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Veterinary Quarterly
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Endocrinology: Hyperaldosteronism in a cat with metastasised adrenocortical tumour
A. Rijnberk , G. Voorhout b , H.S. Kooistra ª , R.J.M. van der Waarden C , F.J. van Sluijs ª , J. IJzer ª , P. Boer e & W.H. Boere e
a Department of Clinical Sciences of Companion Animals
b Division of Diagnostic Imaging, Faculty of Veterinary Medicine , Utrecht University , Utrecht
” Animal Clinic ‘Overtoom’ , Amsterdam
d Department of Pathology, Faculty of Veterinary Medicine , Utrecht University , Utrecht
e Department of Nephrology , University Medical Centre , Utrecht
f Department of Clinical Sciences of Companion Animals , P.O. Box 80.154, Utrecht, 3508 TD Phone: 31 30 253 1697 Fax: 31 30 253 1697 E-mail: Published online: 01 Nov 2011.
To cite this article: A. Rijnberk , G. Voorhout , H.S. Kooistra , R.J.M. van der Waarden , F.J. van Sluijs , J. IJzer , P. Boer & W.H. Boer (2001) Endocrinology: Hyperaldosteronism in a cat with metastasised adrenocortical tumour, Veterinary Quarterly, 23:1, 38-43, DOI: 10.1080/01652176.2001.9695074
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HYPERALDOSTERONISM IN A CAT WITH METASTASISED ADRENOCORTICAL TUMOUR
A.Rijnberk1.6, G. Voorhout2, H.S. Kooistra1, R.J.M. van der Waarden3, F.J. van Sluijs1, J. IJzer4, P. Boer5, and W.H. Boer5
Vet Quart 2001; 23: 38-43 Accepted for publication: January 10, 2000.
SUMMARY
In a 12-year-old male shorthaired cat with attacks of hypo- kalaemic muscular weakness in spite of oral potassium supplementation, highly elevated plasma aldosterone con- centrations in combination with low plasma renin activity pointed to primary hyperaldosteronism. Ultrasonography and computed tomography revealed a large left-sided ad- renal tumour growing into the phrenicoabdominal vein and the caudal vena cava. The tumour and its intravascu- lar extension were surgically removed, but the subsequent stenosis of the caudal vena cava caused congestion and renal failure. At autopsy pulmonary micrometastases of the aldosteronoma were found.
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INTRODUCTION
The adrenal cortices produce two types of corticosteroids, namely glucocorticoids and mineralocorticoids. The two corresponding distinct syndromes of corticosteroid excess that arise in adrenocortical hyperfunction in humans are known as hyperadrenocorticism or Cushing’s syndrome and hyperaldos- teronism or Conn’s syndrome. In cats hyperadrenocorticism is a relatively rare condition in which the glucocorticoid excess may be the result of either adrenocortical tumour or persisting hypersecretion of the adrenocorticotrophic hormone (ACTH) from the pituitary (9,22,24).
Until now, hyperaldosteronism has only been described in a 17-year-old spayed female cat that was presented with relap- sing weakness, characterised by generalised symmetrical flaccid paresis with hypotonia and hyporeflexia. Laboratory examination revealed profound hypokalaemia and a highly increased serum aldosterone concentration. Initially this cat was successfully treated intravenously and orally with potas- sium supplements and finally with an aldosterone antago- nist. After 10 weeks of therapy the cat was euthanatized. Post-mortem examination revealed an adrenocortical carci- noma with pulmonary and hepatic metastases (8).
We report here a case of hyperaldosteronism in a cat caused by a large, malignant adrenocortical tumour, in which surgi- cal resection was attempted.
CASE REPORT
History
On 19 may 1998 a 12-year old castrated male shorthaired cat was brought to a veterinary practice in an emergency situation. The cat was conscious, could walk but not jump, had cervical ventroflexion, and mydriasis, and fell in lateral recumbency.
