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PHENOTYPE OF HEREDITARY ORTHOPEDIC DISEASE – AND THE
ROLE OF DIAGNOSTIC IMAGING
Johann Lang, Dr.med.vet., Dip
ECVDI
Division of Clinical Radiology
Department of Clinical Veterinary
Medicine
Vetsuisse Faculty Bern
Länggassstrasse 128, Postfach
CH-3001 Bern
[email protected]
http://kleintierklinik.unibe.ch
Anaïs Güdel, med.vet.
Division of Clinical Radiology
Department of Clinical Veterinary Medicine
Vetsuisse Faculty Bern
Länggassstrasse 128, Postfach
CH-3001 Bern
Sandra Martig, Dr.med.vet.
2006 World Congress WSAVA/FECAVA/CSAVA
Division of Clinical Radiology
Department of Clinical Veterinary
Medicine
Vetsuisse Faculty Bern
Länggassstrasse 128, Postfach
CH-3001 Bern
272
INTRODUCTION
The role of diagnostic imaging in congenital and
inherited disorders depends on many factors.
In the following article the focus is on the
goals, possibilities and limitations of diagnostic
imaging in the context of breeding programs.
The phenotype of an inherited disorder depends
mainly on the genetic trait and whether the
changes are present at birth or develop later in life.
Only in dominant genetic disorders every carrier
of a specific gene will present as a phenotypically
affected individual - independent whether the
allele is present as homo- or heterozygote.
In contrast, in recessive and even more so in
polygenetic traits the disorder may be passed
to the progeny through several generations by
phenotypically normal carriers. The pattern of
inheritance of many orthopedic diseases, as for
example canine hip dysplasia, indicates a complex
trait controlled by the interaction of several
genes and environmental factors (nutrition, dog
keeping). In such polygenetic hereditary disorders
it is extremely difficult to conclude from the
(radiologically) phenotype to the genotype of an
individual. Therefore, knowledge of the mode of
inheritance of a disease is important for using the
information’s gained from radiographs or other
imaging modalities in an appropriate way. The
second major problem in many inherited skeletal
disorders is the fact that the abnormalities are
often not present at birth, and develop only later
in adult animals. In some diseases the primary
disease process can not readily be detected
radiographically and the diagnosis depends on
secondary sings. An example is the fragmented
medial coronoid process where the diagnosis
often depends on the presence of secondary
osteoarthritis. Many hereditary defects are
associated with the standard of a breed. An
example for this is the Dachshund where chondroid
degeneration of intervertebral discs is associated
with chondrodystrophy, the gene defect used to
develop the standard of the breed. Recognition of
chondrodystrophy is easy, however recognition
of intervertebral disc degeneration at a young age
is a diagnostic challenge. The method proposed
to use radiographs with intervertebral disc
mineralization as a marker has to be done at an
age of 18-36 months.
Not every congenital defect (radiological
detectable abnormality) is a genetic inherited
disorder. A fetus with sound genes may be exposed
during gestation to teratogenic impacts (e.g.
pharmaceutics, infections). Such abnormalities
are congenital but not anchored in genes and are
therefore not passed to the progeny. Examples
are sporadically observed abnormalities such as
hemimelia, syndactylia, or ectodactylia.
GOALS OF DIAGNOSTIC IMAGING
In relation with inherited disorders there are
mainly two tasks for diagnostic imaging.
1. Diagnosis and prognosis in a diseased
individual: In a given case and within the
financial scope of the owner, a combination
of any diagnostic imaging technique such as
radiography, bone scintigraphy, Ultrasonography,
CT and or MRI can be applied. In addition or as
alternative arthroscopy as minimally invasive
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diagnostic technique (therapeutic option) may be
considered.
2. Phenotypical screening in the context of
breeding schemes: All breeding programs are
based on the positive identification of affected
individuals. Affected animals should be
recognized as early in life as possible, preferably
before the animal is being introduced to breeding
or before a lot of time and money are invested into
education of a working dog. Ideally, a screening
method is inexpensive, not invasive and has
a high sensitivity and specificity. In disorders
where genetic testing is not possible, screening is
based on the phenotype. In the ideal situation the
phenotype reflects exactly the genotype, and no
false negative and false positive results are seen.
