Inheritance, mode of inheritance, and candidate genes for primary hyperparathyroidism in Keeshonden

BACKGROUND: Primary hyperparathyroidism (PHPT) is caused by inappropriate secretion of parathyroid hormone (PTH) by autonomously functioning neoplastic or hyperplastic parathyroid "chief" cells. Keeshonden are thought to be over-represented in studies on canine PHPT, but no proof of heritability or mode of inheritance has been published. The canine disease clinically resembles human familial isolated hyperparathyroidism (FIHP). HYPOTHESIS: Primary hyperparathyroidism in Keeshonden is genetically transmitted and is caused by a mutation in 1 of 4 genes implicated in human FIHP: MEN1, CASR, HRPT2, or RET. ANIMALS: Pedigrees consisting of 1647 Keeshonden were created including 219 Keeshonden with known PHPT phenotypes (69 positive). DNA samples were obtained from 176 of the 219 Keeshonden (34 positive). METHODS: Heritability and mode of inheritance were determined by segregation analysis. Canine homologs to the human genes were identified. Exons and surrounding intron regions were sequenced and scanned for sense-altering polymorphisms or polymorphisms that segregated with the disease. Messenger RNA from a parathyroid tumor of an affected Keeshond was analyzed for polymorphisms and splice alterations. RESULTS: PHPT follows an autosomal dominant mode of inheritance in Keeshonden with possible age-dependent penetrance. No polymorphisms identified in the genes analyzed were associated with a change in predicted protein or in hypothesized splice sites. CONCLUSIONS AND CLINICAL IMPORTANCE: PHPT is an autosomal dominant, genetically transmitted disease in Keeshonden. Once the mutation locus is identified, genetic testing should quickly decrease the incidence of PHPT in this breed. It is unlikely that mutations in MEN1, CASR, HRPT2, or RET cause PHPT in Keeshonden.     

Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement

The purpose of this study was to evaluate the clinical safety of pamidronate when administered at a mean dosage of 1.0 mg/kg IV q28d in 33 tumor-bearing dogs. Biochemical tests of renal function were evaluated before each successive pamidronate treatment. Of 33 dogs treated with pamidronate, 1 dog had clinically relevant increases in serum creatinine and blood urea nitrogen concentrations. The biologic activity of IV pamidronate was assessed prospectively in 10 dogs with appendicular osteosarcoma and was assessed on reductions in urine N-telopeptide excretion (P = .042) and enhanced bone mineral density of the primary tumor measured with dual-energy x-ray absorptiometry (P = .024). Additionally, in these 10 dogs, pamidronate's therapeutic activity was supported by subjective improvement in pain control in 4 of the 10 dogs treated. IV pamidronate appears clinically safe in tumor-bearing dogs and may possess modest biologic activity for managing neoplastic complications associated with pathologic bone resorption.     

Primary Hyperparathyroidism Associated With Atypical Headshaking Behavior in a Warmblood Gelding

A 14-year-old Zweibrücker Warmblood gelding was presented for evaluation of lethargy and headshaking. The horse had a history of bouts of lameness in different limbs and back problems. It also had many mild colic episodes in the past. Results of repeat laboratory tests had shown persistent hypercalcemia (4.8 mmol/L; reference interval [RI]: 2.0–3.2 mmol/L) for 1.5 years and later on hypophosphatemia (0.4 mmol/L; RI: 0.5–1.3 mmol/L) and mild hypermagnesemia (1.0 mmol/L; RI: 0.5–0.9 mmol/L). Parathyroid hormone (PTH) concentration was within the RI. Other causes of hypercalcemia, such as renal failure, vitamin D toxicosis, and granulomatous disease, and nutritional secondary hyperparathyroidism were ruled out. Furthermore, there was no evidence of neoplastic disease. Parathyroid hormone–related protein was measured but inconclusive. A diagnosis of primary hyperparathyroidism was established on the basis of hypercalcemia, hypophosphatemia, low fractional excretion of calcium, and high fractional excretion of phosphorus in combination with a PTH secretion refractory to high calcium levels. Because of the bad prognosis, the owner decided to euthanize the horse. Results of postmortem examination were unremarkable. Hypercalcemia should always be considered abnormal, and further examinations need to be performed to proof hypercalcemia and subsequently find the cause. The main differential diagnoses are renal insufficiency and humoral hypercalcemia of malignancy, but also rare diseases, such as hyperparathyroidism, have to be taken into account.     

Rapid calcitonin response to experimental hypercalcemia in healthy horses

Calcium has important physiological functions, and disorders of calcium homeostasis are frequent in horses. We have made important progress understanding equine calcium homeostasis; however, limited information on equine calcitonin (CT) is available, in part because of the lack of validated CT assays. To determine the CT response to high ionized calcium (Ca²⁺) concentrations in healthy horses, we induced hypercalcemia in 10 healthy horses using a calcium gluconate 23% solution (5 mg/kg; 120 mL/500 kg horse) infused over 4 min. Four horses were infused with 120 mL of 0.9% NaCl and used as controls. We validated a human-specific CT radioimmunoassay for use in horses. Serum Ca²⁺ concentrations increased from 6.2 ± 0.3 mg/dL to 9.9 ± 0.5 mg/dL (4 min; P < 0.01). Serum CT increased from 16.7 ± 8.0 pg/mL to 87.1 ± 55.8 pg/mL at 2 min, and 102.5 ± 51.1 pg/mL at 4 min (P < 0.01). Serum CT returned to baseline by 20 min, whereas serum Ca²⁺ returned to baseline by 40 min. Of interest, CT concentrations returned to baseline despite hypercalcemia, suggesting thyroid gland C-cell CT depletion. Resting CT values higher than 40 pg/mL were considered abnormally elevated. No significant changes in serum Ca²⁺ or CT concentrations were found in control horses. The coefficients of variation for the CT radioimmunoassay were lower than 11.9%. We conclude that the equine thyroid gland C-cell responds quickly to changes in extracellular Ca²⁺ concentrations by secreting large quantities of CT into the systemic circulation, indicating that CT is important in equine calcium homeostasis. The human CT radioimmunoassay can be used to measure changes in equine CT.