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4 JVCS, Vol. 2, No. 1, January 2009
Pituitary Dwarfism in German Shepherd Dogs
Annemarie M.W.Y. Voorbij; Hans S. Kooistra, DVM, PhD, Dipl ECVIM-CA
Pituitary dwarfism in German shepherd dogs is an autosomal, recessive inherited disorder cha-
racterized by underdevelopment of the pituitary and a deficiency of growth hormone, thyrotro-
pin, prolactin, and the gonadotropins, but unaffected corticotropin secretion. Probably, a muta-
tion of a gene encoding a transcription factor that precludes effective expansion of pituitary
stem cells after differentiation of the corticotropic cells is the cause of this disorder. Identifica-
tion of the mutation would enable the development of a DNA test for potential breeding animals
and could lead to the eradication of this condition. The main clinical manifestations of pituitary
dwarfism are proportionate growth retardation and alopecia. Definite diagnosis should ideally
rely on the results of a combined pituitary anterior lobe function test. Although the prognosis
improves significantly when dwarfs are properly treated with levo-thyroxine and either porcine
growth hormone or progestins, the prognosis remains guarded.
Key Words: Growth hormone, adenohypophysis, growth retardation, canine
Introduction
he canine pituitary gland consists of
two main parts: the adenohypophysis
and the neurohypophysis. The
adenohypophysis can be divided into two
functional units: the anterior lobe (pars
infundibularis adenohypophysis and pars
distalis adenohypophysis) and the
intermediate lobe (pars intermedia
adenohypophysis). The mature anterior
pituitary contains a functionally diverse
population of highly specialized cell types
that are classified according to the tropic
hormones they produce: somatotropic cells
secreting growth hormone (GH),
lactotropic cells secreting prolactin (PRL),
gonadotropic cells secreting luteinizing
hormone (LH) and follicle-stimulating
hormone (FSH), thyrotropic cells secreting
thyroid- stimulating hormone (TSH) and
corticotropic cells synthesizing the
precursor molecule pro-opiomelanocortin
(POMC), which gives rise to
adrenocorticotropic hormone (ACTH).
The development of the adenohypo-
physis is a highly differentiated process
that is tightly regulated by the coordinated
actions of numerous transcription fac-
tors.1,2 During embryogenesis, the adeno-
hypophysis develops from Rathke’s pouch,
which arises from the oral ectoderm. The
individual hormone secreting cells emerge
from this pouch in a sequential order. Of
the adenohypophyseal endocrine cells, the
corticotropic cells are the first to develop.3
Any defect in the development of the
pituitary gland may result in a form of iso-
lated or combined pituitary hormone defi-
ciency. In dogs, congenital GH deficiency
or pituitary dwarfism is the most striking
example of pituitary hormone deficiency.
Pituitary dwarfism has been mentioned to
occur in different dog breeds, including the
Carelian bear dog and Saarloos wolfhound.
However, the condition is encountered
most often in German shepherd dogs.4-15
German shepherd dwarfs have a combined
deficiency of GH, TSH, PRL, and the go-
nadotropins. In contrast, ACTH secretion
is preserved in these animals.16,17
Pathogenesis
Pituitary dwarfism is known as a simple,
autosomal, recessive inherited abnormali-
ty.18-20 Genealogical investigations indi-
cate that the origin of the recessive gene is
a mutation that occurred at about 1940 or
sometime prior to that year. Additionally,
they point at various champion dogs as be-
ing carriers.19 The genetic defect causing
congenital GH deficiency in German
shepherd dogs is probably also the cause
T
From the Department of Clinical Sciences of Com-
panion Animals, Faculty of Veterinary Medicine,
Utrecht University, Yalelaan 108, PO Box 80154,
NL-3508 TD Utrecht, The Netherlands.
Correspondence: Dr. Hans S. Kooistra
E-mail H.S.Kooistra@uu.nl
Voorbij and Kooistra
JVCS, Vol. 2, No. 1, January 2009 5
of pituitary dwarfism in Carelian bear dogs
and Saarloos wolfhounds, because the dis-
order in the latter breeds was first recog-
nized after German shepherd dogs had
been used in their breeding.21
Originally, the condition has been
ascribed to pressure atrophy of the anterior
lobe of the pituitary gland by cystic en-
largement of the residual craniopharyngeal
duct or Rathke’s cleft.13 However, a more
recent study indicated that this is an un-
likely theory since German shepherd
dwarfs have been found with only a very
small pituitary cyst, unlikely to be
responsible for pressure atrophy.17, 22 Also
the finding that ACTH secretion is
preserved in German shepherd dogs argues
against cyst formation in Ratkhe’s pouch
as the primary cause of pituitary dwarfism
in this breed.17 It was concluded that cyst
formation should be seen as a consequence
of an underlying genetic defect and that it
is more likely that pituitary dwarfism is
caused by a primary failure of differentia-
tion of the craniopharyngeal ectoderm into
normal tropic-hormone-secreting pituitary
cells.
Because ACTH secretion is unaf-
fected in the German shepherd dwarfs, it
was supposed that a mutation of a gene
encoding a transcription factor that
precludes effective expansion of pituitary
stem cells after the differentiation of the
corticotropic cells is the cause of this dis-
order. The identification of this mutation
would enable the development of a DNA
test for potential breeding animals. In turn,
this could lead to the eradication of this
condition. Therefore, several genes have
been investigated as candidate genes for
the mutation that causes pituitary dwarfism
in German shepherd dogs.
The candidate gene investigated first
was POU1F1 (previously known as Pit-1).
