
one cat for genetic studies of the DiGeorge region using
70 Journal of Feline Medicine and Surgery 15(2)

Table 1  Animals included in the study and associated skeletal malformations

Patient number Age Sex Associated malformation

(months)

1 11 Female   •  Thoracicisation of L1
  •  Fifteen ribs in the left side of the thorax
  •  Caudal block vertebra
2 4 Male   •  Two thoracic butterfly vertebrae (T8–T12)
  •  Thoracicisation of L1
  •  Persistent left cranial vena cava
3 4 Female No associated malformations
4 2 Male No associated malformations
5 5 Male   •  Fourteen thoracic vertebrae
  •  Eight lumbar vertebrae
  •  Malformation of two caudal vertebrae
6 6 Male   •  Nine sternebrae
  •  Malformation of a caudal vertebrae

CGH array technology — a high-resolution tool for

human genome-wide DNA copy number variation pro-
filing (Human Genome CGH Microarray, 44K, Agilent)
— and cytogenetic techniques. Both analyses were per-
formed as reported in literature.28
All animals except one underwent a standard thora-
cotomy to confirm the diagnosis and correct the vascular
anomaly.

Results
Six animals with PRAA were included in the study,
including four males (all domestic shorthair) and two
females (Maine Coon and domestic shorthair). Their age
ranged from 2 to 11 months. Two cats (cats 2 and 3)
belonged to the same litter. In 4/6 cats we detected at
least an axial skeletal malformation. Malformations
reported were: supernumerary thoracic and lumbar ver-
tebrae, the presence of 15 ribs in the left side of the tho-
rax, anomalies of thoracic and caudal vertebrae and a
supernumerary sternebra (Figures 1–3). No alterations
of cervical vertebrae were detected. For a detailed list of
the malformations see Table 1.
Cat 1 did not undergo surgery because the owner Figure 4  Karyotype obtained from cat 5. The chromosomes
declined. All other subjects had the diagnosis of PRAA were Giemsa stained and arranged following standard cat
confirmed. In cat 2 concomitant persistence of the cranial karyotype
left vena cava was detected. After surgery animals were
fed with a liquid diet for 1 month. Then, they were fed
four times a day with small amounts of commercial diet. cat-specific copy number variation profiling array,
All animals stopped to regurgitate after the correction of we used a human CGH array. The cytogenetic analy-
the PRAA with the exception of cat 6, which maintained sis did not reveal any gross genomic alterations
the same clinical signs. (Figure 4). Despite the difference between the human
DNA analysis on cat 5 was carried out by both con- and cat genome the analysis worked well. The results
ventional cytogenetic techniques and CGH array obtained did not highlight any deletion in the DGCR
technology. In this case, owing to the absence of a (Figure 5).
Tremolada et al 71
Figure 5  CGH array result. In this case the critical region on
HSA22 for DiGeorge syndrome is displayed in the yellow box.
No duplications or deletions are present in this genomic region
Discussion
The normal spine of cats consists of seven cervical, 13
thoracic, seven lumbar, three sacral and 24 caudal verte-
brae. Usually, the sternum is composed of seven or eight
sternebrae. Any difference is considered to be abnor-
mal.29 From the results of a retrospective radiographic
study performed on vertebral segments of 200 cats
affected by various pathologies, 23% presented congeni-
tal axial skeletal abnormalities. Thoracicisation of L1 and
the malformation of the sacrocaudal junction were the
most notable malformations.30 No animal in this study
had concomitant skeletal and vascular malformation.
In our study 66% of the animals presented a skeletal
alteration located in the thoracic, lumbar, caudal spine or
in the sternum. No animals showed clinical signs related
to those anomalies as reported by Newitt.30 Even though
the number of subjects involved in our study is poor, cats
affected by PRAA seem to be more prone than the nor-
mal population in presenting this condition.
Of the two animals from the same litter only one had
vertebral malformations (male). This cat had persistence
of the left cranial vena cava. The heritability of PRAA has
not been described in cats, but has been demonstrated in
dogs.20,31 In dogs and cats some breeds are reported to be
prone to PRAA.32 However, we found this pathology
only in one declared pure breed cat (Maine Coon) whose
pedigree was not available. This variance should be due
to a larger presence of mixed breed with respect to pure
breed cats in the local population. To our knowledge this
is the first report of a Maine Coon affected by PRAA.
As there is a suspicion of genetic mutations in the
DiGeorge region in dogs affected by PRAA, we postu-
lated similarities between DiGeorge syndrome and
PRAA in cats.
In humans DiGeorge syndrome is caused by a micro-
deletion involving chromosome 22. The deletion occurs
near the middle of the chromosome at a location on the
long arm designated as q11.2. It has a prevalence esti-
mated at 1:4000 live births33 and it is thought to play a
role in as many as 5% of all congenital hearts defects.34
Symptoms consist of cleft palate, heart defects, learning
difficulties, vertebral malformations, renal anomalies,
thymic aplasia and hypocalcaemia.16,35 Butterfly verte-
brae were noted more frequently than in the normal
population. The combination of this anomaly with
conotruncal heart defects should heighten suspicion for
a deletion in the DiGeorge region.36 Alterations in the
cervical spine are described and are considered an
important marker of the 22q11.2 microdeletion syn-
drome.37 The pathogenesis of skeletal malformations
remains unclear in this syndrome at present, but the
