ArticlePDF Available

Hypochondroplastic dwarfism in the Irish setter

Authors:

Abstract and Figures

Two test matings in the irish setter were performed, and genetic, clinical, morphometric, radiographic, bone histological and plasma and urine biochemical features of dwarfism were studied. All offspring were phenotypically normal at birth and weaning, but at the age of 2.5 to 4 months the longitudinal growth of the spine and leg bones was retarded in the dwarfs compared with the normal littermates. Most dwarfs performed well, even in the field. Radiographic and histological evaluations revealed a hypochondroplasia. A morphometric diagnostic method for Irish setter dwarfism was developed. A single autosomal recessive mode of inheritance was verified.
Content may be subject to copyright.
Hypochondroplastic dwarfism
in
the
Irish
setter
Two test matings in the Irish setter were performed, and genetic,
clinical, morphometric, radiographic, bone histological and plasma
and urine biochemical features of dwarfism were studied.
All
offspring were phenotypically normal at birth and weaning, but at
the age of
2-5
to
4
months the longitudinal growth
of
the spine and
leg bones was retarded in the dwarfs compared with the normal
littermates. Most dwarfs performed well, even in the field.
Radiographic and histological evaluations revealed a
hypochondroplasia.
A
morphometric diagnostic method for Irish
setter dwarfism was developed.
A
single autosomal recessive
mode
of
inheritance was verified.
I.
HANSSEN,
G.
FALCH*,
A.
T.
C.
V.
ISAKSEN~
~ouriai
of
Small
AG~/
Practice
(1998)
GRAMMELTVEDTt,
E.
HAUG~
AND
39.
10-14
Strinda Small Animal
Clinrc.
Jonsvannsveien
137.
N
7048
Trondheim Norway
*Departments
of
Pharmacology and
Toxicology.
1
Radiology and
:Pathology,
The
Norwegian
University
of
Science and
Technology. N
7006
Trondheim.
Norway
§Hormone Laboratory, Aker
Hospital N-0514
Oslo,
Norway
10
-
INTRODUCTION
Dwarfism in Irish setters has been previ-
ously described by Hanssen
(1992).
Such
dwarfs were observed in eight litters,
10
females and one male. Construction of
composite pedigree and statistical analyses
indicated that the mode of inheritance
was
a
simple, autosomal recessive and that
the gene was introduced to Norway by a
male imported from Ireland in
1969.
According to breeders, the pups seemed
normal at birth and weaning, but started
to develop abnormal body proportions
from the age of three months. The limbs
and spine became gradually shorter com-
pared with normal Irish setters. Because
the dwarfs appeared in the line of Irish set-
ters recruiting the best field trial dogs in
Norway, it was expected that additional
dwarfs would follow and result
in
a prob-
lem in Irish setter breeding. Time has
shown this
to
be true; dwarfs have
appeared from many different parents
from
the same line during the past four
years, and have also been observed in
Sweden and Finland.
The breeding council
of
the Norwegian
Irish setter
club
decided to ban male dogs
which had bred dwarfs from hrther breed-
ing. This generated a discussion among the
members of the club, and some breeders
declined
to
accept the decision. They
JOURNAL
argued that an objective method to sepa-
rate dwarfs from small, normal Irish setters
should be developed, and were not con-
vinced that the mode of inheritance was
a
simple, autosomal recessive because many
more females than male dwarfs were
observed in the material of Hanssen
(1992)
and subsequently.
The Norwegian Irish setter club
decided therefore on a test breeding pro-
gramme. The objective of this study was to
provide evidence as
to
the mode
of
inheri-
tance and to improve the diagnosis
of
Irish
setter dwarfism by searching for useful
plasma and urine biochemical parameters
and by describing its morphometric, clini-
cal, radiographic and bone histological
features.
MATERIAL
AND
METHODS
Breeding and rearing
Two test matings were performed. One
dwarf female was mated to a normal
phenotype male which had previously pro-
duced dwarfs with a normal phenotype
female (mating
A).
From this mating
a
50/50
distribution
of
normal and dwarf
offsprings was expected. Another female
dwarf was mated to a male dwarf (mating
B). From this mating
all
offspring were
expected
to
be dwarfs.
The females were vaccinated against
parvovirus and parainfluenzavirus (Can-
lan
PP;
Langford Laboratories) a few days
after mating and kept in private homes
during pregnancy. Female
A
delivered her
pups at home, but was moved to a state
recognised kennel after one week. Female
B
was brought to this kennel one week
before expected delivery. The mothers
were fed a chicken based commercial dry
feed (Lone Star Precise Growth; Texas
Farm Products) comprising 27 per cent
protein,
16
per cent fat and 1713
KJ/IOO
g
metabolisable energy). This feed was
also offered to the pups from three weeks
of age.
The pups were individually marked
at
the day of birth; numbers
1
to
13
for pups
SMALL
ANIMAL
PRACTICE
VOL
39
JANUARY
1998
from mating A, and numbers
14
to
19
for
pups from mating B. The pups were
placed in private homes once they reached
five months
of
age.
Bodyweights and morphometry
The pups were weighed weekly from
birth
until they were eight weeks old. Body mea-
surements were performed from five weeks
of
age
until the dogs were one year old.
