DNA testing of Congenital Hypothyroidism with Goiter (CHG)

The thyroid is an extremely important gland that has a lot of influence over hormonal conditions in the body. i.e., it can have a very detrimental effect on the reproductive ability of a dog. That gets the attention of breeders. Thyroid imbalance can cause skin sensitivities, hair loss, weight gain (or loss) behavioral abnormalities, lethargy, and other very serious health problems in people and animals.  Although not related to this problem, Dr. Fyfe makes reference to over supplementing with kelp in pregnant bitches.  Breeders may want to explore the idea that in trying to boost thyroid in suspected problem cases, we are actually contributing to a higher incidence of hypothyroidism with each successive generation!

This hereditary defect is deadly if not diagnosed and treated immediately.  The puppies just "fade away" and die as described in the information provided by Dr. Fyfe.  Knowing what an incredibly healthy breed the Toy Fox Terrier is, I was intrigued and somewhat skeptical about this new  "thyroid problem,"  Was this just another ruse to attack certain bloodlines?  Was it blown out of proportion or precipitated by the excitement (or apprehension) surrounding the breed's eminent acceptance for AKC ring competition?  Click Here for related article on Breeding Priorities

I decided to contact Dr. Fyfe directly so that we could quickly and effectively get the word out to thousands of TFT owners around the world -  or debunk the study if it turned out to be a tempest in a teapot.  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 and validity of the condition.  Responses were tremendous!  TFT people are concerned, involved, and devoted to the breed!  Some responses were defensive, some were unkind (fear? ignorance?) but most were willing to discuss and/or report suspected incidents.  That mailing also brought about the following detailed information from Dr. Fyfe and that is what we will share with you.  Click Here for instant PopUp on how testing developed

Here are the questions he addressed with clarity and consideration for the limitations of our layman's understanding.  At the end of Dr. Fyfe's reply there is a link for info on testing 

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. 

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. 

Click Here for info on testing procedure

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

John C. Fyfe, D.V.M., Ph.D.
Associate Professor of Microbiology 
and Molecular Genetics
Michigan State University
413 Giltner Hall
East Lansing. MI 48824

Tel: 517-432-4071
Fax: 517-353-8957
fyfe@cvm.msu.edu
http://www.msu.edu/unit/mic/facpages/fyfe.html

after May 20, 2002:
Michigan State University
2209 Biomedical, Physical Sciences 
East Lansing, MI 48824 
tel: (517) 355-6463 ext. 1559
same email address

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