POU1F1 is a homeodomain transcription
factor, essential for the development and
survival of the somatotropic, lactotropic
and thyrotropic cells. It is also required for
the subsequent expression of the genes en-
coding GH, PRL and TSH.23 In humans
and mice, a mutation in the POU1F1 gene
causes a deficiency of GH, TSH and PRL,
whereas gonadotropin and ACTH secre-
tion are unaffected.23-25 It was unlikely that
a mutation in the POU1F1 gene was the
cause of pituitary dwarfism in German
shepherd dogs, since German shepherd
dwarfs also exhibit a deficiency of gona-
dotropins. In agreement with this supposi-
tion, sequence analysis of genomic DNA
from German shepherd dwarfs did not re-
veal a disease-causing mutation in the
POU1F1 gene. In addition, linkage analy-
sis of polymorphic DNA markers flanking
the POU1F1 gene revealed no co-
segregation between the POU1F1 locus
and the dwarf phenotype.26 These observa-
tions excluded POU1F1 as a candidate
gene.
In contrast to individuals with
POU1F1 gene mutations, humans and
mice with mutations in the Prop1 gene are
not only characterized by a combined defi-
ciency of GH, PRL and TSH, but they also
have impaired production of LH and
FSH.27-29 This made Prop1 a very strong
candidate gene. However, Prop1 was ex-
cluded as candidate gene, since sequence
analysis of genomic DNA from these ani-
mals showed no alterations in the Prop1
gene. Moreover, linkage analysis revealed
no co-segregation between the Prop1 locus
and the combined pituitary hormone defi-
ciency phenotype.30
Lhx4 is a member of the LIM ho-
meodomain (LIM-HD) factor family. It
acts at an earlier stage of pituitary gland
development than POU1F1 and Prop1 and
plays an important role in the formation of
the definitive pouch.31 In humans, a splice
site mutation of Lhx4 has been identified
in patients with short stature due to GH de-
ficiency. These patients also displayed pi-
tuitary and hindbrain defects and abnor-
malities in the central skull base.32 In
German shepherd dwarfs Lhx4 was ex-
cluded as candidate gene for pituitary
dwarfism. Genotyping in 5 litters in which
pituitary dwarfism occurred showed ab-
sence of linkage between the inheritance
of the dwarf phenotype and a nearby DNA
marker.33
Pituitary dwarfism in dogs
6 JVCS, Vol. 2, No. 1, January 2009
Leukemia inhibitory factor (LIF), a
pleiotropic cytokine, and its receptor
(LIFR) play a modulating role in the onto-
geny of the adenohypophysis.34 In the de-
veloping murine pituitary, LIF inhibits go-
nadotroph, thyrotroph, lactotroph and so-
matotroph lineages and induces develop-
ment of corticotropes. Consistent with the
phenotype of German shepherd dwarfs,
transgenic mice with early pituitary over-
expression of LIF display severe dwarfism
and cystic cavities in the adenohypophy-
sis.35 Impaired development of the somato-
tropes and lactotropes and formation of pi-
tuitary cysts was also found in LIF trans-
genic mice in which the overexpression of
LIF started at a later stage of embryonic
development.36 It was hypothesized that
the canine LIFR gene could be involved in
the etiology of pituitary dwarfism. Be-
cause there was no allelic association be-
tween a polymorphic microsatellite marker
in the near vicinity of the LIFR gene and
the dwarfism phenotype, LIFR was ex-
cluded as a candidate gene for
pituitary dwarfism in German shepherd
dogs.37
Clinical Manifestations
Pituitary dwarfism can lead to a wide
range of clinical manifestations and not all
dwarfs display the same clinical signs and
symptoms. The most common clinical ma-
nifestations of pituitary dwarfism are
marked growth retardation (Figure 1),
retention of lanugo or secondary hairs
(puppy hair coat) with concurrent lack of
primary or guard hairs and bilateral sym-
metrical alopecia (Figure 2). Affected an-
imals may be of normal size during the
first weeks of their life, but they grow
more slowly than their littermates after this
period. By 3 to 4 months of age, affected
dogs are obviously runts of their litter and
they never attain full adult dimensions. In
these animals, the alopecia mostly occurs
at the trunk, the neck and at the proximal
extremities.4-15,38
Other often-encountered manifesta-
tions are skin problems such as hyperpig-
mentation, scales, and bacterial infections.
In addition, the presence of a pituitary cyst
can be identified in a large number of
dwarfs. These cysts are remnants of
Rathke’s cleft and they are lined with
ciliated columnar epithelial cells and
mucin-secreting globet cells.6,8,10 Pituitary
dwarfism is also associated with decreased
glomerular filtration.17 An overview of the
clinical manifestations and post mortem
findings associated with pituitary
dwarfism is given in Table 1.
Figure 1A nine-month-old German shepherd dog
with growth retardation due to pituitary dwarfism.
Figure 2A five-month-old German shepherd dog
with pituitary dwarfism. Note the retention of
secondary hairs (puppy hair coat) and the alopecia.