The selected measurements were recog-
nised differences between dwarf and nor-
mal Irish setters and the identifiable
measure points in the actual
areas
(Fig
1).
Initially, the measurements were made
once weekly, but after five months of age,
when the pups were transferred to private
owners, three body measures
(1,
2
and
3
on Fig
1)
were taken once monthly. At the
age
of
one year, the shoulder height was
measured.
All
measurements were rounded
to
the
nearest
half
centimetre.
Body measurements were also taken
from other adult normal
(21)
and dwarf
(16)
Irish setters, and from other normal
pups. Thus this material consisted of
155
body measure sets from normal dogs, and
131
from dwarfs. Eighteen normals and
five dwarfs were measured once, while the
other4 were measured between four and
20
times, most of them
12
to
15
times.
Statistics
The sum of head length and circumference
was plotted against body length.
For
the
normal dogs, the least squares regression
equation was calculated and the regression
line was plotted with
95
per cent predic-
tion intervals for individual observations.
In Fig
2
a two-tailed
t
test for independent
samples was applied
for
the comparison
between dwarfs and normal individuals.
The binominal distribution was used
to
calculate the probability of giving birth to
an uneven number of dwarfs and normal
phenotypes from maring
A.
Radiographic evaluation
Most of
the
pups were radiographed at
eight weeks, a few for the first time at five
months and some at both eight weeks and
five months. Radiographs included lateral
views
of
the spine and frontal views of the
forelegs in
d
pups; additional lateral views
were taken in several pups and hindlimb
views were
also
available in the majority of
cases. One dwarf and one normal dog were
followed regularly from eight weeks until
12
months.
Bone histology
Bone specimens were taken from the distal
radiuslulna and the thoracic spine in two
FIG
l.
Body
measurements
from
dwarf and nomal phenotype Irish setters.
1
Head length
from
the
nose
Crp
to
the neck depression behind protuberantia occipetalls, 2 Head circumference at the
mlddk afthe skull,
3
Body length
from
the neck depression along the spine to the tall end,
4
Humww
length
from
tuberculum
maJus
to eplcondylus lateralis,
5
Lower foreleg length
from
the
hind
of
the main sole pad to tuber olecrani,
6
tlbla
length
from proximal lateral end to
miledm
laterale,
7
Foot length
from
the hind margin
of
the main sole pad to tuber calcanei,
8
Ghdkr
helght
from
the
ground
dong
the forellmb
to
the highest
point
of
scapula. Measurements
1,2,3
were
taken
by
tape
measure
while the others were taken using
a
stick measure
pups from mating
B
which died
at
six
weeks old following an enteritis. Speci-
mens from
the
same sites were also taken
from two five-month-old dwarfs from
mating
A
which were euthanased, one
because of severe lameness and radiological
changes in the forelimbs, and the other
because of continual seizures. The bone
specimens were preserved in
10
per cent
buffered formalin, decalcified in nitric
acid, embedded
in
parain, sectioned at
4
pm and stained with haematoxylin-
eosin-saffran
(HES)
and periodic acid-
Schiff (PAS).
Blood and urine analysis
Blood samples were taken
from
the
cephalic
or
jugular vein in EDTA tubes
from
all
pups at two, three and
a
half
and
five months of age. Urine samples were
collected from three normals and five
dwarfs at five months of age. The blood
specimens were submitted
to
routine
haematologid investigations. The plasma
levels of insulin-like growth factor
1
(IGF-
I),
osteocalcin, carboxyterminal telopep-
tide of type
I
collagen
(ICTP)
and the
urinary excretion of deoxypyridinoline
(D-
Pyd) were measured by immunoassays
intended
for
human use.
IGF-1
is
an important stimulator
of
<
304050607080
Head
length
+
circumference (cm)
FIG
2.
lndivldual observations from dwarfs are
plotted with the regression line (y=2.3x -39.2)
and
95
per cent confidence
lhb
for lndfvklual
observatlons
from
the normal dogs
JOUR",AI
OF
SMALL
ANIMAL
PRACTICE
VOL
39
JANUARY
1998
11
-
skeletal
growth
and a mediator
of
growth
hormone. Osteocalcin is produced by the
osteoblasts and its concentration in plasma
is
a
sensitive measure of bone turnover in
metabolic bone disease, and has been
found to reflect mainly bone formation.
lCTP
and D-Pyd are fragments from
bone collagen type
I,
and are released to
plasma by bone degradation.
IGF-1
was measured by radio-
immunoassay after acidification and sepa-
ration
of
IGF-1 from binding proteins
using octadecasilyl-silica cartridges (C18
Sep-Pak; Nichols Institute Diagnostics).
Osteocalcin and
1
CTP were measured by
radioimmunoassays (Orion Diagnostica
and Henning Berlin
GMB4,
respectively).
D-Pyd was measured by radioimmuno-
assay (Metra Biosystems) and expressed
as
nmol D-Pydlmmol creatinine. The intra-
assay coefficient of variation
was
5
to
10
per cent and the interassay coefficient
of
variation was
7
to
10
per cent.