An almost ideal disorder for phenotypical
screening using diagnostic imaging is polycystic
kidney disease in Persian cats. The dominant
genetic trait and the fact that the cysts develop
early in life made Ultrasound to an almost perfect
diagnostic tool with very high sensitivity even in
animals far below 1 year of age. In orthopaedic
disorders, the situation is often far more
complicated. Dominant or simple recessive traits
are rare. The avascular necrosis of the femoral
head (Legg-Calvé-Perthes disease) is a noninflammatory (aseptic) necrosis with subsequent
deformation of the femoral head and neck
resulting in pelvic limb lameness. In Minitiature
Poodles and West Highland White Terriers the
disease is a simple (autosomal) recessive trait,
and radiography can be used for assessing the
femoral heads. Eliminating all affected individuals
and littermates from breeding (if the genetic basis
allows such a strict program) will eradicate the
problem in a few generations.
Real challenges for radiologists, genetists, and
breeders are disorders with polygenic traits. An
excellent example is the canine hip dysplasia
(CHD). The pattern of inheritance indicates
that canine hip dysplasia is a complex trait
controlled by the interaction of several genes and
environmental factors and the phenotype often
is only recognized in the adult animal. Because
there are several genes and environmental factors
responsible for the disease, till now there is no
simple genetic test on the market. For the same
reasons, the recognition of the genetic burden
using diagnostic imaging in a single individual is
not possible as well. The problem therefore has
to be addressed combining imaging methods with
refined breeding schemes on the basis of massselection and open database or other methods
such as breeding value estimation.
Canine hip dysplasia is a disturbance of growth,
which is characterized by the presence of an
enhanced passive laxity of the joint, and - in
the course of the disorder - incongruent joints,
deformity of the azetabulum, femoral head an neck,
and osteoarthritis. Several genes with different
loci and environmental factors (up to 80%) take
part in the phenotypical development of CHD. To
make the situation even more complicated, there
may be inductive or protective loci that control
expression of hip OA that are independent from
the “CHD-genotype”. The risk of a German
Shepherd dog with a 50% joint laxity to develop
OA is higher than for a Rottweiler with the same
amount of laxity. Using the classical methods,
the radiographic diagnosis depends on primary
signs such as passive laxity and secondary joint
deformities and OA. However, because there is
no simple genetic test available, radiographic
examination of the hip joint in the scope of
breeding against CHD and other polygenetic
disorders still plays an important role. The
goal of testing is to find the best approximation
of the phenotype of an individual or group of
individuals and the genotype. Furthermore, the
test has to be reliable, safe and inexpensive. For
assessing primary signs of disease, independent
from the presence of OA, measurements of the
Norberg angle and distraction indices have been
developed. Ultrasonographic examinations,
which are used in infants as a screening method,
did not achieve acceptance in dogs (yet) because
of several reasons. This is also true for biometric
procedures as proposed by R. Beuing.
It has been shown, that the joint laxity measured by
the distraction index by Smith, and other methods
as described by Flückiger or Ohlerth have a high
prognostic value. Already in 16-18 weeks old
animals, the status of joints of adults could be
predicted using the Smith method. For example
60% of the 4 months old German Shepherds
with a DI > 0.3 developed OA and CHD at an
older age. However, the joint laxity seems to be
breed specific and these values cannot be alienate
from one breed to another. Some breeds appear
to display different susceptibilities to CHD based
on their DI’s and some breed may tolerate more
passive hip laxity than other breeds. Labradors
with DI values of less than 0.3 have a greater
than 80% probability of not developing hip OA
whereas those with DI’s greater than 0.7 have
a high probability of developing hip OA. The
upper DI value in German Shepard’s is 0.5. An
advantage is that hip laxity has a higher heritability
(0.6) than estimates based on the standard method
(0.2 - 0.45). Therefore, measuring joint laxity
using a standardized method might improve the
radiographic assessment of hip joints; however,
because of several (non medical) reasons the
method is not yet accepted in Europe. Puerto
et al even postulate the combination of several
2006 World Congress WSAVA/FECAVA/CSAVA
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273
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methods for the finishing/terminal assessment of
the hip joints.
