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Abstract Background Hypoadrenocorticism is an important differential for hypercalcemia. The etiology of hypercalcemia in hypoadrenocorticism in dogs is unclear. Objective To review the prevalence of hypercalcemia and use statistical models to identify clinical, demographic, and biochemical variables associated with hypercalcemia in dogs with primary hypoadrenocorticism. Animals One hundred ten dogs with primary hypoadrenocorticism; 107 with recorded total calcium (TCa), 43 recorded ionized calcium (iCa). Methods Multicenter retrospective observational study at 4 UK referral hospitals. Univariable logistic regression analyses were performed to assess the association between independent variables of signalment, hypoadrenocorticism type (glucocorticoid only deficient hypoadrenocorticism [GHoC] vs glucocorticoid and mineralocorticoid deficient hypoadrenocorticism [GMHoC]), clinicopathological variables and hypercalcemia. Hypercalcemia was defined as elevated TCa, an elevated iCa, or both elevated TCa and iCa (Model 1) or as elevated iCa (Model 2). Results Overall prevalence of hypercalcemia was 34.5% (38/110). The odds of hypercalcemia (Model 1) were increased (P < .05) in dogs with GMHoC ([vs GHoC], OR [odds ratio] = 3.86, 95% confidence interval [CI] 1.105-13.463), higher serum creatinine (OR = 1.512, 95% CI 1.041-2.197), and higher serum albumin (OR = 4.187, 95% CI 1.744-10.048). The odds of ionized hypercalcemia (Model 2) were increased (P < .05) with reduced serum potassium concentration (OR = 0.401, 95% CI 0.184-0.876) and younger age (OR = 0.737, 95% CI 0.558-0.974). Conclusions and Clinical Importance This study identified several key clinical and biochemical variables associated with hypercalcemia in dogs with primary hypoadrenocorticism. These findings aid understanding of the pathophysiology and etiology of hypercalcemia in dogs with primary hypoadrenocorticism.

Abstract Background In dogs, duration of hypothalamic-pituitary-adrenal (HPA) axis suppression after systemic glucocorticoid treatment is reported to vary from a few days to up to 7 weeks after glucocorticoid discontinuation. These data are derived mainly from experimental studies in healthy dogs and not from animals with spontaneous disease. Hypothesis and Objective To determine the timeline for recovery of the HPA axis in a group of ill dogs treated with intermediate-acting glucocorticoids (IAGCs). Animals Twenty client-owned dogs that received IAGC for at least 1 week. Methods Single-center prospective observational study. An ACTH stimulation test, endogenous ACTH concentration, serum biochemistry profile, and urinalysis were performed at T0 (2-6 days after IAGC discontinuation) and then every 2 weeks (eg, T1, T2, T3) until HPA axis recovery was documented (post-ACTH cortisol concentration > 6 μg/dL). Results The median time of HPA axis recovery was 3 days (range, 2-133 days). Eleven of 20 dogs showed recovery of the HPA axis at T0, 6/20 at T1, and 1 dog each at T2, T5, and T9. Dose and duration of treatment were not correlated with timing of HPA axis recovery. Activities of ALT and ALP were significantly correlated with the post-ACTH cortisol concentration (rs = −0.34, P = .03; rs = −0.31, P = .05). Endogenous ACTH concentration was significantly correlated with pre (r = 0.72; P < .0001) and post-ACTH cortisol concentrations (r = 0.35; P = .02). The timing of HPA axis recovery of the dogs undergoing an alternate-day tapering dose was not different compared to dogs that did not (3.5 vs 3 days, P = .89). Conclusion and Clinical Importance Most dogs experienced HPA axis recovery within a few days after IAGC discontinuation. However, 2/20 dogs required >8 weeks.

