A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.

Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.

Pelvic fracture triggering symptoms of an underlying primary hypoparathyroidism in an adult spayed bitch: A case report.

A 7-year-old mixed breed spayed bitch (body weight: 10.6 kg) was presented with a history of intermittent episodes of seizures and untreated limb fracture. Appetite loss, nervousness, lateral recumbency, fasciculations, ataxia and poor nutritional condition were found. Venous blood gas analysis highlighted normal acid-base balance and severe low ionized calcium (0.58 mEq/L [range 1.13-1.32 mEq/L]). Marked total hypocalcaemia (6.4 mg/dL [range 8-10] or 1.6 mM [range: 2-2.5]) associated with hyperphosphoraemia (9.3 mg/dl [range 3.5-6.5 mg/dl]) displayed inverted ratio between minerals. ECG showed sinus arrhythmias. Circulating levels of Mg and Cu were within physiological range (1.97 mg/dl and 128 µg/dl respectively) and effects from interactions were excluded. Oral administration of calcitriol at 40 ng/kg/day led to clinical improvement within 48 hours, but circulating iCa levels were still below the lower limit of the reference range. Baseline levels of circulating parathormone (PTH) were 3 pg/ml, along with normal values of circulating vitamin D. Primary hypoparathyroidism was diagnosed as a chronic underlying condition triggered by pelvic fracture.

Progressive alopecia associated with hypoparathyroidism in a Jersey heifer.

BACKGROUND: Chronic progressive generalized alopecia in dairy cattle has been anecdotally discussed in veterinary forums. OBJECTIVE: To describe subclinical changes in an otherwise apparently healthy animal with chronic progressive generalized alopecia. ANIMALS: One 10-month-old Jersey heifer. METHODS: Case report. RESULTS: A heifer was presented for chronic progressive alopecia. The skin was hyperpigmented and very thin (2.4 ± 0.0 mm, compared with 8.1 ± 0.3 mm measured in four contemporaneous Jersey heifers). Histopathological examination of the skin revealed severe epidermal hyperplasia, orthokeratotic hyperkeratosis and diffuse follicular atrophy. Clinicopathological changes included hypocalcaemia that did not respond to calcium therapy. Serum parathyroid hormone (PTH) was not detected, compared with 1.38 ± 0.78 pmol/L in four contemporaneous Jersey heifers. A diagnosis of hypoparathyroidism was made based on hypocalcaemia and low PTH in the presence of normal magnesium levels. The heifer was otherwise healthy and was allowed to continue normal life. A spontaneous abortion occurred at 5.5 months of pregnancy and this was likely due to the presence of twin fetuses. Despite targeted therapy of the ensuing retained placenta, the heifer declined in health and had to be euthanized. From the time of diagnosis with hypoparathyroidism until euthanasia (29 months of age), blood levels of calcium, phosphorus and PTH were regularly monitored. Calcium and phosphorus levels varied widely. Serum PTH was consistently undetectable. At postmortem examination, the parathyroid glands could not be located. CONCLUSIONS AND CLINICAL IMPORTANCE: To our knowledge, this is the first report of naturally occurring hypoparathyroidism in cattle and with a clinical presentation of alopecia.

Prevalence of the RAPGEF5 c.2624C>A and PLOD1 c.2032G>A variants associated with equine familial isolated hypoparathyroidism and fragile foal syndrome in the US Thoroughbred population (1988-2019).

BACKGROUND: Equine familial isolated hypoparathyroidism (EFIH) and fragile foal syndrome (FFS) are both fatal recessive conditions reported in Thoroughbred foals. The causal variants for EFIH (RAPGEF5 c.2624C>A; EquCab3.0. chr4: g.54108297G>T) and FFS (PLOD1 c.2032G>A; EquCab3.0, chr2: g.39927817) were recently reported. Prevalence assessment for these variants in a large cohort of samples is needed to provide evidence-based recommendations for genetic testing. OBJECTIVES: To estimate the frequency of the EFIH and FFS variant alleles in the United States Thoroughbred population between 1988 and 2019, and determine whether these are recent mutations or are increasing in frequency due to current breeding practices. STUDY DESIGN: Population allele frequency study. METHODS: Genomic DNA from hair and serum samples were genotyped for the EFIH and FFS. Allele frequencies between cohorts, based on year of birth (1988-2000, n = 728) and (2001-2019, n = 1059), as well as across the seven geographical regions of the United States were compared by Fisher's Exact tests. RESULTS: EFIH and FFS allele frequencies were not significantly different between the two time points studied (0.008 and 0.004, respectively, in the older cohorts and 0.008 and 0.009 in most recent years). No EFIH or FFS homozygotes were detected. A sample from 1992 was identified as a carrier for EFIH and one from 1993 a carrier for FFS. Non-significant changes in geographical distribution of carriers for both traits were observed. MAIN LIMITATIONS: The earliest samples available for study were from foals born in 1988. CONCLUSIONS: The EFIH and FFS variants are present at low frequency in the United States Thoroughbred population but are not recent mutations. There is no evidence to support changes in allele frequency over time. However, given the closed studbook and breeding practices, continued monitoring of breed allele frequencies and genetic testing is recommended to avoid the mating of carriers and production of affected foals.

