Primary Hyperparathyroidism in German Shepherd Dogs: A Disorder of Probable Genetic Origin
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Vet. Pathol. 21: 370-376 (1984)
Primary Hyperparathyroidism in German Shepherd Dogs: A Disorder of
Probable Genetic Origin
K. G. THOMPSON,
L. P. JONES,W. A. SMYLIE,C. B. QUICK,G. V. SEGRE,D. J. MEUTEN,and
M. B. PETRITES-MURPHY
Department of Veterinary Pathology, The Texas Agricultural Experiment Station and the Texas Veterinary
Medical Diagnostic Laboratory, Texas A&M University, College Station, Tex., and The Endocrine Unit,
Massachusetts General Hospital, Boston, Mass.
Abstract. Primary hyperparathyroidism was diagnosed in two German shepherd pups from a litter of four females. Clinical
signs were apparent by two weeks of age and included stunted growth, muscular weakness, and polydipsia/polyuria.
Radiography revealed diffuse reduction in bone density. Both pups had marked hypercalcemia, hypophosphatemia, increased
plasma immunoreactive parathyroid hormone concentrations and increased fractional clearance of inorganic phosphate in
the urine. Intravenous infusion of one affected pup with calcium gluconate failed to suppress the plasma concentration of
immunoreactive parathyroid hormone, suggesting autonomous secretion of parathyroid hormone. Necropsy of the other pup
at eight weeks of age revealed diffuse hyperplasia of parathyroid chief cells, nodular hyperplasia of thyroid C-cells, skeletal
alterations consistent with fibrous osteodystrophy, hypercalcemic nephropathy, and extensive mineralization of the lungs and
gastric mucosa. The dam and sire were half sibs. One male pup from a previous litter of six had developed similar clinical
signs and radiographic lesions, suggesting autosomal recessive inheritance. This is the first report of hereditary primary
hyperparathyroidism in domestic animals, a disease which may be analogous to hereditary neonatal primary hyperparathy-
roidism in children.
Primary hyperparathyroidism in man occurs most domestic animals. We report the occurrence of primary
often in adults and may be associated with either para- hyperparathyroidism, probably with genetic etiology, in
thyroid neoplasia, usually solitary adenomas, or diffuse two German shepherd pups.
hyperplasia of all four parathyroid gland^.^*^,'*.*^ Some
cases have a genetic etiology and may occur in con- Case History
junction with neoplasms in other endocrine or- At two weeks of age, two German shepherd pups ( 1 and 2)
gans.4, IS. 17.21.30.32
A rare form of hereditary primary from a litter of four females had difficulty suckling and were
hyperparathyroidism developing in the early neonatal dominated by their littermates. By five weeks, both affected
pups had stunted growth, lameness, muscular weakness, and
period has been described in ~hildren.'.~.~. '3*22324.25.28*31
polydipsia/polyuria. Radiographic examination of both pups
The disease in children is characterized by failure to revealed diffuse reduction in bone density with transverse
thrive, muscular weakness, extreme hypercalcemia, hy- sclerotic lines in long bones and narrowing of the cortices.
pophosphatemia, fibrous osteodystrophy, and nephro- Similar radiographic findings were present in pup 2 at eight
calcinosis. Soft tissue calcification involving the lung, weeks of age in addition to a diffuse increase in pulmonary
density consistent with mineralization.
stomach, myocardium, and blood vessels occasionally At eight weeks of age, pup 1 was unable to support weight
is observed. Affected children die in early infancy if on its hind legs and was killed painlessly. Pup 2 was treated
subtotal parathyroidectomy is not d ~ n e . ~Autosomal.~' with ethane- 1 hydroxy- I , 1-diphosphonate (Procter and Gam-
rece~sive'~ and d ~ m i n a n t * ~ . ~ ' of inheritance have
modes ble, Cincinnati, Ohio) in an attempt to prevent bone resorp-
been reported. tion; the results will be reported elsewhere.
