Congenital Hypothyroidism with Goiter (CHG) DNA Testing

Barbara J. Andrews  © TheDogPlace 2005  - We are grateful to Dr. Fyfe for this information on the new disease, Congenital Hypothyroidism with Goiter (CHG), a condition in the Toy Fox Terrier. Links to the Genetic Basis and to Testing Procedure and Cost are provided below.  Bolding is added for speed readers and emphasis.

This is part one of three.  Links to part 2 and part 3 are at the end of this page.

This hereditary defect is fatal.  It is therefore, self-limiting as affected puppies die in the nest.  Given the accuracy of the test as described below by Dr. Fyfe, breeders can avoid ever producing the deadly defect by having their dogs tested, not breeding carrier to carrier and not breeding to untested dogs.

The alternative to rushing to test all breeding stock when a breeder has never produced CHG, is simply to never breed a dog that has produced Congenital Hypothyroidism with Goiter to anything other than a dog that is tested clear, and then test the litter.  A pup is either a carrier or clear.  "Affected" would means it is dead...

That is the premise upon which new breeders are basing the future of their breeding program.  Older breeders are rolling their eyes and I am one of them, having exposed other such "tempests in a tea pot."  But my job is to provide you with the facts and you will decide for yourself which tests are most important to your future and that of the breed.

Knowing what an incredibly healthy breed the Toy Fox Terrier is, I was intrigued but somewhat skeptical about the new "thyroid problem" and testing.  My personal concerns were: Was this just another ruse designed to collect dog DNA for some purpose having little to do with canine research?  For those who were not at the Toy Fox Terrier National Specialty when this was attempted by a "veterinary team" (under insistent questioning, they admitted none of them were vets!!) the "free collection and testing" practice is not uncommon and serves to set off alarms in a breed whereby it is hoped that all breeders will then test.  Was CHG blown out of proportion or precipitated by the excitement surrounding the breed's eminent acceptance for AKC ring competition?  There were many questions so on behalf of Toy Fox Terrier breeders around the world, TheDogPlace decided to seek more information from Dr. Fyfe.

His initial reply raised more questions than it answered so I forwarded it to a group of long time breeders and asked for information re: the incidence of congenital hypothyroidism with goiter (CHG).  Responses were tremendous! TFT people are concerned, involved, and devoted to the breed!  Although some responses were defensive, most were willing to discuss and/or report suspected incidents. None were confirmed.  That mailing also brought about even more detailed information from Dr. Fyfe and that is what we will now share with you.

Here are the questions he addressed with clarity and consideration for the limitations of our layman's understanding. At the end of this interview is other information provided by Dr. Fyfe.

Questions: Is it too early to provide numbers on the accuracy of the test? Does the DNA indicate whether it is hereditary or acquired? Where does a university obtain funding for such a rare problem in a rare breed? Is the disorder present in other breeds and if so, is research being conducted for them? Are there numerical statistics on how many dogs are affected? Why is New Zealand mentioned?

Dr. Fyfe: I would like to respond at more length while I am presently between other immediate deadlines. I have also attached three writings regarding the disorder and the testing procedure which we distribute to TFT breeders and owners when they inquire. I hope to clear up some confusion and provide information of use to TFT breeders. 

Hypothyroidism is a problem which afflicts many breeds of dog, but far and away most canine hypothyroidism is adult-onset and is an immune-mediated disorder associated with production of anti-thyroglobulin antibodies. While this form clearly has an inherited component, it is not simply inherited, and there are unknown environmental factors involved. The Endocrinology Section of the Michigan State University Animal Health Diagnostic Laboratory continues to conduct research on this type of hypothyroidism, and the "thyroid panels" which report the levels of thyroid hormones, TSH, and autoantibodies are part of this effort. They are still collecting data which will eventually make the thyroid panel more predictive of hypothyroidism, the disease. 

Congenital hypothyroidism is quite different. "Congenital" indicates that the hypothyroidism is present at or soon after birth rather than developing years later. Congenital hypothyroidism occurs in different forms in different breeds caused by various abnormalities of the hypothalmus, the pituitary gland, or the thyroid glans itself. In humans, untreated congenital hypothyroidism causes severe mental and physical retardation. It is of such concern in human medicine, that every infant born in this and every developed country of the world is tested for congenital hypothyroidism in publicly funded testing programs, and treatment is initiated immediately. With early diagnosis and immediate initiation of treatment these individuals lead near-normal lives. 

The research in my laboratory on canine congenital hypothyroidism has been funded by the National Institute of Child Health and Development in recognition that discoveries in dog disease are often relevant to human disease. We are not part of the MSU AHDL laboratories. Previously, we have worked primarily on the congenital hypothyroidism of giant schnauzers originally reported by Greco DS, et al (JVIM 1991;5:57-65), but when approached last year by TFT breeders and their veterinarians, we initiated study of the TFT disorder. In addition to the relevance to human disease, we gained some financial support from Merck by using the TFT disorder as a learning problem in training of an interested veterinary student in the molecular investigation of canine genetic diseases. The large goiter that the affected TFT develop was a distinguishing characteristic which, along with some clinical testing conducted by the referring veterinarians, narrowed down the list of possible genes causing the problem. That and some luck solved the problem in about 6 months. 

