Congenital pituitary dwarfism

Pituitary dwarfism is a rare endocrine disorder described in both the dog and the cat, caused by an insufficient secretion of growth hormone (GH) and characterized by a significant growth retardation. In the German Shepherd the condition is combined with the deficiency of other hormones produced by the anterior pituitary lobe, such as thyroid-stimulating hormone (TSH), prolactin (PRL) and gonadotropins. However, ACTH secretion is generally preserved. Although the clinical signs of this endocrine disorder are quite characteristic, both the diagnostic work up and treatment may result complicated.

AETIOLOGY

In the past this condition was attributed to an anterior pituitary lobe atrophy caused by compression, usually due to the presence of cysts in Rathke’s pouch. Recent studies have actually shown that dwarfism is an autosomal recessive inherited disorder, with the mutation site on the gene which codes for the Lhx3 transcription factor. For this reason, the presence of cysts in Rathke’s pouch is today considered the consequence of a genetic defect and not the primary cause of pituitary dwarfism. 

SIGNALMENT

Congenital pituitary dwarfism is mainly described in the German Shepherd and in the Karelian Bear Dog, although it has also been reported in other dog breeds and in the feline species. Affected animals generally exhibit the first clinical signs around the second-third month of age and are taken to the veterinarian within the first year of life because of growth retardation and/or dermatological problems. No gender predisposition is apparently present.

CLINICAL SIGNS

Affected animals are initially lively and active, however with time they progressively become listless, debilitated and sometimes experience loss of appetite. GH deficiency is often associated with inappropriate glomerular development which can be the cause of renal failure. The concomitant deficiency of thyroid hormones, which causes a reduction in glomerular filtration, exacerbates the renal damage, which is the most frequent cause of death in animals suffering from dwarfism.  

Additional clinical signs are:

• Growth retardation: affected animals are usually of normal size in the first 1-2 months of life; after this period their growth is clearly slower than that of their littermates. By 3 to 4 months of age they are clearly the smallest of their litter and they usually never attain full adult size (Fig. 1).Closure of the growth plates is usually delayed and cranial fontanelles may remain open. Dental eruption can be delayed, however dentition is usually normal.
• Endocrine alopecia: initially there is persistence of the puppy fur which appears soft and woolly. Soon thereafter a bilateral symmetric alopecia can appear. Initially the  hair loss is confined to the areas subject to a higher degree of rubbing (neck, armpits and thighs), subsequently it expands to the entire trunk,  sparing the head and the extremities.
• Skin hyperpigmentation:the skin initially appears normal, but it then progressively becomes hyperpigmented, thin, wrinkled and scaly. Moreover, the adult dwarf may develop secondary pyoderma, comedones and papules
• Secondary bacterial infections: infections may affect the skin and the respiratory tract and are a common complication likely to be observed in the long term.
• Hypogonadism: in males hypogonadism may be the cause of testicular atrophy, cryptorchidism and azoospermia; in females hypogonadism may suppress the oestrus cycle or cause anovulatory estrous cycles.

LABORATORY TESTS 

The complete blood count, biochemical profile and urinalysis are generally normal. At times a mild anaemia, increased renal parameters, hypophosphataemia and hypoalbuminaemia are present.

DIAGNOSIS 

The diagnosis is based on the characteristic clinical signs and on specific endocrine tests.

Basal GH concentration
The measurement of  GH concentration alone cannot not be considered diagnostic. This parameter presents a series of limitations:

• GH is secreted in a pulsatile fashion, therefore values within the normal range are often found in dwarf dogs and cats, whereas extremely low values may be found in healthy subjects.
• Only a few laboratories (University of Utrecht) perform this measurement,  which is carried out with a species-specific homologous radioimmunological assay (RIA).

Basal IGF-I concentration
Insulin-like growth factor-I (IGF-I) concentrations are usually low in animals suffering from dwarfism. While having the advantage of not having an episodic secretion and being measured in many laboratories, IGF-I concentrations must still be interpreted with caution. IGF-I concentrations are, in fact, influenced by such factors as age, size and diet. It is therefore recommended to measure plasma IGF-I in both the suspected case and in a normal growth littermate, in order to compare the two values.

GH stimulation test
Clonidine stimulation test: Clonidine is an α-adrenergic agonist which stimulates the secretion of GHRH, which in turn triggers the secretion of GH.
Test protocol: the GH is measured before and 15-30 minutes after the intravenous administration of Clonidine 10 μg/Kg.
Interpretation: in a normal subject, following the administration of  Clonidine the GH concentration increases, reaching the peak (higher than 10 ng/ml) 15-30 minutes after the beginning of the test;  afterwards it decreases rapidly to basal values. In subjects with pituitary dwarfism there is no evidence of a GH increase after Clonidine administration. In the case of subnormal values, a partial GH deficiency may be suspected.
Side effects: Clonidine may cause  a reversible bradycardia and hypotension (treated with phentolamine or yohimbine) .