[Polyendocrine syndromes in dogs]. / Polyendokrine Syndrome beim Hund.

The autoimmune polyendocrine syndrome (APS) refers to a combination of autoimmune endocrine disorders. It is rarely described in dogs. The most common combinations are hypoadrenocorticism and hypothyroidism, followed by diabetes mellitus, and less often hypoparathyroidism and orchitis. The diagnosis of the APS is based on the diagnosis of each endocrinopathy, as is the therapy, which involves the substitution of deficient hormones. If a patient was previously stable under treatment and is showing further signs (e.g. polyuria, polydipsia, or weight loss), the development of additional endocrinopathies like hypoadrenocorticism or diabetes mellitus should be considered. The diagnosis of the initially diagnosed endocrinopathy should also be critically questioned. This article summarizes some cases of our own animal hospital and selected cases published in the available literature.

Primary Hypoparathyroidism and Recurring Hypocalcemia in a Quarter Horse Gelding-A Case Report.

Hypoparathyroidism is an uncommon endocrine disorder in the horse characterized by a transient or permanent parathyroid hormone insufficiency. Hypoparathyroidism is associated with hypocalcemia and hyperphosphatemia, primarily presenting with clinical signs consistent with hypocalcemia. This case report describes clinical presentation and treatment of a horse with severe hypocalcemia due to primary hypoparathyroidism. A 17-year-old, 542 kg Quarter Horse gelding presented for shaking and tremors. Significant findings include generalized muscle fasciculations, synchronous diaphragmatic flutter, and a markedly hypermetric hindlimb gait. Hematology revealed a moderate hyperkalemia, hyperphosphatemia, hypomagnesemia, and severe hypocalcemia. Initial treatment consisted of oral and intravenous calcium supplementation and fluid therapy. Thirty-six hours after presentation, clinical signs resolved, and treatment was discontinued. Clinical signs reoccurred after the discontinuation of treatment. A presumptive diagnosis of primary hypoparathyroidism was made based on low parathyroid hormone in the presence of low ionized calcium. The patient was maintained on oral calcium carbonate (feed grade lime) and vitamin AED supplementation. Hypoparathyroidism is rare but oral supplementation of calcium with calcium carbonate resulted in a favorable outcome with no apparent decrease in performance. Long-term supplementation may be required to prevent disease recurrence.

Trauma-induced primary hypoparathyroidism following severe bite wound injury to the neck in a dog.

OBJECTIVE: To describe the clinical presentation and outcome of a dog with primary hypoparathyroidism secondary to cervical bite wounds. CASE SUMMARY: A 3-year-old male intact Chihuahua presented after being attacked by a large breed dog. The dog sustained severe cervical lacerations, exposing the trachea and jugular veins. A portion of the right thyroid gland was missing. The dog was stabilized before wound debridement and closure. Ionized calcium concentrations were within reference range at the time of presentation. Forty-eight hours after the initial trauma, the dog was presented in lateral recumbency with signs of hypovolemic shock, muscle tremors, and hyperthermia. Bloodwork showed severe ionized hypocalcemia with low normal parathyroid hormone concentration consistent with acute primary hypoparathyroidism. The dog was managed initially with IV calcium gluconate and calcitriol, then long-term oral calcium carbonate and vitamin D3. After 6 months, the dog was successfully weaned off calcium supplementation. NEW OR UNIQUE INFORMATION PROVIDED: This is the first described case of traumatic primary hypoparathyroidism after a bite injury to the neck in a dog.