Voorbij and Kooistra
JVCS, Vol. 2, No. 1, January 2009 7
Table 1. Clinical manifestations and post mortem findings associated with pituitary dwarfism. (Modified from
Nelson, 2003)38
Diagnosis
Combined Anterior Pituitary Function
Test
Although the physical features of
pituitary dwarfism may seem obvious, the
diagnosis of pituitary dwarfism should be
based on endocrine test results. The mean
plasma insulin-like growth factor-1 con-
centration of German shepherd dwarfs is
considerably lower than that of healthy
adult and immature German shepherd dogs,
but there may be some overlap. Therefore,
the definitive diagnosis should rely on
evaluation of pituitary responsiveness to
provocative testing, i.e., challenging the
adenohypophyseal cell types by stimula-
tion with releasing hormones.17
To determine if a dog has GH defi-
ciency, a stimulation test using GH-
releasing hormone (GHRH) in an intra-
venous dosage of 1 μg/kg body weight
may be used. Alternatively, α-adrenergic
drugs such as clonidine (10 μg/kg body
weight) or xylazine (100 μg/kg body
weight) can be used. The plasma GH con-
centration should be determined before
and 20 to 30 minutes after intravenous
administration of the stimulant. In healthy
dogs, plasma GH concentrations should
increase at least two-to-fourfold after ad-
ministration of the stimulant. In the dwarfs
there will be no significant rise in plasma
GH concentration.39
To determine if a dog has a deficien-
cy of ACTH, TSH, PRL or gonadotropins,
the pituitary can by stimulated with corti-
cotropin-releasing hormone (CRH), thyro-
tropin-releasing hormone (TRH), and go-
nadotropin-releasing hormone (GnRH).40
The results of this combined pituitary ante-
rior lobe function test in healthy dogs and
German shepherd dogs with pituitary
dwarfism are depicted in Figure 3.
Ghrelin Stimulation Test
Another test to determine the respon-
siveness of the somatotropic cells is the
ghrelin stimulation test. Ghrelin is a potent
stimulator of GH release in dogs. In young
dogs it is an even more potent stimulator
Musculoskeletal Dermatologic
Stunted growth Soft, wooly haircoat
Thin skeleton Retention of lanugo hairs
Changes in ossification centers Lack of guard hairs
Delayed closure of growth plates Isolated patches of guard hair
Delayed dental erupture Bilateral symmetrical alopecia at
Fox like facial features trunk, neck and proximal extremities
Muscle atrophy Hyperpigmentation of the skin
Thin, fragile skin
Reproduction Wrinkles
Cryptorchidism Scales
Flaccid penile sheath Comedones
Failure to have estrus cycles Papules
Pyoderma
Other signs Seborrhea sicca
Shrill, puppy-like bark
Signs of secondary hypothyroidism Post mortem findings
Mental dullness Pituitary cysts
Impairment of renal function Atrophy adenohypophysis
Hypoplasia thyroid gland
Persistent ductus arteriosus
Pituitary dwarfism in dogs
8
JVCS, Vol. 2, No. 1, January 2009
than GHRH.
41
Human ghrelin is admini-
strated intravenously in a dose of 2 μg/kg
body weight. A post-ghrelin plasma GH
concentration more than 5 μg/l excludes
pituitary dwarfism.
42
Intrapituitary Cysts
The morphology of the pituitary may
be investigated with computed tomogra-
phy or magnetic resonance imaging. In
most German shepherd dwarfs, an intrapi-
tuitary cyst can be identified at a young
age, and the size of this cyst gradually en-
larges during life.
22
Because healthy dogs
may have pituitary cysts as well, a defini-
tive diagnosis of pituitary dwarfism cannot
be based solely upon the presence of
pituitary cysts.
39
Treatment
Heterologous GH
The most logical option would be to
treat the dwarfs with canine GH. Unfortu-
nately, this is not possible, since canine
GH is not available for therapeutic use.
Another option is the use of heterologous
GH. In the past, there have been attempts
to treat pituitary dwarfs with human GH.
Not only is this a very expensive therapy,
formation of antibodies directed against
human GH also precludes its use.
43
A good
option is the use of porcine GH. Adminis-
tration of porcine GH will not result in the
formation of antibodies, because the amino
acid sequence of porcine GH is identical to
that of canine GH.
44
The recommended subcutaneous
starting dose for any kind of heterologous
GH is 0.1 to 0.3 IU per kg body weight,
three times a week. This treatment may re-
sult in GH excess and consequently side
effects such as diabetes mellitus may de-
velop. Therefore, 3-weekly monitoring of
the plasma concentrations of GH and glu-
cose is recommended. Long-term dose
rates should depend on measurements of
the plasma concentration of insulin-like
growth factor-1.
39
Figure 3Mean (± SEM) plasma hormone concen-
trations during a combined pituitary anterior lobe
function test in 8 German shepherd dwarfs () and
8 healthy beagle dogs ().17
Whether therapy will lead to linear
growth of the dwarf is dependent on the
status of the growth plates at the time that
treatment is started. A beneficial response
in the skin and hair coat usually occurs
within 6 to 8 weeks of the start of therapy.
The hairs that grow back are mainly lanu-
go hairs. The growth of guard hairs is vari-
able.
38
Progestins
Alternatively, long-term treatment
with medroxyprogesterone acetate
(MPA)
22
or proligestone
45
can be used.
Progestins are able to induce the expres-
sion of the GH gene in the mammary
Voorbij and Kooistra
JVCS, Vol. 2, No. 1, January 2009 9
Figure 4A male German shepherd dog with pituitary dwarfism before (left) and after 1.5 years of treatment
with medroxyprogesterone acetate.
gland of dogs. In 1998, Kooistra et al. re-
ported an increase in size and a complete
adult hair coat in two German shepherd
dwarfs that were treated with subcutaneous
injections of MPA (Figure 4).22 The dogs
received doses of 2.5 to 5.0 mg MPA per
kg body weight, initially at 3-week inter-
vals and subsequently at 6-week intervals.
Undesirable side effects were recurrent pe-
riods of pruritic pyoderma in both dogs
and cystic endometrial hyperplasia with
mucometra in the female dog. Although
plasma concentrations of GH did not ex-
ceed the upper limit of the reference range,
one of the dogs developed slight acrome-
galic features.