haploinsufficency of the gene TBX1 may be implied.36
We did not report cervical malformations in the cats in
our study. To determine if cats should have a similar
syndrome all animals were evaluated for the presence of
other macroscopic anomalies. No concomitant altera-
tions were noticed at physical and neurological exami-
nation. In humans the diagnosis of DiGeorge syndrome
is made by fluorescence in situ hybridisation (FISH)
using DNA probes from the 22q11.2 chromosomal
region. DiGeorge’s minimal critical region is comprised
between base pair (bp) 17,398,178 and bp 19,779,416 on
chromosome 22 (refer to hg17). This region is a homo-
logue to cat chromosome D3 43,587,024–45,877,480 bp
(National Human Genome Research Institute/Genome
Technology Branch (NHGRI/GTB) V17e/felCat4 genome
assembly). The analyses of the gene content on this cat
genome region confirm that it is the homologue to
human DGCR. The negative results of the test cannot
exclude DiGeorge syndrome in cats because it was only
performed in one animal. However, this finding should
show that, as in dogs, PRAA is inherited in a complex
manner consistent with a polygenic basis15 or chromo-
somal aberrations.20 Another cause of association
between skeletal and vascular malformations can be the
deficiency of glypican 3, a heparan sulphate suspected
to be responsible for Simpson–Golabi–Behmel syn-
drome. This syndrome is characterised by a wide range
72 Journal of Feline Medicine and Surgery 15(2)
of developmental anomalies, including vertebral mal-
formations, vascular anomalies, macroglossia, dysplas-
tic and cystic kidneys, hernias and supernumerary
nipples.38 The vascular anomalies more commonly rep-
resented are patent ductus arteriosus, atrial septal defect,
ventricular septal defect, preductal coarctation of the
aorta and pulmonary stenosis. No aortic arch malforma-
tions were described in humans. Our animals did not
show macroscopic anomalies and a different cardiac
malformation was recognised. It cannot be excluded that
cats present a syndrome similar to that of humans
because mice with deletion of glypican 3, a validated
animal model of Simpson–Golabi–Behemel syndrome,
showed several of the clinical signs, but no vascular
anomalies.38. Looking for mutations of the gene encod-
ing for glypican 3, as in Simpson–Golabi–Behmel syn-
drome, would be important to demonstrate the
correlation between these pathologies.
In dogs and cats few accounts of concomitant malfor-
mations involving different organs have been described.
In dogs the ocular-chondrodysplasia of Labrador
Retrievers and Samoyeds is a syndrome characterized
by short-limbed dwarfism and ocular abnormalities.21,39
Differently from Labradors, Samoyeds can also present
concomitant haematological alterations.40 Kartagener’s
syndrome is another pathology in which multiple mal-
formations are present. Animals affected present situs
inversus totalis, rhinosinusitis and brochiectasia. The lat-
ter two signs refer to the presence of ciliary dyskinesia.
The pathology has also been seen in the Cavalier King
Charles spaniel, Dachshund, Chow Chow, Border Collie
and Doberman Pinscher.41
In cats multiple anomalies mostly affect the cardiac,24
skeletal42,43 and urogenital25 systems. A recent case report
described the presence of vertebral abnormalities, anal
atresia, radial agenesis, and cardiovascular and renal
defects in a kitten. The authors supposed that this ani-
mal was affected by a syndrome present in humans
called VACTERL (vertebral abnormalities, anal atresia,
cardiovascular defects, tracheoesophageal fistula/
oesophageal atresia, renal abnormalities, limb defects).42
In order for a case to be considered a VACTERL associa-
tion, two or more core defects must be present, ie,
oesophageal atresia, anal atresia, upper pre-axial limb
reduction defects and costovertebral abnormalities.44
None of those signs were present in the animals in
the current study with the exception of costovertebral
abnormalities. Moreover, some authors do not include
cardiovascular malformations in the diagnosis of this
syndrome.45 For this reason we discount the possibility
that our animals were affected by VACTERL syndrome.
Owing to the presence of concomitant multiple anom-
alies in animals, we suspected that skeletal malforma-
tions and PRAA could be related. PRAA in cats is
reported as not being a common condition.46 Collecting a
large number of animals from a single centre to deter-
mine the real incidence of the skeletal malformations is
difficult. The retrospective analysis of radiographs of
animals affected by PRAA from different centres should
aid in determining it. A larger number of subjects are
mandatory to confirm the correlation between PRAA
and axial skeletal malformations in cats. The genetic test
performed did not highlight deletion in the DGCR. The
test was only performed in one cat. Therefore, we cannot
consider it to be definitive data.
Conclusion
This study can be considered as the starting point for
further investigations to correlate the presence of these
two malformations and to evaluate the possible genetic
correspondence to human syndromes.
Acknowledgements  We are grateful to Stefania Gimelli
(Geneve University Hospital, Suisse) for help with the CGH
array analysis and to Professor Mauro Di Giancamillo (Univer-
sità degli Studi di Milano, Italy) for the radiographic images.
Funding  This research received no specific grant from any
funding agency in the public, commercial, or not for profit
sectors.
Conflict of interest  The authors do not have any potential
conflicts of interest to declare.
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