,
1 Department of Clinical Sciences of Companion Animals.
2. Division of Diagnostic Imaging, Faculty of Veterinary Medicine, Utrecht University, Utrecht.
3 Animal Clinic ‘Overtoom’, Amsterdam.
4 Department of Pathology, Faculty of Veterinary Medicine, Utrecht University, Utrecht.
5 Department of Nephrology, University Medical Centre, Utrecht
6 Corresponding author: P.O. Box 80.154, 3508 TD Utrecht. Tel .: 31 30 253 1697; fax: 31 30 251 8126; e-mail: A.Rijnberk@vet.uu.nl
Laboratory examination revealed hypohalaemia (1.6 mmol/l; reference range 3.4- 5.7 mmol/l) and echocardiographic find- ings seemed to be compatible with hypertrophic cardiomyo- pathy. Potassium suppletion, first intravenously and then orally, and treatment with the (ß-blocking agent atenolol (Tenormin®, Zeneca; 6.25 mg once daily) and acetylsalicylic acid (40 mg twice daily) resulted in good recovery.
On 29 June, 3 weeks after stopping potassium suppletion and atenolol, the cat was presented to the owner’s veterinarian for weakness in the hind legs. The cat was not lethargic and was eating and drinking normally. The history of cardiomyo- pathy raised the possibility of complicating thromboembo- lism. A saddle thrombus at the distal aortic trifurcation was considered unlikely because the femoral pulses were easily palpated and the footpads of the hind legs were warm and pink. The previous treatment was resumed but the dose of acetylsalicylic acid was lowered to twice weekly 25 mg. The cat did well on this regimen but the plasma concentrations of potassium remained low. When potassium gluconate (Tumil K®, Aesculaap bv, Boxtel, NL) was given orally in a dose of 2 mmol four times daily, the plasma potassium concentration remained ≤ 2.2 mmol/l. On 1 September the cat collapsed again, even though the potassium supplementation had been increased to 2 mmol six times daily for 2 weeks. In addition to muscular weakness, there was mydriasis, restlessness, and panting. Potassium concentrations in plasma ranged from 1.9 to 2.1 mmol/l. An angiotensin-converting enzyme inhibi- tor (once daily 1 mg enalapril, Enalfor®, Mycofarm) was ad- ded to the treatment. The cat recovered but the plasma potas- sium concentration remained at the same low level.
Hyperadrenocorticism was excluded as the cause of the mus- cular weakness by the finding that the basal urinary corti- coid/creatinine ratio (average on two consecutive days: 24 x 10-6) was below the upper limit of the reference range (37 x 10-6) (11) and the urinary corticoid/creatinine ratio was readily suppressed (to 3.0 x 10-6 ) following three oral doses of 0.5 mg dexamethasone. A possible relation to hyperthy- roidism (21) was excluded by the finding of a normal plasma thyroxine concentration (29 nmol/l).
Between the episodes of muscular weakness the cat’s condi- tion and behaviour were unremarkable but in search of an ex- planation for the persistent hypokalaemia the cat was refer- red to the Utrecht University Clinic for Companion Animals in September 1998.
Physical and laboratory examination
The cat was alert and physical examination revealed no ab- normalities, even though the potassium supplement had been discontinued for 48 hours and food had been withheld for 16 hours in preparation for further examinations. Indirect ophthalmoscopy revealed no abnormalities. Systolic arterial blood pressure in the radial artery, meas- ured by an indirect method (Ultrasonic Doppler flow detec- tor), was 190 mm Hg (= 25.3 kPa).
ORIGINAL PAPERS
Urine specific gravity was 1.031 and there were no remarka- ble findings in the urinalysis. Analysis of venous blood re- vealed hypokalaemia (1.8 mmol/l; ref. 3.4-5.2), hypophosp- hataemia (0.67 mmol/l; ref. 1.10-1.60), hypomagnesaemia (0.80 mmol/l; ref. 0.8-1.2), and alkalosis with a pH of 7.420 (ref. 7.206-7.369), normal pCO2 and bicarbonate levels, and elevated base excess (- 1.4 mmol/l; ref. - 10 - - 4).
That night the cat had another attack of muscular weakness, lying in lateral recumbency. Fortunately, it was still able to eat, and the owner could administer potassium gluconate (16 mmol in 12 hours). On the following day the cat had im- proved. Supplementation with magnesium (250 mg once daily) was started and arrangements were made to study ad- renocortical function and morphology with emphasis on mineralocorticoid production.
