Genetic testing for Primary Hyperparathyroidism (PHPT) in the Keeshond

Dogs have two thyroid glands, one on each side of the neck, and two small parathyroid glands lie on top of each thyroid gland, hence the name "para" thyroid. Functionally, the parathyroid glands are distinct from the thyroid gland, and parathyroid diseases are not connected to thyroid diseases like hyperthyroidism or hypothyroidism. Parathyroid hormone (PTH) is an important factor in maintaining calcium homeostasis (normal calcium concentrations and function). When secreted, PTH causes an increase in serum calcium via bone resorption, decreased calcium excretion from the kidneys and increased vitamin D metabolism. Vitamin D causes increased absorption of calcium from the intestines. Parathyroid hormone secretion by parathyroid chief cells is normally regulated tightly by serum ionized (or unbound) calcium. Normally, if the concentration of ionized calcium rises, PTH secretion is decreased through negative feedback, allowing the calcium concentration to go back to normal. The underlying causes of hypercalcemia can be categorized into primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism.

PHPT is caused by an inappropriate secretion of parathyroid hormone (PTH) by autonomously functioning chief cells within the parathyroid glands. In PHPT, PTH secretion persists despite increased calcium concentrations resulting in many instances in severe, life threatening hypercalcemia. Most cases of canine PHPT (80-85%) result from a solitary parathyroid adenoma, which is a solitary benign tumor of the parathyroid gland. Parathyroid hyperplasia affecting multiple glands occurs in most of the remaining cases, while malignant parathyroid carcinoma is considered to be very rare in dogs (1). The Keeshond breed is congenitally affected by PHPT, and it has an autosomal dominant pattern of inheritance (1). Secondary hyperparathyroidism is caused by hypercalcemia of malignancy, chronic renal failure, hypervitaminosis D (vitamin D toxicity) or granulomatous disease (2).

This condition affects middle aged to older dogs with a mean age of approximately 10.5 years, according to the existing veterinary literature, without taking specific breeds into account. In the early phases of this disease, the affected dogs tend to be relatively free of symptoms except for increased drinking and urination, in addition to a gradual onset of weakness, lethargy, shaking and sometimes weight loss. Many have concurrent calcium-containing urolithiasis (bladder or kidney stones). As the hypercalcemia becomes more profound, organ damage occurs, including possible damage to bones as well as severe kidney damage. If the hypercalcemia is left untreated, this secondary kidney disease can eventually lead to severe renal failure and death.

The diagnosis of PHPT is based on the finding of normal or increased serum PTH concentrations in the presence of increased total and ionized calcium concentrations. The enlarged parathyroid gland or glands can frequently also be identified with cervical (neck) ultrasound. The treatment of PHPT involves surgical removal or ultrasound guided chemical ablation or heat ablation of the affected parathyroid gland. When performed early in the disease, prior to the onset of renal failure, and with appropriate post-operative care and monitoring, this treatment is typically very successful with a relatively low percentage of reoccurrence.

The Keeshond PHPT genetic test identifies dogs that are positive for the PHPT gene; the dog may not have the disease currently, but will likely develop it later in life due to late age onset. Because the trait is autosomal dominant, it may be eliminated from breeding dogs through genetic testing. The result can be used by owners two-fold: i) as a health tool to suggest a dog should be watched more carefully for signs of PHPT and ii) as a breeding tool with the aim of reducing the presence of PHPT in the worldwide Keeshond population.

The test is appropriate for Keeshond or Keeshond crosses only.


PHPT testing is now being performed by the Molecular Diagnostic section at the Animal Health Diagnostic Center. Please see the links below for sample submission instructions and forms:

References

  1. Goldstein RE, Atwater DZ, Cazolli DM, Goldstein O, Wade CM, Lindblad‐Toh K. Inheritance, mode of inheritance, and candidate genes for primary hyperparathyroidism in Keeshonden. Journal of veterinary internal medicine. 2007 Jan;21(1):199-203.
  2. Refsal KR, Provencher-Bolliger AL, Graham PA, Cert VR, Nachreiner RF. Update on the diagnosis and treatment of disorders of calcium regulation. Veterinary Clinics: Small Animal Practice. 2001 Sep 1;31(5):1043-62.

Share this: