The Paw Print Genetics Blog

The Genetics of Shortened Limbs and the Association with Canine Intervertebral Disc Disease (IVDD)

The Genetics of Shortened Limbs and the Association with Canine Intervertebral Disc Disease (IVDD)

Shortened legs are a major defining feature for some of today’s most popular domestic dog breeds. Although dogs with extreme shortening of the limbs likely come to mind when pondering this trait (such as dachshunds or basset hounds), many other breeds also display a more subtle or moderate limb shortening (e.g. West Highland white terrier, Nova Scotia duck tolling retriever, beagle). Unfortunately, in some breeds, dogs with shortened legs have also been found to be at an increased risk for early-onset intervertebral disc disease (IVDD). However, over the past several years, genetic discoveries and development of genetic testing have made it possible to better understand the short-legged appearance of some dog breeds and the genetic underpinnings which make some of these dogs more likely to develop IVDD.

Intervertebral Discs and the Spinal Cord

In order to understand IVDD, we must first understand the role, location, and structure of the intervertebral discs (IVDs) and their anatomical relationship to the spinal cord. IVDs play a crucial role as cartilaginous ‘shock absorbers’ for the spine and allow for spinal flexibility. IVDs are often compared to a ‘jelly doughnut’ sitting between the vertebrae as they are composed of an outer ring of tough fibrous tissue known as the annulus fibrosus that is filled with a gelatinous inner layer known as the nucleus pulposus.

The spinal cord runs from the brain stem to the tail in a protective bony pathway called the spinal canal which is formed by aligned holes in each vertebra (known as the vertebral foramina). However, from vertebrae to vertebrae, the spinal cord travels a short distance across the ‘intervertebral space’ in which there is no bony protection. In this space, the spinal cord lies adjacent to the IVDs. The clinical signs associated with IVDD occur when malformations or degenerative changes in IVDs result in bulging or herniation of IVD material into the adjacent spinal cord in this unprotected space. Subsequent compression, injury, hemorrhage, and inflammation of the spinal cord results in the severe pain and neurological dysfunction commonly seen in IVDD-affected patients.

Shortened Legs and Genetic Link to Intervertebral Disc Disease

Two genetic mutations associated with shorter limb length have been reported in domestic dogs2,4,5. Both mutations consist of a copied section of the canine FGF4 gene (called an FGF4-retrogene) which has been inserted into two aberrant locations of the genome; one copy has been inserted into a region on chromosome 12 (CFA12 FGF4 insertion) and another copy has been inserted into a different region on chromosome 18 (CFA18 FGF4 insertion).

Since its discovery in 2009, the retrogene insertion on CFA18 has been associated with the trait known as chondrodysplasia (CDPA), a type of disproportional dwarfism which defines the extreme limb shortening seen in dogs such as the dachshund, basset hound, and corgi4. However, eight years later, a study by Brown and others identified a second retrogene insertion (on CFA12) which was also associated with limb shortening in dogs2. Unlike the CFA18 FGF4 insertion which only appears to play a role in decreased limb length, the insertion on CFA12 was also associated with an increased risk for a type of intervertebral disc disease (IVDD) caused by premature degeneration and calcification of intervertebral discs (IVDs), often referred to as ‘chondrodystrophy’ (CDDY). Interestingly, breeds with the most extreme limb shortening were found to inherit both mutations in high frequency, resulting in their extremely short stature and contributing to their known risk for IVDD. In addition to a better understanding of IVDD risks, genetic testing has also provided an opportunity for breeders of some dog breeds to breed away from the CFA12 FGF4 insertion that increases IVDD risk, and instead, select for the CFA18 insertion which still produces shortened limbs, but does not increase a dog’s overall IVDD risk.

Intervertebral Disc Disease Type II

IVDD occurs as a result of degenerative changes which weaken the structure of IVDs and allow for their protrusion or herniation into the spinal cord. However, it is important to differentiate the variation in types of IVDD to recognize which type is also associated with shortened limbs.

All dogs of advanced age are known to be at risk for one form of IVDD known as Hansen type II IVDD (named for the scientist which defined IVDD types in the 1950’s)3. Type II IVDD is a chronic type of IVDD associated with age-related degenerative changes which occur in every dog (though not every dog will develop clinical signs of type II IVDD) and is especially common in large breed dogs. Dogs with type II IVDD develop cartilage weakness and bulging of IVDs causing compression of the spinal cord, resulting in pain and neurological dysfunction. Some dogs with type II IVDD develop permanent neurological dysfunction due to chronic injury, resulting in an abnormal gait or difficulties rising from a prone position. While this type of IVDD is a chronic condition which may increase in severity with age, acute ‘flare-ups’ can cause significant pain and inflammation resulting in decreased mobility and quality of life. Dogs with this type of IVDD are often managed during flare-ups with rest, pain medications (anti-inflammatory or opioids), and/or muscle relaxers to make them comfortable and to regain pain-free mobility. However, these acute episodes often recur throughout the dog’s life. In some cases, it may be indicated to manage affected dogs with long-term pain therapy. Although dogs with type II IVDD experience discomfort and may develop chronic neurological problems secondary to disc protrusion, most will only experience clinically significant bulging in a handful of IVDs at most and only rarely experience a decrease in quality of life significant enough to justify surgical intervention. While genetics probably play a role in the age of onset and severity of type II IVDD, it is generally considered a disease of normal aging in any breed and is not generally associated with shortened limbs.

Intervertebral Disc Disease Type I

In contrast to type II IVDD, Hansen also identified a generally more severe type of IVDD known as Hansen type I, that on average occurs in younger dogs than type II IVDD, and is now understood to be more common in short-legged dogs inheriting the FGF4-retrogene insertion on CFA122,3. Type I IVDD is marked by early-onset degeneration of IVDs (beginning before the age of 1 year) in which the tissues of the IVDs undergo significant degradation, calcification, and replacement by other tissue types (a process called chondroid metaplasia). Unfortunately, early degeneration of IVDs not only increases the risk of early-onset IVDD, but also increases the risk of traumatic, explosive herniation of IVD material into the spinal canal, often resulting in severe pain, inflammation, hemorrhage, and neurological impairment including partial or complete paralysis. IVD ruptures of this severity are often considered an emergency requiring immediate surgical decompression of the spinal cord to limit permanent spinal cord damage and subsequent sensory and motor dysfunction. In some cases, the dog’s prognosis may be poor enough to justify humane euthanasia. For this reason, discovery of the CFA12 FGF4 insertion was met with great anticipation and excitement by dog breeders as this discovery was the first step in developing genetic testing which had the chance of helping them eliminate type I IVDD from their blood line2. However, in some breeds, we must temper our expectations for what this testing may allow us to achieve when it comes to reducing IVDD incidence.

IVDD Breeding Recommendations

Both insertions are associated with shortened limbs in a dominant fashion, meaning that a dog only needs to require a single copy of either insertion to inherit shortened legs and dogs inheriting insertion variants on both chromosomes 12 and 18 will have the most extreme shortening. However, it should be noted that the CFA12 insertion mutation results in limb shortening in a semidominant (additive) fashion in which the overall limb length decreases as the number of copies of this mutation increases. IVDD type I risk associated with the CFA12 FGF4 insertion is also inherited in a dominant fashion however, it displays incomplete penetrance, meaning that some dogs which inherit the CFA12 FGF4 insertion will never develop clinical signs of IVDD type I.

