Congenital Hypothyroidism With Goiter is an extremely rare, 100% fatal condition in newborn puppies so is DNA testing for CHG just hyped-up research labs income?
Congenital Hypothyroidism with Goiter (CHG)
John C. Fyfe, D.V.M., Ph.D. for TheDogPlace.org 2005
Introduction by Barbara J. Andrews, editor.
This hereditary defect is fatal. It is therefore, self-limiting as affected puppies die in the nest. Given the accuracy of the CHG test as described below by Dr. Fyfe, breeders can avoid ever producing the deadly defect by not breeding carrier to carrier and not breeding to untested dogs. By its very nature, CHG is extremely rare. We present information on the "new disease" with this caveat: an extensive survey of Toy Fox Terrier breeders turned up only six possible but unconfirmed cases.
The obvious alternative to testing all breeding stock for 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. Note that a pup is either a carrier or clear. "Affected" can only mean it is dead...
Experienced breeders are rolling their eyes and I am one of them, having exposed other such financially-motivated "tempests in a tea pot." Our duty is to provide readers with factual information. Breeders can then decide which tests are most important to the future of their breed. Knowing the Toy Fox Terrier is extraordinarily healthy, we are skeptical about the new "thyroid problem" and testing.
Note that such "testing" is most often offered at Specialty Shows where peer pressure and observance of who "didn't test their dogs" is most prevalent. Specialties are also where scare tactics, combined with the "free collection and testing " is designed to elicit grateful compliance. Breeders at the Toy Fox Terrier National Specialty were led to believe the jugular vein draw would be done by a "veterinary team" but under persistent questioning, the three collectors were forced to admit they were not veterinarians!
Was CHG blown out of proportion in order to collect blood samples which could then be sold or used for other unrelated research? There were many questions so on behalf of Toy Fox Terrier breeders around the world, TheDogPlace.org decided to seek more information directly from Dr. Fyfe.
His reply raised more questions than it answered so I forwarded it to a group of long time breeders and asked if they, or anyone they knew, had produced a litter containingcongenital hypothyroidism with goiter (CHG). Although some responses were defensive, most were willing to discuss and/or report suspected incidents. None were confirmed. Not one.
Here are the questions Dr. Fyfe addressed with clarity and consideration for the limitations of our layman's understanding. Other information provided by Dr. Fyfe follows in part 2 and 3.
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 Toy Fox Terrier 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.
"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."