Thyroid Hormones
The recommended therapy to treat the
secondary hypothyroidism is synthetic le-
vo-thyroxine. The starting oral dose is 0.02
mg/kg body weight, q12 hours. Because its
absorption and its metabolism are variable,
the dose of levo-thyroxine may have to be
adjusted before a satisfactory clinical re-
sponse is reached. For this reason, the
therapy should be monitored carefully.46
Prognosis
Without proper treatment, the long-term
prognosis is poor. By the age of 3 to 5
years the animal has usually become a bald,
thin, and dull dog. These changes may be
due to progressive loss of pituitary func-
tions, continuing expansion of pituitary
cysts, and progressive renal failure. At this
stage owners usually request euthanasia
for their dog, if they have not done so long
before this.47 Although the prognosis im-
proves significantly when dwarfs are prop-
erly treated with levo-thyroxine and either
porcine GH or progestins, their prognosis
still remains guarded.
References
1. Savage JJ, Yaden BC, Kiratipranon P, et al. Tran-
scriptional control during mammalian anterior pitui-
tary development. Gene 2003; 319: 1-19.
2. Zhu X, Rosenfeld MG. Transcriptional control of
precursor proliferation in the early phases of pitui-
tary development. Curr Opin Genet Dev 2004; 14:
567-574.
3. Simmons DM, Voss JW, Ingraham HA, et al. Pitui-
tary cell phenotypes involve cell-specific Pit-1
mRNA translation and synergistic interactions with
other classes of transcription factors. Genes Dev
1990; 4: 695-711.
4. Moch R, Haase G. Hypofunktion der Adenohypo-
physe eines Hundes. Tierärztl Umsch 1953; 8: 242-
244.
5. Baker E. Congenital hypoplasia of the pituitary and
pancreas glands in the dog. J Am Vet Med Assoc
1955; 126: 468.
Pituitary dwarfism in dogs
10 JVCS, Vol. 2, No. 1, January 2009
6. Jensen EC. Hypopituitarism associated with cystic
Rathke’s cleft in a dog. J Am Vet Med Assoc 1959;
135: 572-575.
7. Alexander JE. Anomaly of craniopharyngeal duct
and hypophysis. Can Vet J 1962; 3: 83.
8. Muller GH, Jones SR. Pituitary dwarfism and alo-
pecia in a German shepherd with a cystic Rathke’s
cleft. J Am Anim Hosp Assoc 1973; 9: 567-572.
9. Lund-Larsen TR, Grøndalen J. Ateliotic dwarfism
in the German shepherd dog. Low somatomedin ac-
tivity associated with apparently normal pituitary
function (2 cases) and with pan-adenopituitary dys-
function (1 case). Acta Vet Scand 1976; 17: 293-
306.
10. Allan GS, Huxtable CRR, Howlett CR, et al. Pitui-
tary dwarfism in German shepherd dogs. J Small
Anim Pract 1978; 19: 711-727.
11. Cassel SE. Ovarian imbalance in a German shephe-
rd dwarf. Vet Med Small Anim Clin 1978; 73: 162-
163.
12. Scott DW, Kirk RW, Hampshire J, et al. Clinicopa-
thological findings in a German shepherd with pitui-
tary dwarfism. J Am Anim Hosp Assoc 1978; 14:
183-191.
13. Müller-Peddinghaus R, El Etreby MF, Siefert J, et al.
Hypophysärer Zwergwuchs beim Deutchen
Schäferhund. Vet Pathol 1980; 17: 406-421.
14. Eigenmann JE. Diagnosis and treatment of dwar-
fism in a German shepherd dog. J Am Anim Hosp
Assoc 1981; 17: 798-804.
15. DeBowes LJ. Pituitary dwarfism in a German
shepherd puppy. Compend Contin Educ Pract Vet
1987; 9: 931-937.
16. Hamann F, Kooistra HS, Mol JA, et al. Pituitary
function and morphology in two German shepherd
dogs with congenital dwarfism. Vet Rec 1999; 144:
644-646.
17. Kooistra HS, Voorhout G, Mol JA, et al. Combined
pituitary hormone deficiency in German shepherd
dogs with dwarfism. Domest Anim Endocrinol
2000; 19: 177-190.
18. Andresen E, Willeberg P. Pituitary dwarfism in
German shepherd dogs: additional evidence of sim-
ple autosomal recessive inheritance. Nord Vet Med
1976; 28: 481-486.
19. Andresen E. Herkunft und Verbreitung von hypo-
physärem Zwergwuchs beim Hund und Grundlage
zur Ermittlung von Anlageträgern verschiedener ge-
netisch bedingter Krankheiten unter Anwendung bi-
ochemischer Methoden. Kleintier Praxis 1978; 23:
65-74
20. Nicholas F. Pituitary dwarfism in German shepherd
dogs: a genetic analysis of some Australian data. J
Small Anim Pract 1978; 19: 167-174.
21. Andresen E, Willeberg P. Pituitary dwarfism in Ca-
relian bear-dogs: evidence of simple, autosomal re-
cessive inheritance. Hereditas 1976; 84: 232-234.
22. Kooistra HS, Voorhout G, Selman PJ, et al. Proges-
tin-induced growth hormone (GH) production in the
treatment of dogs with congenital GH deficiency.
Domest Anim Endocrinol 1998; 15: 93-102.
23. Li S, Crenshaw III EB, Rawson EJ, et al. Dwarf lo-
cus mutants lacking three pituitary cell types result
from mutations in the POU-domain gene Pit-1. Na-
ture 1990; 347: 528-533.