RESULTS
Pups
and clinical signs
Female
A
delivered 14 pups: eight females
and
six
males. One male was weak at birth
and died the next day while the others
sur-
vived and were reared. Two female pups
showed a markedly lower bodyweight at
birth and during the first two months
compared with their Iitcer sisters; one
became normal, whiie the other became a
dwarf. One fernale dwarf (pup
3)
was
euthanased at the age
of
five months
because of severe lameness in the left fore-
limb. This dog showed a markedly bowed
radiushlna, carpal valgus and elbow pain.
One male dwarf (pup 4)
was
euthanased at
the same age because of epileptiform
seizures.
Female
B
delivered
six
pups: three
females and three males.
At
the
age
of
six
weeks all pups developed diarrhoea which
killed
two
females.
The other pups in both litters
grew
up
without any disease problems during
their
first
year
of
life.
Some dwarfs showed
straight forelimbs, while most
of
them
showed bowing of radiuslulna and carpal
valgus that varied from slight to marked.
In litter
A
there were eight dwarfs (four
of each sex) and five normals (three females
and
two
males). If the probability of giving
birth
to
a
dwarf and a normal phenotype is
equal and
0.5
(Pd=Pn=O-5), the birth
of
13
pups where eight
or
more pups are dwarfs
can be ordered in 2380 combinations giv-
ing an exact probability
of
eight
or
more
dwarfs: 2380X0.513=0.291. Thus, in a lit-
ter
of
13
pups, eight
or
more dwarfs will be
expected in about
30
per cent of matings if
the probability
of
being a dwarf is equal to
the probability
of
being normal. This
is
the
case if
the
trait is inherited autosomal
recessive with a homozygote female mated
with a heterozygote male. Thus the distri-
bution of dwarfs and normals in the
off-
spring is not significantly different from
what is expected in the present situation.
In litter
B
there were four dwarfs (one
female and three males), which is also in
accordance with the hypothesis of the
autosomal recessive mode
of
inheritance.
Bodyweights and measurements
Adults
Table
1
shows the body measurements
of
the adult Irish setters. The head length and
circumference were similar in normal
phenotypic and dwarf dogs, while the
body, humerus, lower
foreleg,
tibia,
foot
length and shoulder height were shorter in
dwarfs compared with normal Irish setters.
The largest difference was found bet-
ween their body lengths. Table
1
also
shows the ratio between body length and
the sum of the head length and circumfer-
ence.
Pups
There was no difference in bodyweight
between normal phenotype and dwarf
pups during the eight first weeks of life.
The relationship between the sum of
head length and circumference
for
each
dog and body length was linear for the
normal dogs and could be expressed as
y=2.3x-39.2, with a lower 95 per cenr
prediction interval
for
any individual
observation, y=2.3x-47.7 (Fig
2).
For
the
dwarfs, the relationship between
the
two
variables was non-linear and best
expressed
as
y=-0.29x2
+
4-7x-72.3.
As
shown in Fig
2,
where the dwarfs have a
head size (Iength+circumference) below
50
cm they are inside the 95 per cent pre-
diction interval
for
the normal phenotype.
However, where the head size reaches
60
cm,
all
have a body length below the lower
95 per cent prediction line for the normal
phenotype.
Table
1.
Body
measurements in centimetres
(flSD)
of adult normal and dwarf
Irish setters
Male
Female
Normal
Dwarf
Normal
Dwprf
(n=8)
(nt9)
(n=W)
(n=7)
Head length
Head circumference
Head length and circumference
Body
length
Ratio body length/head
Tibia length
Shoulder height
Foot
length
Humerus length
Lower forelimb length
*PcO-Ol
(normal versus
dwarf)
tPcO.05
(normal versus dwarf)
length and circumference
27.8 (1-3)
40.3 (2.5)
68.1 (3.2)
119.8 (17.2)
1.8 (0.3)
20.9 (0-5)
63.9 (2.8)
16.4
(0-5)
17.7 (0-8)
31.8 (0.9)
27.6 (1.5)
40.2 (2.2)
67.8 (2.9)
93.3 (8.3)*
1.4 (0.1)*
18.3 (0.6)*
56.1 (1-5)*
15.0
(O.O)*
16.3 (0.6)t
28.3 (1.3)f
26.0 (1.2)
36.2 (1.5)
106.7 62.2
(2.3)
(5.0)
1.7 (0.1)
19.6
(1.1)
58.7 (3.4)
15.3
(0.7)
16.8 (1.1)
30.4 (1.4)
25.0
(1-0)
36.0 (1.5)
61.0 (2.0)
84.9 (5.0)*
1.4
(0.1)*
17.0 (0.7)*
52-7
(1.0)*
13.9 (0.5)*
14.9 (0.3)*
25.5 (1.0)*
JOURNAL
OF
SMALL
ANIMAL
PRACTICE
VOL 39
JANUARY
1998
Radiographic evaluation
The radiographs showed no epiphyseal
irregulxities when normal individuals and
dwarfs were compared. The metaphyses
were regularly shaped in dwarfs with the
exception of pup
3
where the metaphyses
at the age of five months showed some
broadening and flaring (Fig
3).
Measurements showed the long bones
of the dwarfed dogs to be shortened com-
pared with the normal individuals. There
was
some
tendency towards bowing of the
radius 'ulna, most prominently seen in pup
3
at five months of age.
