We are
grateful to Dr. Fyfe of Michigan State University
for the study of this condition
in the Toy Fox Terrier. The
disorder is rare but not limited to just one breed,
therefore it is important to be aware of and contribute
to the work Dr. Fyfe is doing.
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?
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.
Here are the
questions he addressed with clarity and consideration
for the limitations of our layman's understanding.
Questions: Perhaps you have a paper already prepared?
Is it too early to provide numbers on the accuracy
of the test? Does it reveal dogs with active hyper
or hypothyroidism? 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.
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.
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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