In dogs, primary hyperparathyroidism is rare and All four pups were suckled until five weeks of age and then
were fed on commercial dog rations. No vitamin or mineral
usually occurs in aged animals with functional parathy- supplements were provided.
roid adenomas2 Hereditary primary hyperparathyroid- The sire and dam were half sibs. In a previous litter of six
ism has not been reported previously in dogs or other from the same mating, one male pup developed similar
370
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clinical signs and radiographic lesions to those described Table I. Biochemical data from two German shepherd pups
above and subsequently was killed at five months of age with primary hyperparathyroidism ( 1 and 2) and their
without being necropsied. unaffected littermates (3 and 4) at six weeks of age
PUD 1 PUD2 PUD3 PUP4
Materials and Methods Serum calcium (mg/dl) 19.8 15.4 10.4 10.9
Serum alkaline phosphatase activity and concentrations of Serum phosphorus (mg/ 4.0 4.9 7.8 6.8
calcium, inorganic phosphorus, total protein, urea nitrogen dl)
and creatinine were measured using an SMA 12/60 micro Serum alkaline phospha- 880 880 320 356
apparatus (Technicon Instruments Corp., Tanytown, N.Y.). tase (IU/l)
Concentrations of calcium, inorganic phosphorus, and creat- Serum creatinine (mg/ 0.8 1.0 0.3 0.4
inine in the urine were measured using the same apparatus. dl)
In order to test the responsivenesqof the parathyroid glands Serum urea nitrogen 22 26 - -
in pup 2 to increased plasma calcium concentration, hyper- (mg/dl)
calcemia was induced by intravenous infusion of calcium Fractional clearance of 59% 75% - -
gluconate (1 mg/ml in 5% dextrose) at 15 mg elemental Ca/ urinary phosphorus
kg/hour then maintained at 7 mg Ca/kg/hour. This study
was done after the original hypercalcemia had been treated
successfully with ethane- I , hydroxy- 1, 1-diphosphonate. Dur-
ing this study plasma calcium concentrations were measured
values for pups3 Fractional clearance of inorganic phos-
using a Centrifichem 400 apparatus (Baker Instruments, Beth-
phorus in the urine was increased in pups 1 and 2 but
lehem, Pa.).
Immunoreactive parathyroid hormone was measured in was not determined in pups 3 and 4. Subsequent sam-
ples from both affected pups revealed similar abnor-
heparinized plasma by a modification of methods previously
malities. Serum calcium concentrations ranged from
described,26using antiserum GP- 1 (final dilution 1 :450,000).
Either partially purified human parathyroid h o r m ~ n e or '~
17.9 to 23.7 mg/dl for pup 1 and from 14.4 to 20.6
pooled plasma from human patients with hyperparathyroid-
mg/dl for pup 2. Serum alkaline phosphatase activities
ism were used as standards. The former was expressed in pg/
in pups 3 and 4 were considered to be normal for
ml and the latter in pIEq/ml, an arbitrary unit. Antiserum
rapidly growing pups of a large breed, but the levels in
GP- 1 contains antibodies that recognize two major determi-
affected pups were increased.
nants within the parathyroid hormone molecule, one requir-
ing all or part of the 14-34 region and the other requiring all
Immunoreactive parathyroid hormone concentra-
or part of the 53-84 region.26 It has been previously shown
tions in the plasma of pups 1 and 2 at eight weeks of
that when used in radioimmunoassay of canine parathyroid
age were greater than 1000 plEq/ml. Most clinically
hormone, this antiserum readily recognizes both intact hor-
normal dogs previously assayed by the same method
mone and the large carboxy-terminal fragment (G. V. Segre,
had immunoreactive parathyroid hormone concentra-
unpublished data). Moreover, samples of canine plasma with
tions less than 60 plEq/ml. Intravenous infusion of
increased concentrations of immunoreactive parathyroid hor-
mone were diluted and found to have displacement curvescalcium gluconate into pup 2 over a period of 150
which were parallel to those given by standard, partially
minutes increased the plasma calcium concentration
purified human parathyroid hormone.
from 10.9 mg/dl to 12.7 mg/dl, but failed to suppress
Tissues for light microscopy were fixed in 10% formalin
the concentration of immunoreactive parathyroid hor-
immediately after euthanasia of pup I . Following routine
mone (fig. 1).