The
vertebrae were regular in shape in
both dwarfed and normal individuals.
Measurements showed shortening in the
vertebral bodies of the dwarfed dogs.
ossification. The epiphyseal centre
of
ossi-
fication lay near the chondro-osseous junc-
tion, somewhat overlapping this towards
Histological examinations
The distal end of the ulna and radius was
examined histologically in four
of
the pups
(3,4,
17
and 19). Part of the thoracic spine
was al\o examined from puppy
19.
Puppies
17
and
19
were six
weeks
old
and clinically normal while puppies
3
and
4
wert
five
months old and dwarfs. Histo-
logical examination of the distal radius and
ulna in puppy 17 and the distal radius and
thoracic spine in puppy
19
showed well
organwd enchondral ossification and
unremarkable periosteal ossification. The
epiph\.ses of the distal radius in puppies
3
and
4
were widened; the enchondral ossifi-
cation was mostly well organised although
the height
of
the cartilage columns seemed
to vary a little, and in some areas it
appeared to be shorter (Fig
4
).
In rhe spongiosa there also seemed to be
a slight difference, the osseous trabeculae
appearing
to
be more unevenly distributed
and perhaps thicker and more compact
than
in
cases
17 and
19,
although
the
dif-
ference in age makes this difficult to assess.
The changes were most pronounced in
pupp)
3;
in the distal ulna the ossification
zone
was
quite irregular and the bony tra-
beculu thicker.
There was a certain degree
of
over-
growth
of
the periosteal ossification, prob-
ably hecause of
a
decrease in enchondral
The histopathological findings are
most
consistent with a mild achondroplasia, and
the authors choose to call it
a
hypochon-
FIG
3.
Lateral radlographic vlews
of
the dlstai forellmbs at Rve months of age In
(A)
a normal
Indlvldual,
(B)
a dwarf wlth straight radlus/ulna and regularmetaphyses and (C) a dwarf (pup
3)
with some bowing of the radlus/ulna and metaphyseal irregularlty
of
the dlstal ulna. Processus
anconeus is detached (arrow)
FIG
5.
Dlstai ulna of a dwarf (pup
3)
wlth
overlapping
of
the epiphyseal centre of
ossification in the periphery.
HES
x
100
FIG
4.
Cartilage columns in distal radius in a
dwarf (pup
3).
HES
xl00
JOURK
11.
OF
SMALL
ANIMAL
PRACTICE
VOL
39
JANUARY
1998
13
-
Table
2.
IGF-1,
osteocalcin and lCTP in plasma, and DPyd in urine from
five-
monthold
dwarf
and
normal phenotype Irish setters (median and range)
16F-1
OstemWn
lCTP
DPydnmol/md
(nmd/lRre)
nmoi/lftre
g/litre
creatlnine
Normals
(4)
48.1 4.1 22.0 21.3+
Dwarfs
(4) 38.0
4.6
26.9 14.4
Dwarf (pup no.
3)
94.2
8.0
34.1 21.8
14.5-60.4 3.1-7.3 17.6-28.0 96-31.3
7.9-58.5 3.2-6.2 21.2-27.5 12.5-20.4
Forelimb lameness
Haematological
and
plasma
and
urine
biochemical
analyses
The
haemograms
of
the dwarfs were nor-
mal. The plasma and urine concentra-
tions
of
bone turnover indicators were
similar
in
dwarfs and normals, with the
exception
of
one pup (case
3)
with severe
foreleg lameness which showed markedly
increased
IGF-1
and slightly increased
osteocalcin and
lCTP
plasma concentra-
tions (Table
2).
The results show chat the Irish setter
dwarfs have normal body proportion and
bone histolop
for
several weeks after
birth. While the
flar
bones continue to
develop normally,
the
longitudinal growth
of
the
vertebrae and the
long
bones retard
ar
'1
later
momenr compared with the nor-
mal phenotypes. Radiological examina-
tions revealed no obvious irregularities in
rhe growrh zones
of
most dwarfs. Histolog-
ical changes, however, were found in the
growth zones of some dwarfs which are in
accordance with
the
description
of
hypochondroplasia,
a
mild form ofachon-
droplasia (Spranger
1992).
The authors were not able to find a
plasma
or
urine parameter
for
diagnostic
purposes
in
Irish setter dwarfism. The
diagnosis was based on the ratios between
body length and the sum of head length
and circumference, shoulder height (Table
I)
and clinical examinations
of
the dog.
The upper and lower
95
per cent predic-
tion intervals were calculated
for
the indi-
vidual observations
as
well
as
the regression
line
for
the ratio between body length and
the sum
of
head length and circumference
for
normal phenoryyes during growth.
Any individual observation which falls
autside this interval does not, with a prob-
ability
of
95
per
cent, belong to the group
of
normal dogs. Such a plot
(
Fig
3)
is
therefore
useful
in the evaluation
of
whether
a
dog is a dwarf before it is
fully
grown, in fact from
10
to
14
weeks
of
age.