24. Pellegrini-Bouiller I, Bélicar P, Barlier A, et al. A
new mutation of the gene encoding the transcription
factor Pit-1 is responsible for combined pituitary
hormone deficiency. J Clin Endocrinol Metab 1996;
81: 2790-2796.
25. Pfäffle R, Kim C, Otten B, et al. Pit-1: clinical as-
pects. Horm Res 1996; 45 (Suppl 1): 25-28.
26. Lantinga-van Leeuwen IS, Mol JA, Kooistra HS, et
al. Cloning of the canine gene encoding transcrip-
tion factor Pit-1 and its exclusion as candidate gene
in a canine model of pituitary dwarfism. Mamm
Genome 2000; 11: 31-36.
27. Sornson MW, Wu W, Dasen JS, et al. Pituitary li-
neage determination by the prophet of Pit-1 homeo-
domain factor defective in Ames dwarfism. Nature
1996; 384: 327-333.
28. Fofanova O, Takamura N, Kinoshita E, et al. Com-
pound heterozygous deletion of the Prop-1 gene in
children with combined pituitary hormone deficien-
cy. J Clin Endocrinol Metab 1998; 83: 2601-2604.
29. Wu W, Cogan JD, Pfäffle RW, et al. Mutations in
PROP1 cause familial combined pituitary hormone
deficiency. Nat Genet 1998; 18: 147-149.
30. Lantinga-van Leeuwen IS, Kooistra HS, Mol JA, et
al. Cloning, characterization, and physical mapping
of the canine Prop-1 gene (PROP1): exclusion as a
candidate for combined pituitary hormone deficien-
cy in German shepherd dogs. Cytogenet Cell Genet
2000; 88: 140-144.
31. Sheng HZ, Moriyama K, Yamashita T, et al. Multis-
tep control of pituitary organogenesis. Science
1997; 278: 1809-1812.
32. Machinis K, Pantel J, Netchine I, et al. Syndromic
short stature in patients with a germline mutation in
the LIM homeobox LHX4. Am J Hum Genet 2001;
69: 961-968.
33. Van Oost BA, Versteeg SA, Imholz S, et al. Exclu-
sion of the lim homeodomain gene LHX4 as a can-
didate gene for pituitary dwarfism in German
shepherd dogs. Mol Cell Endocrinol 2002; 197: 57-
62.
34. Auernhammer CJ, Melmed S. Leukemia-inhibitory
factor-neuroimmune modulator of endocrine func-
tion. Endocr Rev 2000; 21: 313-345.
35. Yano H, Readhead C, Nakashima M, et al. Pitui-
tary-directed leukemia inhibitory factor transgene
causes Cushing’s syndrome: neuro-immune-
endocrine modulation of pituitary development. Mol
Endocrinol 1998; 12: 1708-1720.
36. Akita S, Readhead C, Stefaneanu L, et al. Pituitary-
directed leukemia inhibitory factor transgene forms
Rathke’s cleft cysts and impairs adult pituitary func-
tion. A model for human pituitary Rathke’s cysts. J
Clin Invest 1997; 99: 2462-2469.
37. Hanson JM, Mol JA, Leegwater PAJ, et al. The leu-
kemia inhibitory factor receptor gene is not involved
in the etiology of pituitary dwarfism in German
shepherd dogs. Res Vet Sci 2006; 81: 316-320.
38. Nelson RW. Disorders of the hypothalamus and pi-
tuitary gland. In: Nelson RW, Couto CG, eds. Small
animal internal medicine, 3rd ed. Mosby, St Louis;
2003; 660-680.
39. Kooistra HS. Acromegaly and pituitary dwarfism.
In: Ettinger SJ, Feldman EC, eds. Textbook of Vete-
rinary Internal Medicine, 6th ed. Elsevier Saunders,
St. Louis; 2005; 1498-1502.
40. Meij BP, Mol JA, Hazewinkel HAW, et al. Assess-
ment of a combined anterior pituitary function test
in beagle dogs: rapid sequential intravenous admin-
istration of four hypothalamic releasing hormones.
Domest Anim Endocrinol 1996; 13: 161-170.
Voorbij and Kooistra
JVCS, Vol. 2, No. 1, January 2009 11
41. Bhatti SFM, Duchateau L, Van Ham LML, et al. Ef-
fects of growth hormone secretagogues on the re-
lease of adenohypophyseal hormones in young and
old healthy dogs. Vet J 2006; 172: 515-525.
42. Bhatti SFM, De Vliegher SP, Mol JA, et al. Ghrelin-
stimulation test in the diagnosis of canine pituitary
dwarfism. Res Vet Sci 2006; 81: 24-30.
43. Van Herpen H, Rijnberk A, Mol JA. Production of
antibodies to biosynthetic human growth hormone
in the dog. Vet Rec 1994; 134: 171.
44. Ascacio-Martínez JA, Barrera-Saldaña HA. A dog
growth hormone cDNA codes for a mature protein
identical to pig growth hormone. Gene 1994; 143:
277-280.
45. Knottenbelt CM, Herrtage ME. Use of proligestone
in the management of three German shepherd dogs
with pituitary dwarfism. J Small Anim Pract 2002;
43: 164-170.
46. Nelson RW. Disorders of the thyroid gland. In: Nel-
son RW, Couto CG, eds. Small animal internal med-
icine, 3rd ed. Mosby, St Louis; 2003; 691-728.
47. Rijnberk A. Hypothalamus-pituitary system. In:
Rijnberk A, ed. Clinical endocrinology in dogs and
cats, Kluwer Academic Publishers, Dordrecht, The
Netherlands; 1996; 11-34.