METHODS
Hormone measurements
Blood samples for hormone measurements were collected from the jugular vein and transferred to ice-chilled EDTA- coated tubes. Samples were centrifuged at 4℃ for ten minu- tes. Plasma was stored at -25 ℃ until assayed.
Plasma ACTH was measured by radioimmunoassay (RIA), using an antibody that binds to the C-terminal region of the molecule and another antibody binding to the N-terminal re- gion (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). Plasma cortisol was measured by RIA (23). Plasma al- dosterone concentrations and plasma renin activity (PRA) were measured according to previously described assays (1). A high-dose dexamethasone suppression test (iv-HDDST) was performed with blood collection at -15 minutes, immediately before, and at 2, 3, and 4 hours after intravenous administration of 0.1 mg dexamethasone per kilogram body weight (25). The test was started at 9.00 h after an overnight fast.
Diagnostic imaging
Ultrasonography was performed with a high-definition ultra- sound system (HDI 3000, Advanced Technology Labora- tories, Woerden, the Netherlands). The adrenal glands were imaged through a ventral and lateral abdominal approach with the animal in supine position using a 10-5 MHz broad- band linear array transducer. Two-dimensional and M-mode echocardiography was performed through the right para- sternal approach with the animal in right lateral recumbency, using a 7-4 MHz broadband phased array transducer.
Radiographs of the thorax were made with a diagnostic X-ray system on regular black-and-white films in combination with high-detail intensifying screens. Computed tomography of the cranial abdomen was performed in the anaesthetised cat with a third-generation computed tomography scanner (Tomo- scan CX/S, Philips NV, Eindhoven, the Netherlands), using 120 kV, 220 mA and 4.5 seconds scanning time. With the ani- mal in supine position, 5-mm-thick consecutive slices were made both before and after intravenous administration of 2 ml contrast medium (Telebrix 350, Guerbet Nederland BV, Gorinchem, the Netherlands) per kilogram of body weight. In addition several 2-mm-thick slices were made following the administration of contrast medium.
During the anaesthesia for computed tomography 9 mmol potassium were added to the intravenous infusion. The cat made a quick recovery and had a plasma potassium concen- tration of 1.9 mmol/1. The oral potassium suppletion was re- sumed immediately, which was facilitated by the cat’s good appetite.
RESULTS
On two separate days the basal plasma aldosterone concentra- tion was 12450 and 11480 pmol/l. The corresponding PRA values were 550 and <20 fmol.1-1.s-1. In two healthy clinic cats, about 4 years of age, the plasma aldosterone concentra- tion was 260 and 270 pmol/l, with corresponding PRA values of 420 and 920 fmol.1-1.s-1. In five healthy privately owned cats of different breeds and aged 1-10 years the basal plasma aldosterone concentration ranged from 190 to 590 pmol/l, and the PRA values ranged from 40 to 170 fmol.1-1.s-1.
In the iv-HDDST basal plasma cortisol and ACTH concen- trations were within the reference ranges, whereas the aldo- sterone concentrations were highly elevated and the PRA levels were immeasurably low. Following dexamethasone
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ORIGINAL PAPERS
administration the cortisol and ACTH concentrations de- clined to low values. Plasma aldosterone levels decreased upon dexamethasone administration, but remained higher than the values found in healthy cats. Plasma renin activity could not be detected at any time during the dexamethasone suppression test (Figure 1).
Echocardiography revealed slight septal hypertrophy, whereas the results of other M-mode measurements were within reference ranges. Ultrasonography of the abdomen revealed a rounded mass with a diameter of 2 to 2.5 cm and a mixed hypo- and hyperechoic internal structure at the loca- tion of the left adrenal gland (Figure 2). The right adrenal
0
was calcified and not enlarged. Ultrasonography revealed no abnormalities in the liver and kidneys.
Thoracic radiographs revealed slight cardiac enlargement but no evidence of pulmonary metastases. Computed tomo- graphy confirmed calcification of the right adrenal gland and the presence of a mass at the location of the left adrenal gland, measuring 2 x 3 x 2.5 cm. There was calcification at the medial aspect of the mass and contrast enhancement re- vealed a slightly irregular pattern. The mass was found to ex- pand through the phrenicoabdominal vein into the caudal vena cava (Figure 3).