Chondrodysplastic dwarfism
has
been
described
for
several dog breeds. Multiple
epiphyseal dysplasia has been identified in
beagles (Rasmussen
1975);
dwarfism with
concomitant macrocytic anaemia is seen in
Alaskan malamutes (Fletch and others
1973);
while dwarfism associated with
ocular defects has been described in
Labrador retrievers and samoyeds (Carrig
and others
1977,
Meyers and others
1983).
Other forms
of
chondrodysplasia
have been reported
in
a German shepherd
dog (Roberg
1979),
English pointers
(Whitbread and others
1983),
Norwegian.
elkhounds (Bingel and Sande
1982),
Pyre-
nean mountain dog (Sande and Bingel
1982),
cocker spaniels (Beachley and Gra-
ham
1973),
Scottish terriers (Mather
1956),
miniature poodles (Riser and others
1980),
St Bernards, Newfoundlands and
Lapphund (Fjeld
1991)
and Scottish deer-
hounds (Breur and others
1989).
For
many
of
these breeds a single auto-
somal recessive mode
of
inheritance
is
sus-
pected. Hanssen
(1
992)
found strong
indications
for
such inheritance in Irish
setters, which has been verified by the pre-
sent study.
The fact that the chondrodysplastic
dwarfisms appear with different expres-
sions in different dog breeds indicates that
the genetic mechanisms which are acting
might not be the same
for
the different
breeds. This means that Future identifica-
tions
of
canine dwarf genes
or
genetic
markers might
be
a
laborious task.
Acknowledgements
The authors thank the chairman
of
the
Norwegian Irish setter club,
B.
Stene,
for
his initiative to this study,
R.
Hamar
for
excellent care
of
the dogs and technical
assistance and
Dr
S.
Kolmanskog
for
valu-
able discussions about dwarf diagnostics.
They would also like to thank Dyreiden-
titet, the Norwegian Small Animal Veteri-
nary Association and the Norwegian Irish
setter club for financial support.
References
BEACHLEY,
M.
C.
&
GRAHAM,
F.
H.
(1973)
Hypochon-
drodysplastic dwarfism (endochondral chondrodys-
row) in a dog. Journal of the American Veterinary
Medical Association
163,
283284
BINGEL,
S.
A.
&
SANDE.
R.
D.
(1982)
Chondrodysplasia in
the Norwegian elkhound. American Journal of Pathol-
ogy
107,219229
BREUR,
G.
J.,
ZERBE,
C.
A.,
SLOCOMBE,
R.
F.,
PANEIT.
G.
A.
&
BRAOEN.
T.
D.
(1989)
Clinical, radiographic,
pathologic, and genetic features of osteochondrodys
plasia in Scottish deerhounds. Journal
of
the Ameri-
can Veterinary Medical Association
195,
606-612
CARRIG.
C.
B.,
MACMILLAN, A., BRUNOAGE.
S.,
POOL,
R. R.
& MORGAN,
J.
P.
(1977)
Retinal dysplasia associated
with skeletal abnormalities in labrador retrievers.
Journal of the American Veterinary Medical Associa-
tion
170,
4957
FJELO,
T.
(1991)
Osteochondrodysplastisk dvergvekst.
In: Hund,
Avl
og Helse (Dog, Breed and Health). Ed
A.
Indrebe. Norwegian Small Animal Veterinary Asso-
ciation,
Oslo.
pp
97-99
FLETCH.
S.
M.. SMART, M.
E.,
PENNOCK.
P.
W.
&
SUBOEN,
R.
E.
(1973)
Clinical and pathologic features of
chondrodysplasia (dwarfism) in Alaskan malamute.
Journal of the American Veterinary Medical Associa-
tion
162, 357-361
HANSSEN,
I.
(1992)
Dwarfism in Irish setter. Norsk Vet-
erinertidsskriff
104.
643-646
MATHER, G.
W.
(1956)
Achondrodysplasia in a litter
of
pups. Journal
of
the American Veterinary Medical
Association
128,
327-328
MEYERS.
V.
N..
JUYK,
P. F., AGUIRRE,
G.
D.
&
PA~ERSON,
D.
F.
(1983)
Shortlimbed dwarfism and ocular
defects in the samoyed. Journal ofthe American Vet-
erinary Medical Association
183,
975-979
RASMUSSEN,
P.
G.
(1975)
Multiple epiphyseal dysplasia.
Acta Pathologica et Microbiologica Scandinavica
83,
493502
RISER,
W.
H..
HASKINS, M.
E..
JFZYK,
P.
F.
&
PATERSON,
D.
F.
(1980)
Pseudoachondrodysplastic
dysplasia in
miniature poodles: clinical. radiological and patho-
logic features. Journal
of
the American Veterinary
Medical Association
176, 335-341
ROBERG,
J.
W.
(1979)
Dwarfism in the German shep-
herd. Canine Practice
6.
42-44
SANDE,
R.
G.
&
BINGEL.
S.
A.
(1982)
Animal models
of
dwarfism. Veterinary Clinics of North America (Small
Animal Practice)
13,
71-89
SPRANGER,
J.
(1992)
International classification of osteo-
chondrodysplasias. the International Working Group
on constitutional diseases in bone (communicated
by
J.
Spranger). European Journal of Pediatrics
151,
407-415
WHITBRLAD,
T.
J.,
GILL,
J.