... 6,10 Common clinical manifestations of canine CPHD are marked growth retardation, retention of secondary hairs (puppy hair coat) with concurrent lack of primary or guard hairs, and bilaterally symmetrical alopecia. 11,12,14 The disorder also can lead to a wide range of other clinical manifestations, but not all dwarfs share the same clinical signs. 14 In humans with CPHD caused by an LHX3 mutation, a short neck, rigid cervical spine, and anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression, defined as an upward displacement of vertebral elements into the 3D 3 Recently, 3 Czechoslovakian wolfdogs and 1 German shepherd dwarf with CPHD were presented to our clinic for neurological signs suggestive of a cervical spinal problem. ...
... 11,12,14 The disorder also can lead to a wide range of other clinical manifestations, but not all dwarfs share the same clinical signs. 14 In humans with CPHD caused by an LHX3 mutation, a short neck, rigid cervical spine, and anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression, defined as an upward displacement of vertebral elements into the 3D 3 Recently, 3 Czechoslovakian wolfdogs and 1 German shepherd dwarf with CPHD were presented to our clinic for neurological signs suggestive of a cervical spinal problem. The investigations demonstrated anatomical abnormalities of the atlanto-axial joint with concurrent atlanto-axial instability and dynamic compression of the spinal cord by the dens axis. ...
... 6,10 The animals were treated with porcine GH a (0.1-0.3 IU per kg body weight 3 times per week) and synthetic levo-thyroxine b (with a starting oral dosage of 0.02 mg/kg body weight, q12h) as described previously. 14 ...
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Background Canine pituitary dwarfism or combined pituitary hormone deficiency (CPHD) in shepherd dogs is associated with an LHX3 mutation and can lead to a wide range of clinical manifestations. Some dogs with CPHD have neurological signs that are localized to the cervical spine. In human CPHD, caused by an LHX3 mutation, anatomical abnormalities in the atlanto-axial (C1-C2) joint have been described.Objectives To evaluate the presence of atlanto-axial malformations in dogs with pituitary dwarfism associated with an LHX3 mutation and to investigate the degree of similarity between the atlanto-axial anomalies found in canine and human CPHD patients with an LHX3 mutation.AnimalsThree client-owned Czechoslovakian wolfdogs and 1 client-owned German shepherd dog, previously diagnosed with pituitary dwarfism caused by an LHX3 mutation, with neurological signs indicating a cervical spinal disorder.Methods Radiography, computed tomography, and magnetic resonance imaging of the cranial neck and skull, necropsy, and histology.ResultsDiagnostic imaging identified abnormal positioning of the dens axis and incomplete ossification of the suture lines between the ossification centers of the atlas with concurrent atlanto-axial instability and dynamic compression of the spinal cord by the dens axis. The malformations and aberrant motion at C1–C2 were confirmed at necropsy and histology.Conclusions and Clinical ImportanceThe atlanto-axial abnormalities of the dwarf dogs resemble those encountered in human CPHD patients with an LHX3 mutation. These findings suggest an association between the LHX3 mutation in dogs with CPHD and atlanto-axial malformations. Consequently, pituitary dwarfs should be monitored closely for neurological signs.
... In dogs, pituitary dwarfism is the most common manifestation of CPHD and this disorder is encountered most often in German Shepherd Dogs. 1 Pituitary dwarfism in this breed is inherited in an autosomal recessive fashion 2 and is characterized by a combined deficiency of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin, and the gonadotropins. In contrast, adrenocorticotropic hormone secretion is preserved in these animals. ...
... 3 The hormone deficiencies can lead to a wide range of clinical manifestations, but the most common ones are marked growth retardation, retention of lanugo or secondary hairs (so-called puppy hair coat) with concurrent lack of primary or guard hairs, and bilateral symmetrical alopecia. 1 Recently, we have reported that molecular defects of the LHX3 gene are associated with CPHD. 4 LHX3, a member of the LIM homeodomain protein family of DNA-binding transcription factors, is an essential regulator of pituitary development. 5,6 All but 1 analyzed German Shepherd dwarfs were homozygous for a deletion of a 7 bp sequence in intron 5 of the LHX3 gene, decreasing the intron size to 68 bp. ...
... Canine pituitary dwarfism is encountered most often in German Shepherd Dogs as a recessively inherited disorder. 1,4 The clinical signs displayed by the Czechoslovakian and Saarloos wolfdog dwarfs reported here (eg, proportionate dwarfism, retention of secondary hairs, and alopecia) strongly resembled those seen in German Shepherd dwarfs. Therefore, we tested whether the dwarfism in the Saarloos and Czechoslovakian wolfdogs also was because of GH deficiency. ...
Article
Background Pituitary dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian wolfdogs.Objectives To investigate whether Saarloos and Czechoslovakian wolfdog dwarfs have the same LHX3 mutation as do Germans Shepherd Dog dwarfs. A specific aim was to determine the carrier frequency among Saarloos and Czechoslovakian wolfdogs used for breeding.AnimalsTwo client-owned Saarloos wolfdogs and 4 client-owned Czechoslovakian wolfdogs with pituitary dwarfism, 239 clinically healthy client-owned Saarloos wolfdogs, and 200 client-owned clinically healthy Czechoslovakian wolfdogs.Methods Genomic DNA was amplified using polymerase chain reaction (PCR). In the Saarloos and Czechoslovakian wolfdog dwarfs, PCR products were analyzed by sequencing. DNA fragment length analysis was performed on the samples from the clinically healthy dogs.ResultsSaarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs. The frequency of carriers of this mutation among clinically healthy Saarloos and Czechoslovakian wolfdogs used for breeding was 31% and 21%, respectively.Conclusions and Clinical ImportanceAn LHX3 mutation is associated with pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs. The rather high frequency of carriers of the mutated gene in the 2 breeds emphasizes the need for screening before breeding. If all breeding animals were genetically tested for the presence of the LHX3 mutation and a correct breeding policy would be implemented, this disease could be eradicated completely.
