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Congenital Hypothyroidism with Goiter (CHG)

by Dr. John C. Fyfe

The Spanish Water Dog Club of America (SWDCA) is proud to sponsor Dr. Fyfe’s research through an AKC Canine Health Foundation ACORN grant.

A cooperative effort of SWD breeders, the SWDCA, the AKC Canine Health Foundation, local veterinarians, and a canine genetics researcher at the Michigan State University College of Veterinary Medicine has recently culminated in discovery of the genetic basis of congenital hypothyroidism with goiter (CHG) in SWD. A reliable, DNA-based carrier test is now available. Thyroid hormone is essential for normal development and metabolism in dogs, especially in the rapid growth period that puppies experience. In the past couple of years, breeders have been aware that pups as described below have been born occasionally, but correct diagnosis was delayed as was realization that the disorder is inherited. At this time it is apparent that CHG carriers have been obtained as breeding stock from kennels in the United States as well as imported from Europe. We do not know whether affected pups have been produced in Europe.

Pups affected with CHG are abnormal prior to weaning, the growth delay typically becoming apparent at about 2 weeks of age. They may not move around as much as normal pups, and when normal litter mates experience a growth spurt at about 2 weeks, the affected pups stop developing. An affected pup may have a seizure and die in that period. Some may die or be euthanized without diagnosis. The photo shows an SWD litter at 3 weeks of age. The brown pup and the small black one next to it are CHG affected. The brown one died suddenly a day after the photo. With nursing care CHG affected pups can survive, but opening of the eyes and ear canals is substantially delayed. Hearing and cognition are quite impaired in the long term. Paired swellings develop on the underside of the neck and continue to enlarge with time, although the curly SWD hair coat may hide them for some time. The swellings are the enlarged thyroid glands (goiter) and may be mistaken for lymph nodes in making an incorrect diagnosis of puppy strangles. If X-rays are taken, it is apparent that the bones do not lengthen appropriately. Delay in lengthening of bones in the legs and spine causes irreversible dwarfism in longer term survivors. Most abnormalities are alleviated by early diagnosis (4-8 weeks of age) and oral administration of thyroid hormone replacement daily thereafter, but this will not make the goiter disappear. Even with treatment, CHG pups do not achieve normal weight and stature, and lifelong treatment of affected pups is not a good solution to the problem. The only reasonable solution is prevention.

Recent studies have demonstrated that the disorder is inherited as a simple autosomal recessive trait. For a puppy to have CHG, it must receive the mutated copy (allele) of the disease gene from both parents, and male and female puppies are equally affected. The parents of affected pups show no outward signs of disease, but they are obligate carriers, by definition. In a breeding program, both male and female carriers will pass on their mutant alleles to 50% of all their offspring, on average. When two carriers are inadvertently mated, on average 25% of the puppies will have CHG. That means that in litters from such matings, there may be some combination of CHG and normal pups, all CHG puppies, or all normal puppies. Unidentified carriers in breeding programs continue to spread the mutant allele throughout the SWD breed.

CHG in SWD is caused by lack of thyroid peroxidase (TPO), an enzyme in the thyroid gland responsible for adding iodine to a protein called thyroglobulin.  A mutation in the TPO gene prevents production of the enzyme and the consequent inability to produce thyroid hormones. Identification of the TPO mutation has allowed us to design a laboratory test to detect the mutation in DNA from blood, cheek cells, and semen. DNA isolated from samples is subjected to a polymerase chain reaction (PCR) to amplify the portion of the TPO gene harboring the mutation. Normal and mutant alleles are differentiated by sequencing the products of PCR amplification. Therefore, carrier dogs can be positively identified in the laboratory on the basis of the presence of the mutant allele in their DNA.