Presumptive Glucocorticoid-Induced Refractory Hypocalcemia in a Dog with Idiopathic Immune-Mediated Hypoparathyroidism, Thrombocytopenia, and Hemolytic Anemia.

Clinically relevant hypocalcemia is a well-documented complication of glucocorticoid administration in people with hypoparathyroidism. The current report describes the phenomenon in a dog. A 7 yr old neutered male Pomeranian was diagnosed with immune-mediated thrombocytopenia, immune-mediated hemolytic anemia, and primary hypoparathyroidism. This dog required long-term parenteral calcium gluconate to prevent clinical hypocalcemia despite appropriate doses of oral calcitriol and calcium carbonate. This is the first description of clinically significant presumptive glucocorticoid induced hypocalcemia in a dog with primary hypoparathyroidism.

Primary hypoparathyroidism in dogs: a retrospective study of 17 cases.

OBJECTIVE: To evaluate the clinico-pathological findings, response to treatment and prevalence of complications in dogs with primary hypoparathyroidism. DESIGN: Retrospective study of 17 dogs presenting to the University of Melbourne Veterinary Clinical Centre and Murdoch University Veterinary Hospital over a 15 year period (1990 to 2004). Case records were evaluated for signalment, body weight, diet type, historical and clinical findings, serum total calcium, phosphate, albumin and parathyroid hormone concentrations, urinary fractional excretion ratios of calcium and phosphate, electrocardiogram (ECG) results, treatments administered, outcome and period of follow-up. RESULTS: The most common breeds identified were St Bernard (three dogs), Chihuahua (two dogs), German Shepherd (two dogs) and Jack Russell Terrier (two dogs). Three dogs were cross bred. Seizures, muscle tremors and fasciculations, stiff gait, tetany, muscle cramping, behavioural change and hyperventilation were the most common clinical signs. Vomiting, inappetence, diarrhoea, abdominal pain, hyperthermia, facial pruritus, ataxia, weakness, cataracts, and circling also occurred with less frequency. The mean duration of observed clinical signs preceding diagnosis was 33 days (median 13 days, range 1 to 173 days). All dogs had marked hypocalcaemia with normal or mildly increased serum albumin concentrations. Mean phosphate concentrations were significantly higher in inappetent dogs (P = 0.049). Mean serum calcium concentrations were significantly lower in dogs with cataracts compared to those without (P = 0.046). There were no other significant relationships between serum calcium or phosphate concentrations and the clinical presentation or outcome. No significant correlations were identified between the presence of a particular clinical sign and the duration of clinical signs. ECGs were obtained in four dogs and all exhibited QT interval prolongation due to a ST-segment prolongation. Sixteen of 17 dogs were treated successfully for hypocalcaemia and discharged from hospital. Acute management included parenteral calcium gluconate (10 dogs) and intravenous anticonvulsants (five dogs). Chronic therapy included oral vitamin D analogues and calcium supplementation. Treatment complications occurred in two dogs and included acute renal failure (one dog) and iatrogenic tissue necrosis following subcutaneous calcium administration (one dog). The mean follow-up period was 14.5 months (median 13 months, range 0 to 39 months). Twelve dogs were alive at the last follow up and two dogs were euthanased for unrelated reasons. The type of vitamin D analogue used was not associated with outcome. CONCLUSION: Primary hypoparathyroidism was an uncommon diagnosis in dogs. Saint Bernards, cross bred dogs, German Shepherd dogs and Terrier breeds were most commonly affected. Neurological signs were the most common presenting clinical signs, although alimentary signs may have been more common than previously reported. Dogs with primary hypoparathyroidism appeared to have a good prognosis following initiation of calcium supplementation and vitamin D therapy. Complications of treatment were uncommon and could be minimised with regular monitoring.

Feline endocrinopathies.

Feline endocrinopathies (excluding diabetes mellitus) include hyperthyroidism, hypothyroidism, acromegaly, hyposomatotropism, diabetes insipidus, hyperadrenocorticism, primary sex hormone-secreting adrenal tumors, primary hyperaldosteronism, pheochromocytoma, hypoadrenocorticism, hyperparathyroidism, and hypoparathyroidism. Each of these conditions will be discussed including their prevalence, cause, clinical signs, diagnosis, treatment options, and prognosis.

Hypocalcaemia due to nutritional calcium deficiency and hypoparathyroidism in an adult dog.