... The proximal tibia and proximal humerus are the last long bone epiphyses to close. The proximal tibia in large breed dogs close at 10-18 months and are less responsive if treatment is started thereafter [21,25]. Treatment with levothyroxine alone does not seem to induce significant growth, although thyroid hormones also play a role in the process of growing and dogs with congenital Table 5. Changes after treatment initiation with levothyroxine (group 2) or levothyroxine and progestogens or GH (group 3). ...
... The underlying mechanisms may include a progressive loss of pituitary function, progressive renal failure and the expansion of pituitary cysts. Euthanasia is usually requested by the owner at that point [25,27]. The results of this study are in accordance with this. ...
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Background Pituitary dwarfism (PD) in German Shepherd dogs (GSD) is a rare endocrinopathy. Cause and inheritance of the disease are well characterized, but the overall survival time, presence of concurrent diseases, quality of life (QoL) and influence of different treatment options on those parameters is still not well investigated. The aim of this study was to obtain data regarding the disease pattern of GSD with PD and to investigate the impact of treatment. Methods 47 dogs with dwarfism (presumably PD) and 94 unaffected GSD serving as controls were enrolled. Data were collected via a standardized questionnaire, which every owner of a participating dog had completed. Dogs with PD were grouped based on three categories of treatment: Group 1 (untreated), group 2 (treated with levothyroxine), group 3 (treated with thyroxine and progestogens or with growth hormone (GH)). Groups were compared using One-Way-Anova, Kruskal-Wallis test or Wilcoxon-rank-sum test. Categorical analysis was performed using Two-Sample-Chi-Squared-test. Results Dogs treated with thyroxine and gestagen or GH were significantly taller and heavier compared to all other dogs with PD. Quality of life was best in dogs with PD treated with thyroxine and similar to unaffected GSD. Treatment increased survival time in dogs with PD independent of the treatment strategy. Dogs receiving thyroxine and progestogens or GH did not develop chronic kidney disease (CKD). Conclusion GSD with PD should be treated at least for their secondary hypothyroidism to increase survival time. Additional treatment with progestogens or GH improves body size and seems to protect against the occurrence of CKD.
... In dogs, the best-known example of congenital central hypothyroidism is that of pituitary dwarfism in German Shepherd Dogs, characterized by a combined deficiency of all adenohypophyseal hormones except ACTH. 7 Combined pituitary hormone deficiency, including TSH deficiency, has also been described in a 12-week-old dog after head injury. 8 Isolated TSH deficiency is very uncommon in dogs being reported in a family of Giant Schnauzers, 9 4 total thyroxine young Boxer, 10 and in a 2-week-old Portuguese Water Dog. ...
... Whereas primary hypothyroidism is commonly diagnosed in dogs, central hypothyroidism is rarely reported. [7][8][9][10][11] The fact that this rare disorder occurred in 7 dogs from the same breed suggests that central hypothyroidism could have a genetic background in Miniature Schnauzers. However, no diseasecausing mutations were found in the TSHB gene and exons of the TRHR gene. ...
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Background: Primary hypothyroidism is a common endocrinopathy in dogs. In contrast, central hypothyroidism is rare in this species. Objectives: The objective of this article is to describe the occurrence and clinical presentation of central hypothyroidism in Miniature Schnauzers. Additionally, the possible role of the thyroid-stimulating hormone (TSH)-releasing hormone receptor (TRHR) gene and the TSHβ (TSHB) gene was investigated. Animals: Miniature Schnauzers with proven central hypothyroidism, based on scintigraphy, and the results of a 3-day-TSH-stimulation test, or a TSH-releasing hormone (TRH)-stimulation test or both, presented to the Department of Clinical Sciences of Companion Animals at Utrecht University or the Department of Medicine and Clinical Biology of Small Animals at Ghent University from 2008 to 2012. Methods: Retrospective study. Pituitary function tests, thyroid scintigraphy, and computed tomography (CT) of the pituitary area were performed. Gene fragments of affected dogs and controls were amplified by polymerase chain reaction (PCR). Subsequently, the deoxyribonucleic acid (DNA) sequences of the products were analyzed. Results: Central hypothyroidism was diagnosed in 7 Miniature Schnauzers. Three dogs had disproportionate dwarfism and at least one of them had a combined deficiency of TSH and prolactin. No disease-causing mutations were found in the TSHB gene and the exons of the TRHR gene of these Schnauzers. Conclusions and clinical importance: Central hypothyroidism could be underdiagnosed in Miniature Schnauzers with hypothyroidism, especially in those of normal stature. The fact that this rare disorder occurred in 7 dogs from the same breed suggests that central hypothyroidism could have a genetic background in Miniature Schnauzers.
... This condition is encountered most often in German shepherd dogs (GSD). Common clinical manifestations are marked growth retardation, retention of secondary hairs (puppy coat) with concurrent lack of primary or guard hairs, and bilateral symmetrical alopecia (Figure 1) [10]. Pituitary dwarfism in the GSD breed is characterized by underdevelopment of the pituitary gland and a combined deficiency of growth hormone, thyroid stimulating hormone, prolactin, and gonadotropins. ...
... The splicing deficiency of the canine LHX3 intronic deletion in the in vitro system was not absolute and accordingly we detected wild type LHX3 mRNA in the two available pituitaries from dwarfs. Possible variations in the level of residual activity between dwarfs could be related to the high level of phenotypic variability that we observe [10]. Because there was only one pituitary available of a dwarf that was homozygous for the 7 bp deletion, we could not adequately evaluate the expression level of LHX3 in dwarfs. ...