embedding in paraffin, 6 pm sections were cut and stained
with hematoxylin and eosin (HE). Selected sections were Necropsy examination of pup 1 revealed flabby,
stained with either von Kossa's or Masson's trichrome moderately atrophic limb muscles. The thyroid glands
method. Bones were demineralized in saturated solutions of
were pale tan. All four parathyroid glands were enlarged
ethylene diamine tetracetate before embedding.
slightly. Bones were fragile and had narrow cortices,
although there were segmental regions of sclerosis in
Results the metaphysis of some limb bones. Firm, pale yellow,
The biochemical data obtained from all four pups at thickened regions in the metaphysis of each rib ex-
six weeks of age are presented in table I. The most tended approximately 2 to 3 cm along the shaft from
remarkable biochemical abnormality was extreme hy- near the costochondral junction. Similar swollen seg-
percalcemia in pups 1 and 2. Serum inorganic phos- ments sometimes were present in the diaphysis of ribs.
phorus concentrations in these pups were low in com- The capsular surface of both kidneys was pitted finely.
parison to their clinically normal littermates (pups 2 The renal cortex was pale tan and in the outer medulla
and 4) and when compared with published reference there was a narrow, incomplete white band interpreted
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c5
dilatation, especially in medullary rays, focal interstitial
a
a
v
2ooo1 fibrosis,focal mineralization of tubular basement mem-
C branes and epithelial cells in the cortex, and more severe
.-c0
E focal mineralization in the outer medulla.
c
C In the lungs there was diffuse mineralization of al-
:1000-
Q,
0
veolar septa, bronchi, and bronchioles (fig. 5). Bron-
0 chiolar mineralization was most severe in the superficial
I lamina propria and muscularis. Alveolar septa were
!i thickened with dense mineral deposits and sometimes
m 9
5a I
Calcium Infusion
Emm contained moderate numbers of mononuclear and
E I l l I 1 I 1 1 I h polymorphonuclear inflammatory cells. Occasional
-30 0 30 60 90 120 150 180 210
Time (minutes) mineral deposits were in pulmonary arteries. The lam-
Fig. 1: Effect of intravenous infusion of calcium gluconate ina propria and muscularis mucosa of the stomach also
on the plasma concentrations of calcium (A)and immuno- were diffusely mineralized but submucosal arteries usu-
reactive parathyroid hormone (0)in pup 2 after hypercal- ally were spared.
cemia had been corrected by treatment with ethane-1 hy-
droxy-1, 1-diphosphonate.
Discussion
The presence of elevated plasma immunoreactive
to be mineralization. The lungs were diffusely firm and parathyroid hormone and diffuseparathyroid hyperpla-
failed to collapse when the thoracic cavity was opened. sia in two German shepherd pups with marked hyper-
Microscopically, parathyroid glands contained uni- calcemia, in addition to increased fractional clearance
form populations of chief cells with an increased of inorganic phosphate in the urine and fibrous osteo-
amount of lightly basophilic cytoplasm (fig. 2). Perivas- dystrophy, suggests a diagnosis of primary hyperpara-
cular spaces were indistinct and chief cells sometimes thyroidism. A genetic etiology is suspected because the
formed acinar structures. Occasional chief cells were disease occurred in only two pups from a litter of four.
undergoing mitosis. These changes indicated diffuse Parental consanguinity, and the possible occurrence of
hyperplasia and hypertrophy of chief cells. C-cells in a similarly affected pup in a previous litter add further
thyroid glands also were hyperplastic. Focal aggregates support to this hypothesis and suggest autosomal reces-
of plump C-cells with abundant cytoplasm separated sive inheritance. The clinical and pathological altera-
thyroid follicles (fig. 3). Mitoses were common and tions observed in our pups closely resemble those re-
occasional cells contained eosinophilic intranuclear in- ported in young children with severe hereditary primary
clusions that probably represented cytoplasmic invagi- hyperparathyr~idism.~**- 9, 13- 22*24*25,27*28,31 The disease
nations. in children is associated with diffuse hyperplasia of
The skeletal alterations were consistent with fibrous parathyroid chief cells rather than a functional parathy-
osteodystrophy and were most severe in the ribs. The roid a d e n ~ m aAlthough
.~~ it is not possible to differ-
metaphyseal and diaphyseal swellings observed macro- entiate grossly or microscopically between adenoma-
scopically in the ribs consisted of thickened trabeculae tous and hyperplastic parathyroid glands,6*I* the en-
of woven bone separated by loose fibrous connective largement of all four glands in pup 1 and the presence
tissue. Osteoblastic and osteoclastic activities were of apparently active chief cells throughout each gland
prominent. Trabeculae sometimes contained resorp- suggests hyperplasia.