Abstract Background Dogs with hypoadrenocorticism (HA) frequently show signs of gastrointestinal disease (SGD). The prevalence of dogs presented for chronic SGD with HA is unknown. Objectives The aims of this study were to determine the prevalence of HA in dogs with chronic SGD and to identify clinical and laboratory variables for HA in this population. Animals One hundred fifty-one dogs with chronic SGD. Methods In this multicentered prevalence study a standardized workup was performed in prospectively enrolled dogs with SGD > 3 weeks duration. Basal serum cortisol concentration was measured in every dog with ACTH stimulation test (ACTHST) if basal serum cortisol concentration was <3 μg/dL. Results Basal serum cortisol concentration was <3 μg/dL in 80/151 (53%) dogs, <2 μg/dL in 42/151 (28%) dogs, and < 1 μg/dL in 9/151 (6%) dogs. In 6/151 dogs HA was diagnosed based on ACTHST (stimulated serum cortisol concentration < 2 μg/dL), a prevalence of 4%. There was no difference in history, physical examination, and laboratory variables between dogs with HA and those with other causes of chronic SGD. In 4/6 dogs with HA, there was melena or hematochezia indicating gastrointestinal blood loss. Hyperkalemia, hyponatremia, or both was not observed in any dog. Conclusion and Clinical Importance The prevalence of HA among dogs with chronic SGD is higher than in the general population. Based on these results, testing adrenal function should be performed as a standard screening test in dogs with chronic SGD to differentiate between HA and chronic enteropathies.

Abstract Background Dogs with eunatremic, eukalemic hypoadrenocorticism (EEH) typically show signs of chronic gastrointestinal disease (CGD). Previous glucocorticoid administration (PGA) can give false-positive results on the ACTH stimulation test (ACTHst). Hypothesis/Objectives To determine the prevalence of EEH in dogs with signs of CGD, and to identify clinical and clinicopathological features for EEH and PGA. Animals One hundred twelve dogs with CGD (101 non-PGA and 11 PGA), 20 dogs with EEH. Methods Multicenter prospective cohort study. Basal serum cortisol (BSC) concentration was measured in dogs with signs of CGD. When BSC was <2 μg/dL and in PGA dogs, ACTHst plus measurement of endogenous ACTH (eACTH) were performed. Records of dogs with EEH from 2009 to 2021 were reviewed. Results The BSC concentration was <2 μg/dL in 48/101 (47.5%) non-PGA and in 9/11 (82%) PGA dogs. EEH was diagnosed in 1/112 dog (prevalence 0.9%; 95% CI, 0.1%-4.8%); the ACTHst provided false-positive results in 2/11 PGA dogs. PGA dogs showed lower C-reactive protein-to-haptoglobin ratio (median 0.01, range 0.003-0.08; P = .01), and higher haptoglobin (140, 26-285 mg/dL; P = .002) than non-PGA dogs (0.04, 0.007-1.5; 38.5, 1-246 mg/dL, respectively). eACTH was higher (P = .03) in EEH (396, 5->1250 pg/mL) than in non-PGA dogs (13.5, 7.3-46.6 pg/mL). Cortisol-to-ACTH ratio was lower (P < .0001 and P = .01, respectively) in EEH (0.002, 0.0002-0.2) than in non-PGA (0.1, 0.02-0.2) and PGA dogs (0.1, 0.02-0.2). Conclusions and Clinical Importance The prevalence of EEH in dogs with signs of CGD was lower than previously reported. The clinical and clinicopathological features herein identified could increase the index of suspicion for EEH or PGA in dogs with an unclear history of glucocorticoid administration.

Satoshi Narumi, Tomonobu Hasegawa and colleagues describe a new adrenal hypoplasia syndrome termed MIRAGE that is caused by mutations in the endosome fusion facilitator SAMD9 . They find that patients with these mutations have severe growth restriction phenotypes, and they observe adaptation by aneuploidy, where there is accompanying protective loss of mutation-carrying chromosome 7. Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9 . Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Abstract Background Primary hypoadrenocorticism in dogs is thought to be multifactorial with roles for both genetic and environmental factors. The contributions of environmental factors remain unexplored. Objective Identify environmental and lifestyle exposures associated with primary hypoadrenocorticism in 2 dog breeds with high risk of developing the disease. Animals Animals were not used in this study. Owners of Standard Poodles (STPDs) and Portuguese water dogs (POWDs) participated in a survey. Methods Retrospective case-control study. Dog owners were invited to participate in an online survey through convenience sampling. Questions regarded the demographics, health histories, and indoor/outdoor environments in which their dogs live and play. Responses for dogs with primary hypoadrenocorticism were compared to those without the disease using univariate and multivariate logistic regression models. Results Five thousand forty-seven responses (358 cases, 4689 controls) met initial inclusion criteria. Significant associations with modest effect size were found for community type, ingestion of canned food, and use of lawn fertilizer in some analysis models. Reproductive (spay/neuter) status exhibited the strongest association with high effect size across all models with adjusted odds ratio (OR) 2.5 (95% confidence interval [CI], 1.4-4.5; P = .003) for spayed females and 6.0 (95% CI, 2.6-13.9; P < .001) for neutered males. Conclusions and Clinical Importance The large effect size for reproductive status reflects its high potential clinical relevance, whereas modest effect sizes for other environmental variables suggest lower potential clinical relevance. These findings are associations and do not necessarily imply causation. Before any actionable recommendations are warranted, additional evidence regarding biological mechanisms is needed.