The functional studies and the diagnostic imaging justified the conclusion that the severe hypokalaemia was the result of primary hyperaldosteronism due to an adrenocortical tumour that extended into the vena cava. It was decided to attempt surgical resection of the tumour.
SURGERY AND POST-OPERATIVE COURSE
Prior to surgery a jugular catheter was placed to facilitate in- travenous administration of potassium. Immediately before surgery the plasma potassium concentration had’increased to 3.0 mmol/l.
Celiotomy via a cranial midline approach revealed that the adrenocortical tumour extended into the caudal vena cava through the phrenicoabdominal vein. The tumour was freed from the coeliac vessels cranially and from the renal vein caudally. The phrenicoabdominal vein was doubly clipped dorsal to the tumour and transected between the clips7. A Satinsky vascular clamp was placed on the caudal vena cava at the point where the phrenicoabdominal vein entered the
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vena cava. The clamp reduced the lumen of the vena cava by approximately 75%. The tumour was removed together with the part of the wall of the vena cava that it had invaded. The vena cava was closed with a simple continuous suture of 6-0 PDS. The surgical site was covered with an absorbable gela- tin sponge. The abdominal wall was closed in a routine man- ner.
Post-operative analgesia comprised four times daily admin- strations of 60 µg buprenorphin8. On the following morning the cat was walking, alert, and eating well. Without further supplementation plasma potassium concentrations ranged from 3.5 to 4.2 mmol/l. At 24 hours after surgery the plasma aldosterone concentration had decreased to 2810 pmol/l. In addition there were measurable amounts of PRA: 170 and 360 fmol.1-1.s-1 at 15 and 24 hours after surgery.
However, from about 18 hours after surgery the cat’s condi- tion deteriorated. Haemorrhagic fluid accumulated in the ab- dominal cavity, and the plasma urea and creatinine concen- trations increased rapidly. Under the supposition that the abdominal fluid accumulation could be the result of suture leakage, a second laparotomy was undertaken. There was no leakage at the suture line. The caudal vena cava was patent, but markedly narrowed at the suture line. Both renal veins were slightly dilated. The cat died during this procedure.
PATHOLOGY
At necropsy the abdominal cavity was found to contain a large quantity of haemorrhagic transudate and there were haemorrhages in the omentum, perirenal tissues, and the oedematous urinary bladder wall. The liver and kidneys were pale, the latter having an irregular surface. Multiple 1-3 mm solid, dark, hyaline nodules were present in the lungs. The left atrium was dilated. There were no gross lesions in the brain or pituitary.
The mass removed surgically was an epithelial tumour, growing in small clusters and cords on scant, vasculated,
7. Autosuture Surgiclip MII’, Autosuture Nederland, Zeist, the Netherlands.
8 Temgesic®, Schering-Plough, Amstelveen, the Netherlands.
stromal tissue and infiltrating in vessels. The polygonal tu- mour cells had vacuolated cytoplasm and a very low ( << 1/10 high-power field) mitotic index. There were local varia- tions in the degree of differentiation. There was extensive necrosis of the tumour.
The nodules in the lungs had a maximal diameter of 3 mm and were recognised microscopically as metastases of the re- sected tumour. The tumour infiltrated vessels and lung parenchyma and consisted of cords and dense acini-like clus- ters on a thin basal layer (Figure 5). In the kidneys there was moderate interstitial mononuclear nephritis with radial fibro- sis, degeneration of the proximal tubular epithelium, and protein leakage in Bowman’s space and the tubular lumen. Few tubules were cystically dilated. A moderate mononu- clear reaction was present in the liver and the sinusoids were filled with proteinaceous fluid. There were no histological abnormalities in the pituitary gland.
DISCUSSION
Initially, the attacks of muscular weakness were considered to be due not only to hypokalaemia but also to possible car- diomyopathy. However, echocardiography revealed only slight septal hypertrophy and there were no gross pathologi- cal findings compatible with either dilated cardiomyopathy or hypertrophic cardiomyopathy at necropsy. Thus it seems justified to conclude that in the present cat the paroxysmal flaccid paresis was solely the result of hypokalaemia.
