Genetic Control of Hereditary Skeletal Diseases
WSAVA 2002 Congress
H.A.W. Hazewinkel, DVM, Pd, Dipl ECCS, Dipl ECVCN
Dept. Clinical Sciences of Companion Animals, Utrecht University
The Netherlands

Introduction

Halfway foetal development, the cartilaginous anlage of the skeleton is present together with ligaments characteristic for the complete skeleton. Before birth the primary and some of the secondary ossification centers have been developed via the process of endochondral ossification. The cartilaginous zone between primary and secondary ossification centers consists of well-arranged chondrocytes forming the physeal plate, allowing for postnatal growth in length of the long bones. The well-arranged cartilage is continued to cover the bony ends of the long bones, i.e., epiphyses, allowing for growth in diameter of these epiphyses. The increase in diameter of the diaphyseal bone takes place by direct apposition of osteoid by the osteoblasts originating from the periosteum. Osteoclasts remodel the bone by removing bone at the metaphyseal areas and at inner surface of the diaphyses to create the medullary cavity. Disturbances in skeletal development can occur in each sequential step of skeletal development including cartilage growth, cartilage maturation and eventually mineralization, osteoid quality or osteoclast activity causing skeletal diseases as chondrodysplasia, osteochondrosis of growth plates and epiphyseal surface, osteogenesis imperfecta, and osteopetrosis. These are all hereditary skeletal diseases with serious consequences for skeletal function, although with different incidences in the canine species. Some hereditary diseases of extra-skeletal organs may have severe effects on skeletal growth or integrity. These diseases include deficiency in growth hormone synthesis (dwarfism as in German Shepherd dogs), thyroid deficiency (as described in a family of Giant Schnauzers), and canine leucocyte adhesion deficiency (CLAD as in Irish Setters).

Diagnosis and genetic control

In some of the secondary causes of skeletal diseases the hereditary pattern has been elucidated (frequently autosomal recessive) and even in some its genetic characterization has been completed. So far, these successes has not been reached in genetics of primary skeletal diseases, limiting consequences for out-breeding those hereditary diseases. For installing breeding measures, breeders will depend on the ability to register the abnormality, with differences in different hereditary skeletal diseases:

1.  When a limited amount of representatives of a breed is affected with a skeletal disease and the diseases has a clear abnormal phenotype, breeders are able to trace back the founding ancestors of the abnormality and exclude the affected family from breeding. Examples of this are chondrodysplasia in Malamutes and Labradors. This allows breeders to erase the abnormality soon after its discovery.

2.  A possible course of events can be that one hereditary abnormality with minor consequences spreads unnoticed within a breed and becomes manifest due to the occurrence of a second abnormality. An example of this may be fragmented coronoid process (FCP) in the elbow joint seen together with elbow incongruity (INC) in 80% of the cases of elbow dysplasia in Bernese Mountain Dogs, leading to lameness in 100% of the cases of FCP + INC. The lameness can be missed though due to its bilateral occurrence.

3.  A major threat for breeds are the hereditary diseases which spread within the population unnoticed since not all carriers reveal phenotypical or clinical abnormalities. Example of this is FCP in a variety of breeds, including the above mentioned Bernese Mountain dog, but also Labradors, Rottweilers and German Shepherd dogs as well as series of other popular breeds.

4.  By breeders not well understood and thus frustrated by its repeated re-occurrence are the hereditary diseases with a major influence of the environment, i.e., hereditary skeletal diseases with a low h2 including hip dysplasia. Litter-mates raised with overweight can exhibit severe osteoarthrosis whereas the slim dogs have not.

The last three examples warrant a sensitive detection method for its exclusion by breeders. Since no laboratory tests are available to detect the major skeletal diseases like HD and elbow dysplasia (ED), imaging techniques have to be employed. Since radiography is widely distributed among veterinarians, radiographic screening tests are developed to detect these diseases. Great successes for detection and thus eradication of HD and ED can be reached at the beginning of the screening program by detecting the more severe cases and the advantage of any program to start at the steep part of the exponential curve typical for the decrease in occurrence of genetic diseases. However, soon tests are needed with a high sensitivity and specificity to continue the effects of selected breeding.

HD and ED

Since HD is characterized by joint laxity, and this can easily be detected with clinical or radiological tests, this aspects of HD is promoted as an additional test for detection of HD. However laxity is also seen in breeds without HD and not all dogs from a HD-affected breed with joint laxity developed HD at a higher age, as revealed from a follow-up study, the sensitivity and specificity of laxity testing alone is limited. The predictability for HD increases when other conditions of the hip, including the Norberg angle and the presence of osteophytes are also taken into account. Recent publications report about biogenetic research on hip laxity, demonstrate that laxity might be a dominant trait but, since HD is a complex polygenic diseases with major environmental influence, other trait loci will complicate detection of HD by testing a single HD-representing alleles.