This test is offered to SWD breeders through the Laboratory of Comparative Medical Genetics at Michigan State University in hopes that it will be used to eliminate CHG from SWD breeding programs. This type of carrier testing will facilitate elimination of the mutant gene from SWD without unduly selecting against the good traits of any particular line, reducing variability of the SWD gene pool, or inadvertently selecting for some other inherited disorder. Though the laboratory will happily receive whole blood samples (0.2-0.4 cc in a purple top tube), most convenient sample for an owner to obtain for testing is a brushing of cheek cells. For a cheek brush sampling kit with submission form and instructions, please contact Dr. Fyfe by email: fyfe@cvm.msu.edu or at the address below. Give your own mailing address, and indicate how many dogs you wish to test. At present, the test is offered at $85 per dog. All samples should be mailed to the following address: Dr. John C. Fyfe, Laboratory of Comparative Medical Genetics, 2209 Biomedical Physical Sciences, Michigan State University, East Lansing, MI 48824  (517) 884-5348. Test results are confidential and will be returned only to the dog owner.

Frequently Asked Questions

How could such a disorder like CHG get established in SWD?

Inherited disorders occur in all dog and other animal breeds. 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 with the advent of shipping chilled semen, thereby increasing the “productivity” of some dogs. After a few more generations, carriers are inadvertently mated in one or more kennels and the disorder 'suddenly' appears, usually in several places almost at once. That scenario appears to have happened with CHG in the SWD. If would certainly be interesting to learn how many SWD breeders have seen affected pups over recent years.

While many inherited disorders are relatively rare when considered across all breeds, when a genetic disease gains a foothold in a breed, the carrier prevalence can become quite high, and the disease becomes rather common in that breed. A good 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 then because they can now be identified by DNA testing. We only hope that we can prevent the CHG carrier rate from rising higher in SWD as breeders begin to use the available genetic test. It is our wish to put the testing program out of business, so to speak.

Should all SWD breeders be concerned?

When we speak of eliminating CHG from the SWD breed, we are speaking of individual kennels and the responsibilities of individual breeders. As for any breed-specific disorder, the concerned breeders are those who have experienced the problem, those with related dogs, and those who wish to avoid future problems. Really, there are two things that responsible breeders wish to avoid and which the CHG test makes possible. No one wants to produce affected puppies, and no wants to increase the number of carriers in the breed. Any breeder can test their breeding stock, and if they only breed non-carriers thereafter, they will never have a problem with CHG. CHG tests should become one criterion upon which SWD breeders choose dogs to which they will breed their own. We can test frozen semen of an already deceased dog prior to insemination of a bitch, and we can test dogs being considered for shipping of chilled semen.

It is important, however, to realize that long-term investments in a particular line of SWD need not be abandoned just because your prized dog or bitch tests as a CHG carrier. If one has a CHG carrier that has many other good traits and is not also a carrier of other disorders, such as PRA, then one may breed the dog to another SWD that has tested clear of the CHG mutation. None of the pups produced in such a mating will be affected, and one can then pick puppies that exhibit desired traits to carry on the line. The pups chosen to establish the next generation should be tested to ensure they are not carriers too. This is a “test and replace” approach to eliminate a disease allele from one’s breeding program. The remaining puppies of such a litter that will not go into one’s own or other breeding programs need not be tested because the carrier state has no effect on health. This method will maintain the desired variation in the SWD gene pool and prevent an inadvertent selection for some other problems.

Is this showing up as a recessive trait when inbreeding is done?

Exactly!  CHG in SWD is inherited as a simple autosomal recessive trait. From our studies, it clear that the disease-causing mutation has been around for at least a decade. It is just now that folks are enough aware of it and talking about it. One thing that has slowed recognition of the disorder is that it occurs in very young pups; they can seem to fade away by a few weeks of age. The swelling in the neck has even been misinterpreted by some veterinarians as swollen lymph nodes, or in some cases the swelling is missed because the curly hair covers it. SWD in general are not highly inbred, but the maintenance of “purebred” dogs and the line breeding that may produce desirable traits is a form of inbreeding that can also lead to recessive disease showing up.

As an autosomal recessive trait, male and female offspring are equally affected by CHG, and the parents of litters with affected offspring are obligate carriers. Carriers are completely healthy and normal looking. For a puppy to be affected it must get the disease gene from both sire and dam, so to produce an affected pup two carriers must be mated. You may have been fortunate enough to have not bred two carriers so far. If a carrier is bred to a non carrier, none of the puppies will have the disease, but one half (on average) of the pups will get the disease gene from the carrier parent and will be carriers themselves. So, while the disease can skip many generations it can come back whenever two carriers are mated.