Xylazine stimulation test: Xylazine is a sedative with analgesic properties which is structurally similar to Clonidine.
Test protocol: the test is carried out following the same procedure described for the previous test, this time with the intravenous administration of Xylazine 100-300 μg/Kg.
Interpretation: the test interpretation is similar to that of the previously described test.
Side effects: the higher dose can cause deep sedation, hypotension, shock and rarely seizures. The lower dose causes instead minor side effects.

Growth Hormone-Releasing Hormone (GHRH) stimulation test (Graph):
Test protocol and interpretation: in healthy subjects the administration of recombinant human GHRH, at an intravenous dose of 1 μg/Kg, determines a rapid increase in blood GH, with a peak of almost  14,7 +/- 3,7 ng/ml reached after 10-30 minutes. In subjects with dwarfism there isn’t instead an increase in GH levels (Graph 1). Blood samples for the measurement of  GH should be taken before and 10-20 minutes after the intravenous administration of GHRH.
Side effects: adverse reactions to GHRH administration have not been reported, however the disadvantage of this molecule is that it is not easily found on the market and that it is expensive. 

Evaluation of other hormonal deficiencies
In the German Shepherd a lack of GH is associated with TSH deficiency; in view of this it is important to assess the concentration of thyroid hormones and to supply thyroxine supplementation.

THERAPY

GH.  To date, there is no GH based product registered for use in the dog. The administration of human and bovine GH triggers antibody reactions against the heterologous molecule, resulting in poor therapeutic success.Porcine GH (Figs. 2 and 3) is more effective in treating pituitary dwarfism, as its amino acid sequence is identical to that of canine GH, however it is not easily available on the market. The recommended dose of porcine GH is 0,1-0,3 IU/Kg s.c. three times a week. The dose is then adjusted based on the clinical response and on IGF-I plasma concentrations. Goal of the therapy is to maintain IGF-I values within the reference range. 

Side effects: hypersensitivity reactions, carbohydrate intolerance and development of diabetes mellitus are the most frequent adverse events. In the presence of diabetes mellitus GH therapy must be suspended.

Progestins. In dogs, the administration of progestins increases the expression of GH by the mammary glands, therefore representing a valid alternative to porcine GH in the treatment of this disorder. In the cat, instead, these drugs are apparently not really effective.

The more commonly used progestins are:

• Medroxyprogesterone acetate: 2,5-5,0 mg/Kg s.c. initially every three weeks and then every six weeks. Dose and administration intervals must be adjusted according to the patient’s clinical response and to GH and IGF-1 values.
  • Side effects: in females, endometrial cystic hyperplasia with mucometra, and in males, signs of acromegaly; both genders can develop diabetes mellitus and pyoderma .
• Proligestone: 10 mg/Kg s.c. at three-week intervals.

RESPONSE TO THERAPY AND PROGNOSIS

Major skin and hair improvements may be observed after approximately 6-8 weeks of GH therapy and supplementation with thyroxine (Figs. 2 and 3). However, only an early therapeutic intervention may guarantee an evident body growth.

The prognosis of these animal remains guarded, and is partially dependent on the IGF-I values achieved with therapy and on the possible development of therapy-induced complications.

Non-treated animals progressively exhibit symptoms linked to the progression of renal damage, such as lack of appetite, weight loss and fatigue. For this reason owners usually opt for euthanasia during the first 3-5 years of life.

Suggested readings

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3.  Andresen E, Willeberg P.- Pituitary dwarfism in German Shepherd dogs: Additional evidence of simple, autosomal recessive inheritance. Nord. Vet. Med. 28: 481-486, 1975.
4. Andresen E, Willeberg P - Pituitary dwarfism in Carelian Bear-dogs: Evidence of simple autosomal recessive inheritance. Hereditas 84: 232-234, 1976.
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9. Eigenmann JE - Diagnosis and treatment of dwarfism ia a German Shepherd dog. JAAHA 17: 798, 1981.
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11. Kooistra HS, Voorhout G, Mol JA, Rijnberk A - Combined pituitary hormone deficiency in German Shepherd dogs with dwarfism. Dom Anim Endo 19: 177, 2000.
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13. Eingenmann, Patterson DF, Zapf J, Froesch ER - Insulin-like growth factor-I in the dog: a study in different dog breeds and in dogs with growth hormone elevation. Acta Endocrinol (Copenh) 105: 294, 1984.
14. Herrtage ME, Evans H – The effect of progestogen administration  on insulin-like growth factor concentrations in two pituitary dwargs. J Vet Int Med 12: 212, 1998.