J.
B.
&
LEWIS, D.
G.
(1983)
An
inherited enchondrodystrophy in the English pointer
dog.
A
new disease. Journal
of
Small Animal Practice
24, 399-411
14
-
JOURNAL
OF
SMALL ANIMAL
PRACTICE
VOL
39
JANUARY
1998
... Several forms of hereditary disproportional dwarfism have been described in dogs [4][5][6][7][8][9][10]. A recessive mode of inheritance is reported in many breeds [4][5][6][7][8][9][10] and associated genes or possible causative mutations are known in some of them. ...
... Several forms of hereditary disproportional dwarfism have been described in dogs [4][5][6][7][8][9][10]. A recessive mode of inheritance is reported in many breeds [4][5][6][7][8][9][10] and associated genes or possible causative mutations are known in some of them. A nonsense-mutation in the ITGA10gene cause chondrodysplasia in Norwegian elkhounds and Karelian bear dogs [4]. ...
Article
Full-text available
Background Cases of foreleg deformities, characterized by varying degrees of shortened and bowed forelegs, have been reported in the Havanese breed. Because the health and welfare implications are severe in some of the affected dogs, further efforts should be made to investigate the genetic background of the trait. A FGF4-retrogene on CFA18 is known to cause chondrodystrophy in dogs. In most breeds, either the wild type allele or the mutant allele is fixed. However, the large degree of genetic diversity reported in Havanese, could entail that both the wild type and the mutant allele segregate in this breed. We hypothesize that the shortened and bowed forelegs seen in some Havanese could be a consequence of FGF4RG-associated chondrodystrophy. Here we study the population prevalence of the wild type and mutant allele, as well as effect on phenotype. We also investigate how the prevalence of the allele associated with chondrodystrophy have changed over time. We hypothesize that recent selection, may have led to a gradual decline in the population frequency of the lower-risk, wild type allele. Results We studied the FGF4-retrogene on CFA18 in 355 Havanese and found variation in the presence/absence of the retrogene. The prevalence of the non-chondrodystrophic wild type is low, with allele frequencies of 0.025 and 0.975 for the wild type and mutant allele, respectively (linked marker). We found that carriers of the beneficial wild type allele were significantly taller at the shoulder than mutant allele homozygotes, with average heights of 31.3 cm and 26.4 cm, respectively. We further found that wild type carriers were born on average 4.7 years earlier than mutant allele homozygotes and that there has been a gradual decline in the population frequency of the wild type allele during the past two decades. Conclusions Our results indicate that FGF4RG-associated chondrodystrophy may contribute to the shortened forelegs found in some Havanese and that both the wild type and mutant allele segregate in the breed. The population frequency of the wild type allele is low and appear to be decreasing. Efforts should be made to preserve the healthier wild type in the population, increase the prevalence of a more moderate phenotype and possibly reduce the risk of foreleg pathology.
... As a result of the unique population history, linkage disequilibrium is relatively long within breeds, enabling genome-wide association studies (GWAS) to be performed using small sample numbers [25,26]. Inherited chondrodysplasia has been described in several breeds, including the Alaskan Malamute [27][28][29], Norwegian Elkhound [30], Miniature Poodle [31] Samoyed [32], Labrador Retriever [33,34], Scottish Deerhound [35], English Pointer [36], Great Pyrenees [37] and the Irish Setter [38]. Autosomal recessive inheritance has been proposed in Alaskan Malamutes [39], Great Pyrenees [37] and Irish Setters [38]. ...
... Inherited chondrodysplasia has been described in several breeds, including the Alaskan Malamute [27][28][29], Norwegian Elkhound [30], Miniature Poodle [31] Samoyed [32], Labrador Retriever [33,34], Scottish Deerhound [35], English Pointer [36], Great Pyrenees [37] and the Irish Setter [38]. Autosomal recessive inheritance has been proposed in Alaskan Malamutes [39], Great Pyrenees [37] and Irish Setters [38]. The causative mutation is known in few breeds but the majority of the phenotypes have an unknown molecular genetic cause. ...
Article
Full-text available
The skeletal dysplasias are disorders of the bone and cartilage tissues. Similarly to humans, several dog breeds have been reported to suffer from different types of genetic skeletal disorders. We have studied the molecular genetic background of an autosomal recessive chondrodysplasia that affects the Norwegian Elkhound and Karelian Bear Dog breeds. The affected dogs suffer from disproportionate short stature dwarfism of varying severity. Through a genome-wide approach, we mapped the chondrodysplasia locus to a 2-Mb region on canine chromosome 17 in nine affected and nine healthy Elkhounds (praw = 7.42×10(-6), pgenome-wide = 0.013). The associated locus contained a promising candidate gene, cartilage specific integrin alpha 10 (ITGA10), and mutation screening of its 30 exons revealed a nonsense mutation in exon 16 (c.2083C>T; p.Arg695*) that segregated fully with the disease in both breeds (p = 2.5×10(-23)). A 24% mutation carrier frequency was indicated in NEs and an 8% frequency in KBDs. The ITGA10 gene product, integrin receptor α10-subunit combines into a collagen-binding α10β1 integrin receptor, which is expressed in cartilage chondrocytes and mediates chondrocyte-matrix interactions during endochondral ossification. As a consequence of the nonsense mutation, the α10-protein was not detected in the affected cartilage tissue. The canine phenotype highlights the importance of the α10β1 integrin in bone growth, and the large animal model could be utilized to further delineate its specific functions. Finally, this study revealed a candidate gene for human chondrodysplasias and enabled the development of a genetic test for breeding purposes to eradicate the disease from the two dog breeds.