tion cavities lined by osteoclasts. Similar alterations Parathyroid hyperplasia and fibrous osteodystrophy
were observed in all limb bones examined. The primary may be associated with advanced renal failure, and
spongiosa contained irregular trabeculae of woven bone familial renal disease was considered in the differential
lined by either osteoclasts or active osteoblasts, and diagnosis. Hypercalcemia would not be expected in a
separated by loose connective tissue (fig. 4). There was dog with renal failure although it has been reported as
excessive thickening of trabeculae in the distal metaph- a possible sequela: presumably secondary to prolonged
ysis of some bones. Resorption cavities were common stimulation of parathyroid chief cells by low plasma
in the cortices. ionized calcium concentrations. However, serum bio-
Renal alterations were mild and consisted of tubular chemical alterations and results of urinalysis did not
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Fig. 2: Parathyroid gland; chief cells have an increased quantity of lightly basophilic cytoplasm, occasional mitotic figures
(arrows),and indistinct penvascular spaces. HE. Bar = 30 pm.
Fig. 3: Multiple aggregates of plump C-cells in thyroid gland separating thyroid follicles. HE. Bar = 50 pm.
indicate impaired renal function in either of our pups, Other possible causes of hypercalcemia such as hy-
and the renal lesions observed in pup 1 at necropsy pervitaminosis D, hypervitaminosis A, thyrotoxicosis,
were considered to be secondary to hypercalcemia. The and localized bone resorption secondary to skeletal
inability of both pups to concentrate urine was presum- neoplasia or osteomyelitis could be excluded on the
ably due to inhibition of antidiuretic hormone by cal- basis of clinical history, pathological findings in pup 1,
cium. hypophosphatemia and elevated plasma concentrations
Pseudohyperparathyroidism is the most common of immunoreactive parathyroid hormone. Hypercal-
cause of symptomatic hypercalcemia in dogs.3 This cemia and hypophosphatemia, in association with
condition is associated with the production by neoplas- slightly elevated plasma immunoreactive parathyroid
tic tissue of substances capable of promoting bone hormone concentration, recently was described in an
resorption. In dogs, malignant lymphoma and apocrine aged dog with parathyroid chief cell hyperplasia, med-
adenocarcinoma of the anal sac have been implicated ullary thyroid carcinoma and pheochromocytoma, a
most frequently.3In contrast to the disease in our pups, syndrome resembling multiple endocrine neoplasia
skeletal alterations in pseudohyperparathyroidism are type IIA in man.” No endocrine neoplasms were de-
mild and parathyroid glands usually are atrophic.” tected at necropsy in our pup and the C-cell hyperplasia
Furthermore, there was no evidence of neoplasia in was considered to be secondary to persistent hypercal-
either pup. cemia.
Downloaded from vet.sagepub.com by guest on September 14, 2015374 Thompson el al.
Fig. 4: Prominent osteoblastic and osteoclastic activity in metaphysis of distal ulna. Bone trabeculae separated by loose
connective tissue. HE. Bar = 70 pm.
Fig. 5: Diffuse mineralization of pulmonary alveolar septa, bronchiolar lamina propria, and muscularis. Von Kossa. Bar
= 200 um.