ED is a collection of diseases located in the elbow joint with different genetic background and thus with a polygenetic mode of inheritance. A less detailed screening will use the advantages of screening at the beginning of the steep slope of the exponential curve, and will improve the breed considerably when breeders draw consequences on these screening findings. However, the h2 of ED is not very high and analysis of complete litters revealed that FCP might be a dominant trait with variable penetrance, i.e., 70% of the genetic affected males and 23% of the genetic affected females reveal abnormalities on radiological screening of the elbow joints including four views per joint. Population analysis revealed that FCP is seen in Bernese Mountain Dogs 50/50 in males and females, whereas in Labradors it is 75/25 divided between the sexes, revealing that the hereditary pattern of even one entity of ED (i.e., FCP) may differ between breeds. Population analysis demonstrated that FCP and INC, as well as FCP and OCD are independent hereditary traits seen both together and separately in Bernese Mountain Dogs and Labradors, respectively, demonstrating that different entities of ED will pass independently into the next generation. Separation of ED between breeds and in its different entities is necessary to reduce its polygenetic character into monogenetic traits.

Biogenetic techniques are necessary to screen the populations at risk for disabling diseases including HD and ED seen in high frequencies in the most popular dog breeds. Although there are indications that both HD and ED in Labradors may be dominant traits, due to the high environmental influences for HD (and possibly ED) and the variance in penetration for ED a large amount of individuals with genetic but not phenotypic abnormalities are present, being a constant threat for the population when used in the breeding program. Relative risk assessment and pedigree analysis can be employed to decrease the risk of producing more carriers or affected offspring. Selection of all relatives of affected individuals may select also genetically normal dogs and thus narrow the gene pool of the breed. Molecular screening test, utilizing polymerase chain reaction techniques to amplify the DNA-segment with the mutation(-s) responsible for the skeletal disease in question, became available for a growing amount of clinical diseases in dogs. Supported by the demands of breeders, these should be developed for skeletal diseases as well to screen breeds at risk and thus register carriers and breeding stock.

Breeders and their national and international organizations, including FCI and GDC, will take their responsibility to initiate and support further worldwide biogenic research to the benefit of the affected populations.

Breeders and veterinarians together

The high incidence of ED and HD, the suffering of the affected dogs, the wide scale of breeding and trading dogs, and the international exchange of genetic material warrants a supra-national strategy of detection these diseases, registration of the breeds and families at risk and the formulation of action plans to fight against its occurrence. It is the ethical task of both breeders and veterinarians to unite for the battle against hereditary diseases in animals which are bred for the joy of mankind.

Breeders have to register the dogs, determine the incidence of occurrence of skeletal diseases, and produce insight in the health status of complete litters allowing for investigation of the importance and mode of inheritance of these diseases. Open registration and complete information on international certificates indisputable linked to the individual dog has to be installed by kennel clubs allowing for well-decided use or abundance of certain breeding dogs by breeders.

Veterinarians assembled in the WSAVA will be prepared to offer their knowledge and services to assist in this major task. Uniform screening and grading techniques, exchange of results of evidence based research, reliable cooperation in screening, certification and registration procedures are necessary aspects for a successful breeding program.

References

1.  Everts RE, Hazewinkel HAW, Rothuizen J, van Oost BA. Bone disorders in the dog: a review of modern genetic strategies to find the underlying causes. Vet Quart 22, 63-70, 2000

2.  Hazewinkel HAW Calciotropic hormones and bone metabolism in: Clinical endocrinology of dogs and cats (ed. Rijnberk) Kluwer Academic Publ. 1996

3.  International Elbow Working Group: www.vetmed.ucdavis.edu/iewg/iewg.htm

4.  Jezyk PF, Constitutional disorders of the skeleton in dogs and cats in: Textbook of small animal orthopedics (ed. Newton & Nunamaker), Lippincott 1985

5.  Morgan JP, Wind A, Davidson AP. Hereditary bone and joint diseases in the dog. Schlütersche Verlag, 2000.

6.  Ubbink G. Inherited disease in purebred dog populations: predictions based on common ancestry. Thesis Utrecht University, 1998

7.  Todhunter RJ, Acland GM, Olivier M, Williams AJ et al. An outcrossed canine pedigree for linkage analysis of hip dysplasia. J. Hered. 90, 83-92, 1999

8.  Trowald-Wigh G, Ekman S, Hansson K, Hedhammar, A, Hard af Segerstad C. Clinical, radiological and pathological features of 12 Irish Setters with CLAD, JSAP 41, 211-217, 2000

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Herman A.W. Hazewinkel, DVM, Pd, Dipl ECCS, Dipl ECVCN
Dept. Clinical Sciences of Companion Animals
Utrecht University
The Netherlands


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