OTHER DISORDERS
2006 World Congress WSAVA/FECAVA/CSAVA
Appendicular skeleton
Standard
radiographic
and
evaluation
protocols exist for many inherited orthopedic
disorders. Examples are elbow dysplasia (ED),
osteochondrosis (several joints), or avascular
necrosis of the femoral head (Legg-CalvéPerthes disease). In radiographic diagnostic of
elbow dysplasia, often the fragmented medial
coronoid process (FCP) can not readily be
identified using radiographs and the diagnosis
depends on the identification of osteoarthritis.
Computed Tomography (CT), the method of
choice to identify affected joints can not be
used as screening method up to now, because
CT is not readily available and too expensive
as a screening tool. In contrast to the FCP the
overall accuracy of a radiographic examination
to correctly identify isolated anconeal process
(IPA) and ostechondrosis OCD) of the elbow
joint is very high. The heritability is similar
as described in CHD. Incomplete ossification
of the humeral condyle (IOHC: autosomal
recessive trait?) in some breeds such as Cocker
-, Brittany -, Springer -, Clumber -, and CKC
Spaniel, (but also Labrador Retriever, Rottweiler,
German Shepherd dog, German Wachtelhund),
medial and lateral Patellar luxation and many
other congenital and hereditary disorders of the
appendicular skeleton exist where radiography
and other imaging modalities are important to
diagnose or characterize the problem. However
it is beyond the scope of this paper to list and
describe all these diseases.
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Axial skeleton
Spondylosis of Boxers show an average to high
heritability (up to 0.6; depending on the author,
model and localization of the spondylosis), even
though the mode of inheritance has not been
reported (Langeland, others). Often, 1.5 years
old boxers already show advanced spondylosis
which are readily identified on radiographs,
making radiographic screening very promising.
Some Kennel Clubs and countries already have
established breeding schemes, while others seem
not to be interested.
Mineralized intervertebral discs are reliable
signs of intervertebral disc degeneration. The
risk for a chondrodystrophc dog suffering from
an intervertebral disc hernias, which often leads
to neurologic deficits, seems to increase with
the number of mineralized discs. Furthermore
heritabilities of over 0.4 have been estimated for
mineralized discs. Dachshunds show a considerable
predisposition of mineralized intervertebral
disc, and several countries introduced screening
methods based on the number of mineralized
intervertebral discs (Jensen). Radiographic
imaging shows mineralized intervertebral discs
easily and reliable. However, The number of
mineralized discs in an individual varies over
time. After an increase in the first 2 years of age,
mineralization without herniation may disappear
over time (mineral is reabsorbed) and the optimal
time for screening is between 18 and 36 months
of age.
Examples of non-skeletal diseases
Many other inherited disorders where imaging
techniques are used have been described.
Ultrasonography is used in cardiac diseases
with hereditary background such as in Boxers
(subaortic stenosis), Cavalier King Charles
Spaniels (av-valve dysplasia), several large
breed dogs (dilated cardiomyopathy), or Maine
Coon cats (hypertrophic cardiomyopathy).
Several breeds (Cairn Terrier, Golden Retriever,
Irish Wolfhound, Labrador Retriever, Maltese,
Miniature Schnauzer and Yorkshire Terrier) have
a higher risk to develop a portosystemic shunt and
Ultrasound and Scintigraphy are used as screening
methods. Magnetic Resonance Imaging is used
in dogs with idiopathic epilepsy, and in Cavalier
King Charles Spaniel with Syringohydromyelia
(Arnold-Chiari type I malformation).
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Jensen, V. F. and K. A. Christensen. 2000.
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