A 13-year-old intact male poodle had suffered periodic tetanic crises for two months. It was cachectic and moderately dehydrated, and during the crises blindness, a stiff gait and behavioural changes were observed. Routine haematological and biochemical profiles showed that it was severely hypocalcaemic, with a corrected plasma calcium concentration of 1.13 mmol/litre (reference range 2.25 to 3 mmol/litre). The dog was fed a home-made diet composed of chicken and basmati rice cooked with a soup bouillon cube; an analysis of its daily allowance indicated that the dog was generally malnourished and received only 0.222 g of calcium per day rather than the 0.6 g it required. In addition, the dog had a low blood concentration of parathyroid hormone of 12 ng/litre (reference range 20 to 80 ng/litre). Supplementing the dog with calcitriol for four days and correcting its diet increased its blood calcium to the lower part of the reference range and resolved the clinical signs, although its parathyroid hormone concentration was still low one year later.

Synchronous Diaphragmatic Flutter Secondary to Primary Hypoparathyroidism in a Dog.

A 3 yr old, spayed, female miniature mchnauzer was presented for rhythmic, spontaneous contractions of the abdominal wall and across the costal arches. The rate of contractions coincided with the heart rate and increased during exercise. The dog was diagnosed with primary hypoparathyroidism based on low plasma ionized calcium and serum parathyroid hormone (PTH) concentrations. Fluoroscopic exam confirmed the diagnosis of a synchronous diaphragmatic flutter. Treatment of the hypocalcemia led to resolution of the diaphragmatic flutter.

Primary hypoparathyroidism in the dog. Report of 15 cases and review of 13 previously reported cases.

Fifteen dogs with primary hypoparathyroidism diagnosed at the University of California Veterinary Medical Teaching Hospital were compared with 13 previously reported cases. Age, sex, breed, and historical and physical findings were similar in both groups of dogs. Middle-aged females were affected primarily. A history of neurologic or neuromuscular disease was present in all 28 dogs, with 18 dogs having seizures. Posterior lenticular cataract formation secondary to hypocalcemia was suspected in six dogs. The most characteristic biochemical finding in all dogs was profound hypocalcemia (less than 6.5 mg/dl) and mild hyperphosphatemia. Serum magnesium concentrations were decreased in two dogs. Serum parathyroid hormone concentrations were consistent with the diagnosis of primary hypoparathyroidism in eight of nine dogs. Lymphocytic parathyroiditis was diagnosed in the 12 dogs from which tissue was submitted for histopathology. Successful management of the patient depended on frequent monitoring of the serum calcium concentration during initial and maintenance therapy.

Idiopathic hypoparathyroidism in five cats.

Idiopathic hypoparathyroidism was diagnosed in five young to middle-aged cats of mixed breeding. Three of the cats were male and two were female. Historic signs included lethargy (n = 5), anorexia (n = 5), muscle tremors (n = 4), weakness (n = 4), generalized seizures (n = 3), ataxia (n = 3), mental dullness or disorientation (n = 3), panting (n = 2), pruritus (n = 1), ptyalism (n = 1) and dysphagia (n = 1). Weakness (n = 4), dehydration (n = 2), cataracts (n = 2), hypothermia (n = 1), and bradycardia (n = 1) were found on physical examination. Results of electrocardiography revealed a prolonged Q-T interval in two cats. Results of initial laboratory tests revealed profound hypocalcemia and severe hyperphosphatemia with normal renal function. The diagnosis of hypoparathyroidism was made on the basis of the history, clinical signs, and results serum biochemical testing (i.e., severe hypocalcemia and hyperphosphatemia); in two cats, the diagnosis was also confirmed by histologic examination of parathyroid glands. Initial treatment included intravenous administration of 10% calcium gluconate and oral administration of large loading doses of calcium and vitamin D (dihydrotachysterol). Successful long-term management with dihydrotachysterol and calcium was achieved in all cats. The final dosage of dihydrotachysterol required to maintain normocalcemia in the five cats ranged from 0.004 to 0.04 mg/kg/day (mean = 0.015 mg/kg/day). Long-term calcium supplementation was given to three of the cats in dosages ranging from 29 to 53 mg/kg/day (mean = 42 mg/kg/day) of elemental calcium. One cat died after 28 months of therapy from widely metastatic hemangiosarcoma; the other three cats are still alive and well after 5 to 37 months of treatment.