Appropriate breeding decisions regarding dogs which have inherited the CFA12 FGF4 insertion need to address both the potential loss of genetic diversity in a population which would occur if dogs with this mutation were prohibited from breeding as well as the loss of the short-legged appearance that is a defining physical characteristic for some breeds. In breeds which are known to inherit both mutations associated with short-legged appearance, breeders may be able to use results of genetic testing to selectively breed for the CDPA (CFA18 FGF4 insertion) mutation while breeding away from the CDDY and IVDD risk (CFA12 FGF4 insertion) mutation in order to reduce IVDD risk and retain a short-legged appearance. However, the frequency of each mutation varies between breeds and in some cases, may not be conducive to such a breeding strategy. For example, breeds with extreme limb shortening (e.g. basset hound, dachshund, corgi) typically develop their appearance due to inheritance of both the CFA12 and CFA18 FGF4 insertions. Therefore, elimination of either mutation from breeds with extreme limb shortening, may result in offspring which exceed breed standard leg length. Similarly, breeding strategies to eliminate IVDD in breeds expected to have moderately short legs may result in offspring with legs which are too long to meet breed standards if born without either the CFA12 or CFA18 FGF4 insertions.

Contact Paw Print Genetics

Paw Print Genetics offers testing for both the CDDY and IVDD risk (CFA12 FGF4) insertion and the CDPA (CFA18 FGF4) insertion on the Canine HealthCheck, a genetic screening tool which now tests for over 250 different genetic mutations associated with disease and traits in an individual dog from a single DNA sample. Because the Canine HealthCheck is a broad genetic screen, it will test a dog for all 250+ mutations regardless of the breed. Therefore, we have been identifying many dog breeds, not previously identified to be at an increased risk for IVDD, to have the CFA12 FGF4 insertion and are presumably at risk for IVDD. The relative risk of IVDD depends on the breed1 and for those breeds that are just now being identified, the risk is unknown at this time.

Individual testing for the genetic mutations associated with short legs is now available by Paw Print Genetics . Orders can be taken over the phone while the test is being added to our website.  For breeds in which all dogs are fixed for the CFA12 FGF4 insertion (dachshunds, basset hounds, corgis), testing will not provide useful information, as nearly all of these dogs are expected to have two copies.  For many other breeds, and mixed breed dogs, testing for the CDDY and CDPA mutations will help identify dogs who may be at risk for IVDD and help guide breeding decisions. If you have questions about how to effectively use genetic testing to decrease the incidence of Type I IVDD or have general questions about CDDY and IVDD risk, CDPA, the Canine HealthCheck, or Paw Print Genetics, please feel free to contact the knowledgeable geneticists and veterinarians at AskUs@pawprintgenetics.com or give us a call during normal business hours at 509-483-5950 (Monday through Friday; 8 am to 5 pm Pacific time)

Citations:

  1. Batcher K, Dickinson P, Giuffrida M, Sturges B, Vernau K, Knipe M, Rasouliha SH, Drogemuller C, Leeb T, Maciejczyk K, Jenkins CA, Mellersh C, Bannasch D. Genes (Basel). Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes (Basel). 2019 Jun 7;10(6). pii: E435. doi: 10.3390/genes10060435. [PubMed: 31181696]
  2. Brown EA, Dickinson PJ, Mansour T, Sturges BK, Aguilar M, Young AE, Korff C, Lind J, Ettinger CL, Varon S, Pollard R, Brown CT, Raudsepp T, Bannasch DL. FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11476-11481. doi: 10.1073/pnas.1709082114. [PubMed: 29073074]
  3. Hansen H-J (1952) A Pathologic-Anatomical Study on Disc Degeneration in Dog: With Special Reference to the So-Called Enchondrosis Intervertebralis, Acta Orthopaedica Scandinavica, 23:sup11, 1-130, DOI: 10.3109/ort.1952.23.suppl-11.01. [PubMed: 14923291]
  4. Murphy BG, Dickinson P, Marcellin-Little DJ, Batcher K, Raverty S, Bannasch D. Pathologic Features of the Intervertebral Disc in Young Nova Scotia Duck Tolling Retrievers Confirms Chondrodystrophy Degenerative Phenotype Associated With Genotype. Vet Pathol. 2019 Nov;56(6):895-902. doi: 10.1177/0300985819868731. [PubMed: 31526126]
  5. Parker HG, VonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA. An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs. Science. 2009 Aug 21;325(5943):995-8. doi: 10.1126/science.1173275. [PubMed: 19608863]

*Photo courtesy of Dallas Krentzel via Flickr Creative Commons license