Causes of hypokalemia include: [1] lack of dietary K, such as during fasting, [2] gastrointestinal losses via vomiting and/or diarrhoea, [3] potassium shifts from extracellular to intracellular as a result of alkalosis and/or nutritional factors, and [4] renal K wasting. There was no history of anorexia, vomiting, diarrhoea, or peculiar food constituents, and thus the hypokalaemia was attributed to excessive renal loss of K. Two types of conditions are associated with renal K loss: those with primary Na retention and those with Na wasting. In the former group volume expansion leads to suppressed renal renin secretion and hypertension, whereas in the latter group volume depletion stimulates renin secretion. In humans, the second group comprises a number of genetic disorders in children and young adults, known as syndromes of Bartter and Gitelman, which are the result of inborn defects in renal electrolyte trans- port (26). The hypokalaemia and episodic weakness with neck ventroflexion known to occur in young Burmese cats (16) as a homozygous recessive inherited condition (18) may be due to a
ORIGINAL PAPERS
similar defect. However, a genetic defect was considered unli- kely in the cat described here, because of the animal’s age at onset.
The observations in this cat were compatible with the first category of conditions of renal K loss. In most instances, re- nin secretion was completely suppressed. This hyporenine- mic hypokalaemia was associated with elevated aldosterone secretion. Therefore, the most likely explanation for the per- sistent hypokalaemia was primary hyperaldosteronism, a condition first described in humans by Conn (3). The disease is primarily characterised by hypokalaemia (with alkalosis, hypomagnesaemia, and hypophosphataemia), hypertension, suppressed PRA, and increased aldosterone production, al- though as early as 1965 normokalaemic hyperaldosteronism was recognised (4). At least six subtypes of primary hyper- aldosteronism have now been identified (31).
Findings in this cat were consistent with the classic form of hyperaldosteronism. The plasma aldosterone concentrations were extremely high in comparison with values in our con- trol cats and the values found by others for healthy cats (32), and in cats with hypertension associated with chronic renal disease (13,20). Although there was some decline in aldo- sterone,concentration in the iv-HDDST, the results of this test indicated autonomous (non-ACTH-dependent) hyperal- dosteronism and an intact hypothalamus-pituitary-glucocor- ticoid axis. The autonomy of the hyperaldosteronism was further substantiated by the PRA values, which were un- measurably low, except when the cat had not received potas- sium supplementation for about 48 hours and experienced an episode of muscular weakness a few hours after the visit to the clinic. This single non-suppressed PRA value is difficult to explain. One possibility could be that the cat was in a pro- dromal stressful state at the time the blood was collected. Both adrenomedullary catecholamines and the sympathetic nervous system may have stimulated renin release (15).
Autonomous overproduction of aldosterone is one of the (rare) causes of hypertension in humans. The aldosterone ex- cess leads to retention of sodium and water, but this is us- ually limited: ‘escape’ occurs when extracellular volume has increased by approximately 1-2 liters. In primary hyper- aldosteronism, Na retention occurs primarily in the cortical collecting ducts. The ‘escape’ is the result of compensatory suppressed Na resorption in nephron segments proximal to the collecting ducts (2,14). There is evidence that atrial natriuretic peptide (ANP) plays an important role in minera- locorticoid escape (30,33). The mechanisms responsible for an increase in peripheral resistance and the associated hyper- tension are unclear (10).
In cats, indirect blood pressure measurements using the Doppler principle are regarded as being the most accurate (17,28), the main problem being the subjectivity of the ob- server, especially for diastolic readings (17). In the cat de- scribed here, systolic blood pressure was just above the reference value of 180 mm Hg (17,28) and just below a re- cently reported upper limit of 200 mg Hg (29). This is consis- tent with the ophthalmologic observation that there were no signs of hypertensive retinopathy.
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Abdominal ultrasonography and computed tomography re- vealed a unilateral adrenal mass and a contralateral gland of normal size. In addition, computed tomography revealed tu- mour growth into the caudal vena cava. The calcification in the contralateral adrenal gland was regarded as unrelated to the disease as it is known to occur in up to 30% of cats with- out being of clinical significance (12,27). This information
was the impetus for unilateral adrenalectomy (6). Removal of the tumour from the vena cava necessitated narrowing of this vessel just cranial to the entrance of the renal veins. This probably impaired venous return to such a degree that it led to the congestion, fluid accumulation, and fatal renal failure. Necropsy revealed lung metastases of the tumour too small to be visualised by radiography.