... Hypochondroplasia in humans is characterised by dwarfism and limited elbow and hip extension features. In the Irish setter a similar condition is present (28). Thus, FGFR3 is a candidate gene for the hypochondroplastic dwarf phenotype in the Irish setter. ...
... Recently, Hanssen et al. (28) performed test matings between a dwarf Irish setter female and a carrier sire as well as a mating between two dwarf Irish setters. From this study it was concluded that an autosomal recessive gene caused the dwarfism in the Irish setter in Norway. ...
Article
Full-text available
In man, the genetic defects of more than 600 inherited diseases, of which at least 150 skeletal diseases, have been identified as is the chromosomal location for approximately 7000 genes. This rapid progress has been made possible by the generation of a genetical and physical map of the human genome. There is no reason to believe that for the dog not a similar development may occur. This review is therefore focussed on the use of novel tools now available for comparative molecular genetic studies of skeletal dysplasias in the dog. Because the genomes of mammals at the subchromosomal level are very well conserved, likely candidate disease genes known from other species might be considered. In this review, formation of the bones and the most important canine disorders of the skeleton influencing locomotion will be discussed first. The canine disorders discussed are canine hip dysplasia, the three different forms of elbow dysplasia (fragmented coronoid process, ununited anconeal process, osteochondrosis dissecans and incongruency) and dwarfism. Where possible a link is made with similar diseases in man or mouse. Then, the molecular biological tools available to analyse the genetic defect will be reviewed and some examples discussed.
Article
Full-text available
Chondrodysplasia is a type of genetic skeletal disorder associated with abnormalities in the development of cartilage tissues. Affected dogs suffer from disproportionate short-limbed dwarfism and/or hyperplasia of the skull bones. Visible symptoms occur only during growth period. Early studies demonstrated that chondrodysplasia in domestic dog is an autosomal recessive disease. Therefore, the only way to detect carriers in the population without performing test matings is a genetic test. Current knowledge of the genetic background of chondrodysplasia is limited to Norwegian Elkhound and Karelian Bear Dog. In case of other breeds, for example Labrador Retriever, known research only excludes participation of certain genes in the origin of the disease. Therefore, the authors of this article decided to develop diagnostic genetic tests that will detect carriers on the basis of previously identified mutations, causing chondrodysplasia.
Article
Bone metabolism can be monitored in humans and several animal species in vivo by measuring enzymes and other protein products released by osteoplasts and osteoclasts, respectively. the biochemical markers of bone formation currently in use include bone isoenzyme of alkaline phosphatase, osteocalcin and propeptides derived from the N or C terminal ends of the type I procollagen molecule. The most useful markers of bone resorption are breakdown products of type I collagen. The oldest established method is the measurement of hydroxyproline in urine, which is not specific for bone, because it can be found in all collagen types and is also derived from diets. The measurement of collagen crosslinks, deoxypyridinoline and pyridinoline, is comparatively more specific to monitor bone resorption. Deoxypyridinoline and pyridinoline are used in human medicine for diagnosis and evaluation of bone diseases and in predicting the occurrence of fractures and rates of bone loss. The carboxyterminal telopeptide of type I collagen, which has been used in several animal species, is also a promising bone marker. This article reviews the use of different bone markers in veterinary medicine and the possibilities for diagnosing and preventing bone diseases.
Article
Three groups of six cats were kept in similar carpeted pens in which a self-replicating population of Ctenocephalides felis had been established. One group was left untreated, but the other groups were treated every 28th day with 0.5 ml of a 10 per cent fipronil spot-on formulation, and the cats in one of the treated groups also wore a methoprene collar. No fleas were found on any of the treated cats, either during the first 13 weeks of the study, when heavy flea burdens were developing in the control pen, or over the next 11 weeks when a declining number of fleas was present on the control group.
Article
Bone metabolism can be monitored in humans and several animal species in vivo by measuring enzymes and other protein products released by osteoblasts and osteoclasts, respectively. The biochemical markers of bone formation currently in use include bone isoenzyme of alkaline phosphatase, osteocalcin and propeptides derived from the N or C terminal ends of the typ I procollagen molecule. The most useful markers of bone resorption are breakdown products of type I collagen. The oldest established method is the measurement of hydroxyproline in urine, which is not specific for bone, because it can be found in all collagen types and is also derived from diets. The measurement of collagen crosslinks, deoxypyridinoline and pyridinoline, is comparatively more specific to monitor bone resorption. Deoxypyridinoline and pyridinoline are used in human medicine for diagnosis and evaluation of bone diseases and in predicting the occurrence of fractures and rates of bone loss. The carboxyterminal telopeptide of type I collagen, which has been used in several animal species, is also a promising bone marker. This article reviews the use of different bone markers in veterinary medicine and the possibilities for diagnosing and preventing bone diseases.