Background X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization. Methods The clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed. Results Hyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P  < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy ( P  < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year. Conclusions This study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.

Primary hypoadrenocorticism, also known as Addison’s disease, is an autoimmune disorder leading to the destruction of the adrenal cortex and subsequent loss of glucocorticoid and mineralocorticoid hormones. The disease is prevalent in Standard Poodles and is believed to be highly heritable in the breed. Using genotypes derived from the Illumina Canine HD SNP array, we performed a genome-wide association study of 133 carefully phenotyped Standard Poodles (61 affected, 72 unaffected) and found no markers significantly associated with the disease. We also sequenced the entire genomes of 20 Standard Poodles (13 affected, 7 unaffected) and analyzed the data to identify common variants (including SNPs, indels, structural variants, and copy number variants) across affected dogs and variants segregating within a single pedigree of highly affected dogs. We identified several candidate genes that may be fixed in both Standard Poodles and a small population of dogs of related breeds. Further studies are required to confirm these findings more broadly, as well as additional gene-mapping efforts aimed at fully understanding the genetic basis of what is likely a complex inherited disorder.

BACKGROUND: Some dogs with primary hypoadrenocorticism (HA) have normal sodium and potassium concentrations, a phenomenon called atypical Addison's disease. The assumption that the zona glomerulosa and aldosterone secretion in these dogs are normal seems widely accepted; however, aldosterone measurements are missing in most published cases. OBJECTIVES: To measure aldosterone in dogs with HA with and without electrolyte abnormalities and to determine the time point of aldosterone peak concentrations during ACTH stimulation. ANIMALS: Seventy dogs with HA, 22 dogs with diseases mimicking HA, and 19 healthy dogs. METHODS: Prospective study. Blood samples were taken before and 60 minutes after injection of 250 μg ACTH in all dogs. Additional blood samples were taken 15, 30, and 45 minutes after ACTH in 7 dogs with HA and in 22 with diseases mimicking HA. RESULTS: Baseline and ACTH‐stimulated aldosterone was significantly lower in dogs with HA than in the other groups. Aldosterone was low or undetectable in 67/70 dogs with HA independently of sodium and potassium levels. In 3 dogs, sodium/potassium concentrations were normal; in 1 dog, sodium was normal and potassium decreased. In all 4, ACTH‐stimulated aldosterone concentrations were below the detection limit of the assay. Aldosterone concentrations were not different at 30, 45, or 60 minutes after ACTH administration. CONCLUSION AND CLINICAL IMPORTANCE: Cortisol and aldosterone secretion is compromised in dogs with HA with and without electrolyte abnormalities. The term atypical Addison's disease, used for dogs with primary HA and normal electrolytes, must be reconsidered; other mechanisms allowing normal electrolyte balance without aldosterone should be evaluated in these dogs.

We are presenting a monozygotic twin brothers presented at different ages with different presentations. Twin-A presented at age of 18 days with salt losing crisis. Investigations revealed high plasma renin with low-normal aldosterone. Adrenocorticotropic hormone stimulation test revealed low 17-OH progesterone at 0 and 60 minutes. Adrenocorticotropic hormone level and serum cortisol were normal, which excluded initial impression of congenital adrenal hyperplasia. He was diagnosed to have isolated primary hypoaldosteronism. At age of 18 months, he was noticed to have hyperpigmentation of lips and gum. Adrenal failure was suspected, and hydrocortisone was added. Twin-B presented at 9 years and 6 months of age with adrenal crisis. Both were having unilateral undescended testis. Adrenal hypoplasia congenita (AHC) was suspected after his twin's presentation. Molecular analysis for gene study for both of them revealed adrenal insufficiency, NR0B1 (DAX1) gene mutation. In conclusion, gene analysis is important for the diagnosis of AHC and for genetic counseling.