Phenotype of Hereditary Orthopedic Disease--and the Role of Diagnostic Imaging
Johann Lang, Dr.med.vet., DECVDI; Sandra Martig, Dr.med.vet.; Anads Güdel, med.vet.
Division of Clinical Radiology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty Bern, Bern
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 ectrodactylia.
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 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 non-inflammatory (aseptic) necrosis with subsequent deformation of the femoral head and neck resulting in pelvic limb lameness. In Miniature 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, geneticists, 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 mass-selection 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 acetabulum, femoral head and 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 alienated 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 methods for the finishing/terminal assessment of the hip joints.
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-Calvé-Perthes 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 osteochondrosis 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.
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 chondrodystrophic 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).
1. Biller DS et al: Inheritance of Polycystic Kidney Disease in Persian Cats. J Hered 87 (1): 1-5 (1996)
2. Eaton KA et al: Autosomal Dominant Polycystic Kidney Disease in Persian and Persian-cross Cats. Vet Pathol 34: 117-26 (1997)
3. Flückiger M et al: A Radiographic Stress Technique for Evaluation of Coxofemoral Joint Laxity in Dogs. Vet Surgery 28: 1-9 (1999)
4. Flückiger M et al: Correlation between Hip Joint Laxity and subsequent Coxarthrosis in Dogs. Zentralbl Veterinarmed A. 45 (4):199-207 (1998)
5. Henninger W und Köppel E: Die Bedeutung des kraniolateralen Pfannenrandes für die HD-Beurteilung. Tierärztl Prax 22: 278-85 (1994)
6. Jensen, V. F. 2001. Asymptomatic radiographic disappearance of calcified intervertebral disc material in the Dachshund. Vet. Radiol. Ultrasound 42:141-148
7. Jensen, V. F. and K. A. Christensen. 2000. Inheritance of disc calcification in the dachshund. J. Vet. Med. A Physiol Pathol. Clin. Med. 47:331-340.
8. Langeland M und Lingaas F: Spondylosis Deformans in the Boxer: Estimates of Heritability. J Small Anim Pract 36(4):166-9 (1995)
9. Lust G et al: Joint Laxity and its Association with Hip Dysplasia in Labrador Retrievers. Am J Vet Res 54: 1990-99 (1993)
10. Ohlerth S et al: Comparison of three Distraction Methods and Conventional Radiography for early Diagnosis of Canine Hip Dysplasia. J Small Anim Pract 44 (12): 524-9 (2003)
11. Popovitch CA et al: Comparison of Susceptibility for Hip Dysplasia between Rottweilers and German Shepherd Dogs. J Am Vet Med Ass 206: 648-50 (1995)
12. Puerto et al: Relationship between Results of the Ortolani Method of Hip Joint Palpation and Distraction Index, Norberg Angle, and Hip Score in Dogs. J Am Vet Med Ass 214: 497-501 (1999)
13. Ruvinsky A and Sampson J: The Genetics of the Dog. CABI Publishing Oxon UK and New York (2001)
14. Smith, G. K., C. A. Popovitch, T. P. Gregor, and F. S. Shofer. 1995. Evaluation of risk factors for degenerative joint disease associated with hip dysplasia in dogs. J. Am. Vet. Med. Assoc. 206:642-647.
15. Smith, G. K., D. N. Biery, and T. P. Gregor. 1990. New concepts of coxofemoral joint stability and the development of a clinical stress-radiographic method for quantitating hip joint laxity in the dog.J. Am. Vet. Med. Assoc. 196:59-70.
16. Young AE et al: Feline Polycystic Kidney Disease is linked to the PKD1 region. Mammalian Genome 16: 59-65 (2005)