Article
Effective, non-invasive bone assessment methods for screening, diagnosis and follow-up of the skeleton are more and more requested in veterinary medicine. In contrast to clinical parameters, invasive methods and imaging techniques, indices of bone turnover is a tool for bone metabolism evaluation of the whole skeleton. Biochemical bone markers therefore provide a more real-time assessment of the bone status with simple blood- or urine-analysis. This article surveys currently available biochemical marker of bone metabolism used in veterinary medicine. Additionally, information is provided about physiological and pathological, as well as therapeutic variations of biochemical bone marker concentrations in various species.
Article
This report describes the clinical, radiological, pathological and genetic features of an inherited dwarfism in the English Pointer. Gross enlargement of the distal ulnar, radial and tibial growth plates occurred in the first 6 weeks of life and radiographic skeletal abnormalities were present at other sites. The enlargement was due to increase in width of the zone of hypertrophic cartilage, but the columns of chondrocytes were well ordered. By 12 weeks of age an unusual type of degeneration was present beneath the surface of articular cartilage; this developed to widespread, patchy erosion of joint surfaces by 32 weeks. The genetics are compatible with a homozygous recessive mode of inheritance.
Article
The cartilage of epiphysis and cuboid bones from three Beagle puppies bred from parents with a constant heredity of multiple epiphyseal dysplasia, was examined macroscopically, histo-morphologically and histochemically. The puppies were euthanized at the age of one week, three weeks and five weeks, respectively. The investigation showed that foci of the disease develop in a broad subarticular zone where normally strong three-dimensional growth of the cartilage takes place. The first signs of the disease appeared about the time of birth and new foci reached a climax when the puppies were about three weeks old. Histomorphological and histochemical examination of the cartilage showed that the disease developed in a sequence of confluent stages. In the initial stage, there was an accumulation of abnormal cartilage matrix in the chondrocyte and/or chondrocyte lacunae. The abnormal substance consisted apparently of concentrated or free chondroitin sulphates not bound to protein. Then followed a second stage of liquefaction and coalescence of the abnormal cartilage matrix which formed cysts of different sizes, some of them visible macroscopically. In the third stage of calcification of the cyst content and surrounding abnormal cartilage, it was found that the calcium was deposited in grains bound to chondroitin sulphates. The results of the present study of the pre-calcification stage of the disease in Beagle dogs seem to be comparable with or equivalent to the results of the study of the post-natal stage of the disease in children and may explain something of the prenatal pathogenesis in children.
Article
The clinical, radiographic, and pathologic features of skeletal and ocular dysplasia in 6 Labrador Retrievers were studied. Abnormalities in the appendicular skeleton included retarded growth in the radius, ulna, and tibia; ununited and hypoplastic anconeal and coronoid processes; hip dysplasia, and delayed development of epiphyses. Ocular changes were characterized by retinal dysplasia, with retinal detachment and cataract formation. Dogs from 4 litters were affected.
The cartilage of epiphysis and cuboid bones from three Beagle puppies bred from parents with a constant heredity of multiple epiphyseal dysplasia, was examined macroscopically, histomorphologically and histochemically. The puppies were euthanized at the age of one week, three weeks and five weeks, respectively. The investigation showed the foci of the disease develop in a broad subarticular zone where normally strong three-dimensional growth of the cartilage takes place. The first signs of the disease appeared about the time of birth and new foci reached a climax when the puppies were about three weeks old. Histomorphological and histochemical examination of the cartilage showed that the disease developed in a sequence of confluent stages. In the initial stage, there was an accumulation of abnormal cartilage matrix in the chondrocyte and/or chondrocyte lacunae. The abnormal substance consisted apparently of concentrated or free chondroitin sulphates not bound to protein. Then followed a second stage of liquefaction and coalescence of the abnormal cartilage matrix which formed cysts of different sizes, some of them visible macroscopically. In the third stage of calcification of the cyst content and surrounding abnormal cartilage, it was found that the calcium was deposited in grains bound to chondroitin sulphates. The results of the present study of the pre-calcification stage of the disease in Beagle dogs seem to be comparable with or equivalent to the results of the study of the post-natal stage of the disease in children and may explain something of the prenatal pathogenesis in children.
Article
Clinical, radiographic, pathologic, and genetic features of a form of osteochondrodysplasia in 5 related Scottish Deerhound pups from 2 litters were evaluated. All pups appeared to be phenotypically normal at birth. At approximately 4 or 5 weeks, exercise intolerance and retarded growth were observed. Kyphosis, limb deformities, and joint laxity gradually developed. Radiography of the affected pups revealed skeletal changes characterized by abnormalities in long bones and vertebrae, with involvement of epiphyses, growth plates, and metaphyses. Short long bones and vertebrae and irregular and delayed epiphyseal ossification were most noticeable in younger pups; in older pups, bony deformities became more prominent. In skeletally mature dogs, osteopenia and severe deformities were seen. The histologic changes of the growth plate were compatible with a diagnosis of chondrodysplasia. Growth plate chondrocytes contained periodic acid Schiff-positive, diastase-resistant cytoplasmic inclusions. A single autosomal recessive mode of inheritance was suspected.