Intact parathyroid hormone assay and total calcium concentration in the diagnosis of disorders of calcium metabolism in dogs.

Serum samples from eight dogs with primary hyperparathyroidism, seven dogs with hypercalcemic lymphosarcoma (hypercalcemia of malignancy), and four dogs with primary hypoparathyroidism were submitted to the Animal Health Diagnostic Laboratory at Michigan State University for intact parathyroid hormone (PTH) assay. When compared with the adjusted total serum calcium concentration, the intact PTH concentration was consistent with the correct diagnosis in all cases. Two dogs with hypercalcemic lymphosarcoma were mildly azotemic. In both of these cases the intact PTH concentration was consistent with hypercalcemia of malignancy despite the presence of azotemia. These data support a significant role for intact serum PTH assay in the differential diagnosis of disorders of calcium metabolism.

Fanconi's syndrome in a dog with primary hypoparathyroidism.

An 11-year-old castrated male mixed breed dog was referred for evaluation of muscle twitching, polyuria, polydipsia, anorexia, and periocular alopecia. Primary hypoparathyroidism was diagnosed by documenting decreased serum concentrations of parathyroid hormone and ionized calcium. Neurological, gastrointestinal, and dermatological signs resolved after calcium repletion. Initially, 1,25-dihydroxycholecalciferol PO was required to correct the hypocalcemia. Dihydrotachysterol, in combination with oral calcium supplementation, was used for long-term maintenance of normal serum calcium concentration. Aminoaciduria, glucosuria, and hyperchloremic metabolic acidosis were consistent with a diagnosis of Fanconi's syndrome. This diagnosis was further supported by the presence of hypokalemia and increased urinary fractional excretion of sodium, potassium, calcium, phosphorus, and magnesium. Renal tubular dysfunction resolved after oral supplementation with calcium and vitamin D3. Fanconi's syndrome in this dog may have been caused by decreased serum concentration of 1,25-dihydroxycholecalciferol, which was secondary to decreased parathyroid hormone production.

Idiopathic hypoparathyroidism in a dog.

Idiopathic hypoparathyroidism in a 3-year-old dog was manifested clinically as periodic episodes of depression, vomiting, and tetanic convulsions. Hypocalcemia and hyperphosphatemia were detected late in the course of the illness, but the dog died before corrective measures could be instituted. The pathologic features were similar to those reported in dogs in which hypoparathyroidism was induced by injection of homologous parathyroid tissue, thus suggesting an auto-immune pathogenesis.

Secondary hypoparathyroidism attributed to hypomagnesemia in a dog with protein-losing enteropathy.

Severe hypomagnesemia (0.8 mg/dl; reference range, 1.6 to 2.3 mg/dl), hypocalcemia, and protein-losing enteropathy were identified in a 5-year-old castrated male 3-kg (6.6 lb) Shih Tzu examined because of anorexia, lethargy, paresis, and abdominal distention. Histologic examination of intestinal biopsy specimens revealed lymphangiectasia and lymphocytic, plasmacytic, neutrophilic infiltrates. Initial treatment included administration of magnesium (0.80 mEq/kg [0.36 mEq/lb]) of body weight in a balanced electrolyte solution. This treatment resulted in normalization of the serum magnesium concentration (1.7 mg/dl); resolution of the lethargy, paresis, and tachycardia; and an increase in the serum parathyroid hormone and ionized calcium concentrations. Findings were consistent with secondary hypoparathyroidism attributable to hypomagnesemia. Magnesium concentration should be monitored in all dogs with gastrointestinal tract disease, especially those with protein-losing enteropathy, anorexia, and weakness.

Primary hypoparathyroidism in the dog.

Primary hypoparathyroidism was diagnosed in six dogs with profound hypocalcemia. Muscle tremors, tetany, generalized seizures, ataxia, and behavioral aberrations were the most common clinical signs. Lymphocytic parathyroiditis was found in four of five dogs that were biopsied. The serum concentration of immunoreactive parathyroid hormone was abnormally low in one dog in which it was measured. Treatment with vitamin D and calcium was successful in restoring and maintaining normal concentration of serum calcium in all six dogs. During treatment, large daily doses of vitamin D were required, dose response was unpredictable, serum calcium concentration fluctuated while treatment remained unchanged, and hypercalcemia occurred frequently.