Article
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Dwarfism in German shepherd dogs is due to combined pituitary hormone deficiency of unknown genetic cause. We localized the recessively inherited defect by a genome wide approach to a region on chromosome 9 with a lod score of 9.8. The region contains LHX3, which codes for a transcription factor essential for pituitary development. Dwarfs have a deletion of one of six 7 bp repeats in intron 5 of LHX3, reducing the intron size to 68 bp. One dwarf was compound heterozygous for the deletion and an insertion of an asparagine residue in the DNA-binding homeodomain of LHX3, suggesting involvement of the gene in the disorder. An exon trapping assay indicated that the shortened intron is not spliced efficiently, probably because it is too small. We applied bisulfite conversion of cytosine to uracil in RNA followed by RT-PCR to analyze the splicing products. The aberrantly spliced RNA molecules resulted from either skipping of exon 5 or retention of intron 5. The same splicing defects were observed in cDNA derived from the pituitary of dwarfs. A survey of similarly mutated introns suggests that there is a minimal distance requirement between the splice donor and branch site of 50 nucleotides. In conclusion, a contraction of a DNA repeat in intron 5 of canine LHX3 leads to deficient splicing and is associated with pituitary dwarfism.
Article
This chapter discusses pathogenesis, classical signs, diagnosis, and treatment, of hyposomatotropism in dogs. Congenital hyposomatotropism or pituitary dwarfism occurs most often as an autosomal, recessive inherited disorder in German shepherd dogs or breeds in which German shepherd dogs have been used in the breeding. Congenital hyposomatotropism in these breeds is characterized by underdevelopment of the pituitary gland and a deficiency of growth hormone (GH), thyrotropin, prolactin, and gonadotropins, whereas corticotropin secretion is unaffected. Because progestins are able to induce the expression of the GH gene in the mammary glands, and because mammary GH in dogs is released into the systemic circulation, dogs with hyposomatotropism can also be treated with progestins, such as medroxyprogesterone acetate (MPA). Treatment of dogs with congenital hyposomatotropism with either porcine GH or MPA should, in most cases, be accompanied by treatment with synthetic levothyroxine.
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The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.
Article
Pituitary dwarfism was diagnosed in a two-year-old intact female white German shepherd. Clinical abnormalities included dwarfism, bilaterally symmetrical alopecia, and an open cranial fontanelle. Laboratory abnormalities included depressed TSH and ACTH response tests, and very low levels of plasma GH. Histopathological examination of affected skin revealed decreased amounts of dermal elastin and collagen, hypertrophy and vacuolation of arrector pili muscles, and other more nonspecific changes consistent with endocrine skin disease. Necropsy revealed a multicystic malformation of the craniopharyngeal duct (Rathke's cleft).
Article
An alopecic German shepherd male dwarf was observed clinically from the age of 9 mth until he was nearly 4 yr old, when he was euthanized at the owner's request. The pituitary gland was almost completely replaced by multicystic remnants of Rathke's cleft. These were filled with mucin and lined by cuboidal and ciliated columnar epithelium containing numerous goblet cells.
Article
Eight pituitary dwarfs have been born recently in six different litters from registered German Shepherd parents in the Sydney region of New South Wales, Australia. A genetic analysis has been carried out to determine whether there is any hereditary basis to the syndrome.In agreement with recent Danish findings, the Australian data indicate that pituitary dwarfism is inherited as an autosomal recessive condition, with the possibility that some recessive homozygotes die before or soon after birth. Thus the observed proportion of dwarfs in a litter from heterozygous parents is often less than 25%.
Article
Although methods for purification of dog (Canis familiaris) growth hormone (cfGH) were described in the late Sixties, the cloning of its cDNA has not been achieved until now. In order to clone the cfGH cDNA, we capitalized on the high degree of nucleotide sequence conservation among mammalian G H genes to design a pair of consensus oligodeoxyri bonucleotide primers. With these, and starting with dog pituitary gland total RNA, we specifically amplified the cfGH cDNA using the reverse transcription-polymerase chain reaction. Its coding sequence (651 bp), as well as its 3' untranslated region (101 bp), resemble those of a typical mammalian GH cDNA. Interestingly, its encoded mature protei is identical to pig growth hormone (pGH).
Article
The recent demonstration of the ability of progestins to induce the expression of the growth hormone (GH) gene in the mammary gland of dogs and cats opens possibilities for the treatment of some forms of GH deficiency with progestins. Therefore, one male and one female German shepherd dog with congenital dwarfism because of a pituitary anomaly were treated with subcutaneous injections of medroxyprogesterone acetate (MPA) in doses of 2.5-5.0 mg per kg body weight, initially at 3-wk intervals and subsequently at 6-wk intervals. In both dogs, body sizes increased and a complete adult hair coat developed. Undesirable side-effects were recurrent periods of pruritic pyoderma in both dogs and cystic endometrial hyperplasia with mucometra in the female dog. Parallel with the physical improvements, plasma insulin-like growth factor I concentrations rose sharply. Plasma GH concentrations tended to rise, but never exceeded the upper limit of the reference range. Nevertheless, one of the dogs developed slight acromegalic features, possibly because mammary GH, unlike pituitary GH, is released evenly throughout the day. Even moderate increases in circulating GH concentration may, therefore, give rise to overexposure. It is concluded that long-term treatment with MPA can be used as an alternative for heterologous GH in the treatment of congenital GH deficiency in the dog.