That is not to say that the carrier state can skip generations. Affected puppies can only come from carrier parents. The carriers show no signs of disease so without a carrier test they stay in breeding programs and produce more carriers like themselves. When a carrier dog becomes a popular sire, he can produce a lot of carrier offspring all over the country before carriers are inadvertently bred to each other and produce affected offspring that catch someone’s attention.

Should all of the carrier dogs be neutered or spayed at this time? Could I breed a carrier to a non carrier and then test the litter to cull out any new carriers from that matting?

Neutering is one (rather drastic) option, but now that a definitive carrier test is available, mass neutering is not necessary. Many breeders like yourself have a lot of time, money and sweat invested in your particular lines. Simply test the dogs you are going to sell into breeding programs so the purchasers don’t end up with carriers. For your own dogs, tests the ones you want to keep in your breeding program. If a dog tests normal, you will have no CHG problems from it, and it will not produce more carriers. A dog cannot be a carrier if both of its parents have tested as normal, so with a little testing at the beginning, a breeder can get to a secure position of knowing that none of the future dogs produced is a carriers. If a dog tests as a carrier, but it has important characteristics you want to maintain, you can breed it to a non-carrier, which won't produce affected pups, but then test the pups from that litter which carry on the traits you want to keep in our program. Dog breeding has always been a procedure of selective breeding; we simply have a new criterion upon which to select.

Some of my dogs have tested as CHG carriers. Do you think that there is more of it in other lines of which we are not aware but are just now beginning testing?

Dogs from your line have not shown up as carriers much more than some others. It is already clear that the disease gene has come from dogs several generations behind yours including European imports, and it was transmitted into a number of lines in addition to yours. We will learn more as more dogs are tested, if the breeders sending samples continue to submit pedigrees too.

Are the test results on the dogs published or do you keep them completely confidential?

The test results and the pedigrees people send are kept completely confidential in the Laboratory of Comparative Medical Genetics. No one but my technician and me has access to them. We send the results directly to the person who sent in the sample (that does not mean the veterinarian who drew blood), whether that is the dog’s owner or not, though it almost always is the owner. However, if you arrange to have some of your dogs tested who are now owned by other people and you pay for the test, we send you the results. Each dog tested receives a certificate indicating the result.

Any knowledge that people have of testing results of other peoples' dogs is because the owners have chosen to share that information. It has not gone from the testing laboratory to anyone but the owner. From what I can tell, it appears that people are pretty open and are sharing their test results, now that there is something concrete one can do about it. Some breed clubs have chosen to maintain a database of DNA test results, but that is up to the club, and dog owners must approve release of their results to the database or provide the results themselves.

What is the procedure for the test?

The test is a DNA based PCR detection of the mutation which causes CHG in SWD. The mutation and, therefore, the test is different from those that cause CHG in toy fox or Tenterfield terriers. We isolate the dog’s DNA from the submitted blood or cheek brush sample and amplify the portion of DNA where the mutation occurs. In the last step we sequence the amplified DNA. This test is only for a specific mutation, so it is applicable only to CHG and only in SWD.

Where is it sent and how?

0.2-0.4 cc of whole blood should be collected in a purple top (EDTA) tube so that it will not clot. Alternatively, cheek brush samples can be collected at home. Either sample can be sent in the mail, but if it is blood, be sure to pad the tubes against breakage. There is no need to send samples on ice or cold packs, but if there is a delay in mailing, keep blood samples in the refrigerator (not the freezer). Contact the laboratory for submission forms and/or a cheek brush sampling kit, specifying the number of dogs you wish to test and your postal mailing address. Mail samples to: John C. Fyfe, Laboratory of Comparative Medical Genetics, 2209 Biomedical Physical Sciences, Michigan State University, East Lansing, MI 48824

What is the cost per dog, and is there a cut rate for several at once?

Please send a check made out to Michigan State University (CHG testing) for $85/sample. There is no bulk rate. We have kept the cost to a minimum, and $85 is our cost to provide the test. Personal checks are fine, but we ask that submissions from outside the United States be accompanied by a postal money order in USD. Include the payment in the package with the sample(s) and submission form(s). Sorry, but we do not accept credit cards or electronic payments.

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