In dogs, congenital hypothyroidism occurs almost entirely as a simple autosomal recessive trait, with mutations in different genes in each different breed. I say 'almost entirely' because we have observed congenital hypothyroidism with goiter in a litter of golden retriever pups in which the bitch was ill advisedly supplemented with kelp powder during late gestation and lactation. The high level of iodine in kelp powder is apparently toxic to fetal and newborn pup thyroid glands as it is in humans. Our investigation in TFT turned up a mutation in the thyroid peroxidase gene. Thyroid peroxidase is an enzyme the thyroid gland uses to attach iodine to thyroglobulin in the production of thyroid hormone. The genetic test we developed detects the mutation directly.

A paper describing these results is currently out for review with a veterinary professional journal, and we hope it will be published sometime this year. The paper describes the test exactly so that others may confirm our results or even offer the test themselves. If someone can do it more cost effectively, that is fine with us, but for now we have offered this test to TFT breeders through word of mouth. Of course today word of mouth includes internet and email. The $40 fee/dog tested is only our cost. Recently, we have converted to using cheek brush samples rather than blood samples to save the dog owner the expense of having blood drawn by their veterinarian. 

To answer some of your particular questions, the test is for a mutation specific to the TFT breed of dogs that causes hypothyroidism. If one sees a similar disease in one of the breeds which originally contributed to the TFT gene pool it would be interesting to determine whether it is the same mutation causing it. However, no one has reported a similar inherited disorder in any other breed, so we certainly would not suggest testing for the TFT mutation in other breeds at this time. CHG in TFT is entirely hereditary and has no discernable environmental component. Because the test is for a specific mutation, it is 100% accurate and reliable. To date we have received samples from 12 dogs known to have produced CHG affected puppies, what we call obligate carriers, and every one has come up as a carrier on the laboratory test. Thirty-five of 145 other TFT tested so far have been determined to be carriers as well. The CHG mutation was not found in any of 50 dogs of other breeds that we've tested. This does not represent an accurate estimate of breed prevalence in the TFT because the sample population is biased; most DNA samples have been submitted by breeders who have dogs related to other known carriers. Even so, we have found carriers and affected pups in kennels from coast to coast and north to south due to the widespread sharing of breeding stock.

The affected New Zealand TFTs were diagnosed by Dr. Boyd Jones, an endocrinologist at the Dublin, Ireland School of Veterinary Medicine, when he lived and worked in New Zealand. He is contacting TFT breeders there for DNA samples, so that we may determine definitely that it is the same genetic disease. (Editor's note: no one we have spoken with knows of any Toy Fox Terriers in New Zealand, Ireland, or England at this time or in the past.)  It is not correct to think of the TFT as a small (in number) breed. The UKC registered more than 11,000 new TFT puppies in 2001, and that was similar to several previous years. As for any breed specific disorder, the concerned breeders are those that have experienced the problem, those who know they have related dogs, and those who wish to avoid future problems. In many inherited disorders of dogs, there is what is called a 'founder effect'. Typically, a popular sire that is an undetected carrier of a recessive disease produces a lot of puppies, half of which are also carriers. This is even more of a problem lately with the advent of shipping chilled semen. After a few more generations, carriers are inadvertently mated in several kennels and the disorder 'suddenly' appears in several places almost at once. That scenario appears to have happened with CHG in the TFT. What were probably affected pups produced a decade ago and intermittently since in different kennels around the country have been described to us. Most often a firm diagnosis was never made, though in at least three cases the breeder had diagnosis confirmed through necropsies.  ((Editor's note: Perhaps with good reason, no one has admitted to having produced affected pups.)

When we speak of eliminating CHG from TFT breeding programs, we are speaking of individual kennels. Really, there are two things that concerned TFT breeders wish to avoid and which the CHG test has made possible. No one wants to produce affected puppies, and no wants to increase the number of carriers in the breed. Any breeder who wishes may test their breeding stock. Thereafter, if they only breed non carriers they will never have a problem with CHG. It has already become a criterion upon which TFT breeders choose dogs to which they want to breed their own. We have tested frozen semen of a dead dog prior to insemination of a bitch, and we have tested dogs being considered for shipping of chilled semen. In the latter instance, the testing allowed the breeder to avoid breeding to a carrier dog. 

It certainly is true that many inherited disorders are relatively rare when considered across all breeds. However, when a genetic disease gains a foothold in a breed, the carrier prevalence can become quite high, and the disease is in no way rare for that breed of dog. An example is that prior to the availability of genetic testing for carriers of GM1 gangliosidosis in Portuguese water dogs, 20% of PWDs were carriers. Of course, that extreme carrier rate has dropped in the years since because they can be identified. We only hope the same will happen for CHG in TFT, as breeders use the genetic testing available. We want to put ourselves out of business, so to speak.

It would certainly be interesting to me to learn how many TFT breeders have seen affected pups. It is very gratifying to me that as CHG information gets out and breeders realize that the testing doesn't threaten them, more and more have sent in samples, and we continue to identify carriers to them. Conversely we identify normal dogs to them with which they can continue their breeding programs secure in the knowledge that they won't produce CHG affected pups or more carriers.

If you have other questions regarding this subject, please do not hesitate to contact me.
 

Part 2 Genetic Basis for CHG and Part 3 Info on testing procedure and cost
More on VWD, CHD Testing & Breeding Priorities