A common cause of fibrous osteodystrophy in young finding even in human hyperparathyroidism. Most hu-
pups is nutritional secondary hyperparathyroidism as- man patients have elevated immunoreactive parathy-
sociated with the feeding of all-meat diets. This is an roid hormone concentrations in the face of hypercal-
unlikely possibility in our cases since all four pups were cemia, suggesting an abnormality in immunoreactive
fed similar diets and clinical signs first developed in parathyroid hormone regulation. l9 However, several
pups 1 and 2 while they were still suckling. Further- studies", ' . l 9 have demonstrated that in patients with
more, nutritional secondary hyperparathyroidism primary hyperparathyroidism, due to either parathy-
should not be associated with hypercalcemia. roid hyperplasia or neoplasia, immunoreactive parathy-
The synthesis and secretion of parathyroid hormone roid hormone is suppressed by increased concentrations
is regulated closely by the extracellular concentration of plasma calcium. Greater than normal concentrations
of ionized calcium," although parathyroid hormone of ionized calcium may be required to suppress the
secretion is not suppressed completely during hypercal- synthesis and release of parathyroid hormone from such
cemia.16 Induced hypercalcemia in pup 2 failed to glands, but failure to suppress immunoreactive para-
suppress plasma immunoreactive parathyroid hormone thyroid hormone at least partially, with increased
concentration (fig. I), suggesting autonomous secretion plasma calcium concentration is rare. It has been sug-
of parathyroid hormone in this pup. This is an unusual gested that a combination of both increased mass of
Downloaded from vet.sagepub.com by guest on September 14, 2015Primary Hyperparathyroidism 375
glandular tissue and abnormal regulation of parathy- roid hormone. N Engl J Med 299:635-644, 1978
roid hormone secretion contribute to the mechanism 12 HABENER, J.F.; POTTS,J.T. JR.: Parathyroid physiology
and primary hyperparathyroidism In: Metabolic Bone
of hyperparathyroidism.” In our pups, however, the
Disease, ed. Avioli and Krane, pp. 1-147, vol. 2. Aca-
glands were enlarged only slightly, and it appeared that demic Press, New York, 1978
the parathyroid glands failed to respond to elevations I3 HILLMAN, D.A.; SCRIVER, C.R.; PEDVIS, S.; SHRAGOVITCH,
in plasma calcium concentration. I.: Neonatal familial primary hyperparathyroidism. N
Although a genetic etiology appears likely for these Engl J Med 270:483-490, 1964
cases of primary hyperparathyroidism in German shep- 14 KEUTMANN, H.T.; BARLING, P.M.; HENDY, G.N.; SEGRE,
G.V.; NIALL,H.D.; AURBACH, G.D.; POTTS,J.T. JR.:
herd pups, confirmation will require additional breed- Isolation of human parathyroid hormone. Biochemistry
ing studies. If a breeding colony could be established, (Washington) 13: 1646- 1652, 1974
this canine disease would provide an excellent model 15 MARX,S.J.; ATTIE, M.F.; SPIEGEL, A.M.; LEVINE, M.A.;
for studying the pathogenesis and treatment of human LASKER, R.D.; Fox, M.: An association between neonatal
diseases associated with hypercalcemia and hyperpara- severe-primary hyperparathyroidism and familial hypo-
calciuric hypercalcemia in three kindreds. N Engl J Med
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306:257-264, 1982
16 MAYER, G.P.; HABENER, J.F.; POTTS,J.T. JR.: Parathyroid
Acknowledgements hormone secretion in vivo. Demonstration of a calcium-
This study was supported by Organized Research Reserve independent, non-suppressible component of secretion. J
Grant 1-82 and Biomedical Research Support Grant 2-82. Clin Invest 57:678-683, 1976
The authors are grateful for the technical assistance of Celia 17 MEUTEN, D.J.; COOPER, B.J.; CAPEN,C.C.; CHEW,D.J.;
R. Seiglie. KOCIBA, G.J.: Hypercalcemia associated with an adeno-
carcinoma derived from the apocrine glands of the anal
sac. Vet Pathol 18:454-471, 1981
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Request reprints from Dr. K.G. Thompson, Department of Veterinary Pathology, College of Veterinary Medicine, Texas
A&M University, College Station, TX 77843 (USA).
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