As in the first reported case (8), this case report illustrates that with appropriate diagnostic procedures the diagnosis of primary hyperaldosteronism can be made in cats. It is likely that with early recognition and less malignant disease resec- tion can lead to definite cure.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the dedication and support of the owners, mrs Sabine van der Helm and Arthur Kleipool, MD. Mrs J.D. Sinke, DVM generously made her cats available for the collection of control values. The authors thank dr. M.H. Boevé, for performing the ophthalmolo- gic examination and mrs N. Willekes-Koolschijn and mrs. A. Dijk for their skill in carrying out the measurements of the plasma concentrations of PRA and aldosterone. The contribution of Bruce Belshaw, DVM, in editing the manuscript is highly appreciated.
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During the review process of the manuscript the following related articles have been published:
- Flood SM, Randolph JF, Gelzer ARM, and Refsal K. Primary hyperaldosteronism in two cats. J Amer Anim Hosp Ass 1999; 35: 411-6.
- Mackay AD, Holt PE, and Sparkes AH. Successfull surgical treatment of a cat with primary aldosteronism. J Feline Med Surg 1999; 1: 117-22.
- Moore LE, Biller DS, and Smith TA. Use of abdominal ultrasonography in the diagnosis of primary hyperaldosteronism in a cat. J Am Vet Med Assoc 2000; 217: 213-5.
POPULATION PARAMETERS TO COMPARE DOG BREEDS: DIFFERENCES BETWEEN FIVE DUTCH PUREBRED POPULATIONS
A.L.J Nielen1, S. van der Beek2, G.J. Ubbink1,3, and B.W. Knol1,4
Vet Quart; 2001; 23: 43-9
Accepted for publication: February 24, 2000.
SUMMARY
Differences in five purebred dog populations born in 1994 in the Netherlands were evaluated using different parameters. Numerically, the Golden Retriever was the largest breed (840 litters of 234 sires) and the Kooiker Dog (101 litters of 41 sires) the smallest. The litter per sire ratio was largest in the Bernese Mountain Dog (4.59) and lowest in the Kooiker Dog (2.46). The mean related- ness and the actual mean level of inbreeding in the stud- ied generations were 0.102 and 0.056 respectively for the Bernese Mountain Dog, 0.041 and 0.046 for the Bouvier
1 Department of Clinical Sciences of Companion Animals, Utrecht University, P.O. Box 80154. 3508 TD Utrecht, the Netherlands.
2 Animal Breeding and Genetics Group, Wageningen Institute of Animal Sciences, Wageningen University, P.O. Box 338. 6700 AH Wageningen, the Netherlands. Present Address: Nederlands Rundvee Syndicaat, Arnhem, the Netherlands.
3 Present Address: Willem de Zwijgerlaan 56, 3583 HD Utrecht, the Netherlands.
Corresponding author: B.W. Knol: Department of Clinical Sciences of Companion Animals, Utrecht University, P.O. Box 80154. 3508 TD Utrecht, the Netherlands. Phone: 030 2532103. Fax: 030 2518126. E-mail: b.w.knol@vet.uu.nl
des Flandres, 0.087 and 0.061 for the Boxer, 0.020 and 0.018 for the Golden Retriever, and 0.146 and 0.070 for the Kooiker Dog. Quantification and visualization of population parameters for purebred dogs will facilitate the comparison of breeds and the comparison of breeds in different periods or countries. It appears unlikely that the increase in inbreeding is a major determinant of the possible increase in the frequency of genetic diseases.
INTRODUCTION
More than 400 genetic diseases are known in purebred dogs (11). Breeders and owners of dogs, veterinarians, kennel clubs, animal welfare associations, and governments are paying special attention to genetic diseases in dogs, which might be a reflection of the increasing frequency of genetic diseases in dog populations (17). Part of this increase is a re- lative one, due to a reduced frequency of infectious, parasitic and nutritional diseases (10). However, another part of the increase is probably absolute, although, partly caused by an improvement of diagnostics and a better registration of