Clinical features of hypoadrenocorticism in soft-coated wheaten terrier dogs: 82 cases (1979–2013)

Abstract

The objective of this retrospective case series, which included 82 client-owned soft-coated wheaten terriers, was to characterize clinical features of hypoadrenocorticism in this breed. Median age at diagnosis was 3.5 years. There was no gender predilection. Clinicopathologic findings included sodium/potassium ratio < 27 (85%), hyperkalemia (76%), hyponatremia (63%), elevated blood urea nitrogen (83%) or creatinine (71%), and hypercalcemia (36%). Nine dogs with normal sodium and potassium (11%) were older and less often azotemic, hyperphosphatemic, or hypercalcemic. Twenty-one dogs (26%) developed protein-losing nephropathy (n = 18) and/or end-stage renal disease (n = 3). Overall median survival time was 5.4 years, but was shorter in dogs with normal sodium and potassium at diagnosis (4.2 years), or those with subsequent protein-losing nephropathy (4.2 years). This population showed no gender predilection, unlike that reported in the general canine population with hypoadrenocorticism, and more comorbid protein-losing nephropathy than in the general soft-coated wheaten terrier population.

Introduction

Hypoadrenocorticism is a clinical syndrome resulting from glucocorticoid deficiency with or without a concurrent mineralocorticoid deficiency (1). These hormones are required for the regulation of a variety of metabolic pathways, including fluid and electrolyte balance, mounting and maintenance of a stress response and normotension, and energy metabolism (1,2). As a consequence of these deficiencies, dogs present with a variety of non-specific clinical signs, including lethargy, anorexia, vomiting, and diarrhea (1,3–6). Canine hypoadrenocorticism is most commonly a consequence of complete loss of adrenal cortical function, though selective immune-mediated destruction of the zonae reticularis and fasciculata, with sparing of the zona glomerulosa, is reported (1,7,8). Canine glucocorticoid deficiency is uncommonly due to impaired pituitary secretion of adrenocorticotropic hormone (ACTH) (1). There are also rare reports of mineralocorticoid deficiency without glucocorticoid changes (9,10).

In the largest retrospective case series to date, involving 225 dogs with spontaneous hypoadrenocorticism, 71% were female, median age at diagnosis was 4.0 y, and only 4% had normal sodium (Na) and potassium (K) values at presentation (5). Breeds with increased risk for hypoadrenocorticism include the bearded collie (BRDC), great Dane, Leonberger, Nova Scotia duck tolling retriever (NSDTR), Portuguese water dog (POWD), rottweiler, soft-coated wheaten terrier (SCWT), standard poodle (SPOO), and West Highland white terrier (WHWT) (5,11–16). To date, breed-specific characterizations have been reported for BRDC, Leonberger, NSDTR, POWD, and SPOO (11–16). There was no gender predilection found in these 5 breeds. An autosomal recessive or complex mode of inheritance is proposed in NSDTR, POWD, and SPOO (11–16). Recent work in a variety of breeds has identified a major histocompatibility complex (MHC) class association in several breeds, but failed to identify such in SCWTs (17–22).

The first North American stock of SCWTs was brought from Ireland in the 1940s by a single breeder (23). Admitted to the American Kennel Club (AKC) in 1973, SCWTs were ranked 49th in AKC popularity in 2015 (24). Though additional breeding stock have been added to the North American population over the last several decades, much of the existing population was derived from this initial small foundation stock and popular sires. As a result, SCWTs in North America represent a relatively small, isolated breeding population. Early recognition of genetic disease is important for the individual as well as the continued health of the breed.

The goals of this study were to evaluate the clinical features of naturally occurring hypoadrenocorticism in SCWTs and to compare them to those of the general canine hypoadrenocorticoid population and other predisposed breeds. We hypothesized that the clinical features of naturally occurring hypoadrenocorticism would differ in affected SCWTs in comparison to the affected general population and other predisposed breeds.

Materials and methods

Case selection

Identification of client-owned SCWTs with suspected naturally occurring hypoadrenocorticism was conducted at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania (MJR-VHUP) via 3 routes: i) a search of the SCWT Open Registry (23), a database of SCWT health information established in 1996 (maintained by author ML), in which owners and breeders voluntarily send medical files and pedigrees to register their SCWTs affected with protein-losing enteropathy (PLE), protein-losing nephropathy (PLN), inflammatory bowel disease, juvenile renal disease, and hypoadrenocorticism; ii) private consultations (by author ML) with veterinarians or owners of SCWTs seeking help with individual cases not necessarily included in the Open Registry; and iii) a computerized search of MJR-VHUP medical records for SCWTs diagnosed with hypoadrenocorticism. The years of diagnosis ranged from 1979 to 2013.

Adrenocorticotropic hormone stimulation tests were performed in accordance with standard protocols (25). Soft-coated wheaten terriers were included if their pre- and post-ACTH serum cortisol concentrations were ≤ 55 nmol/L. Dogs were excluded if results of cortisol concentrations were inconclusive for hypoadrenocorticism, there was a history of treatment of hyperadrenocorticism, or there was glucocorticoid administration within the previous 30 d.

Clinical and clinicopathologic data acquisition

Medical records of SCWTs meeting inclusion criteria were reviewed by one author (RH); information regarding signal-ment, history, physical examination, complete blood (cell) count (CBC), serum chemistry panel, urinalysis, ACTH stimulation testing at diagnosis, concurrent and subsequent disease conditions, survival time and cause of death, were recorded. As diagnostic tests were performed at several laboratories, results were recorded as an absolute value and then interpreted as within, greater than, or less than the reference interval provided by the relevant laboratory. Dogs were diagnosed with PLN and/or PLE based on blood, urine, and/or histopathologic criteria, as previously described (26).

Statistics

Continuous variables were evaluated for normality by the Shapiro-Wilk test; many variables were not normally distributed; therefore, range and median values were determined for each. The 2 independent sample Wilcoxon rank-sum test was used to evaluate significance for each continuous variable between dogs with and without normal Na and K at diagnosis; a non-parametric approach was selected to maintain consistency between variables, given the lack of consistent normal distribution. Means and standard deviations were included for the clinicopathologic variables presented in Tables 1 and 2, to facilitate comparisons with previous studies. Categorical values were described with percentages; Pearson’s Chi-squared test was used to compare values between dogs with and without normal Na and K at diagnosis, unless an expected cell count in the contingency table was < 5, in which case Fisher’s exact test was used.

Table 1.

Selected clinicopathologic data in 70 soft-coated wheaten dogs (SCWTs) with at least 1 abnormal serum electrolyte (Na or K) concentration

Test	Number of SCWT assessed	Mean	Standard deviation	Range	Number of dogs with value greater than reference limit (%)	Number of dogs with value less than reference limit (%)	Reference interval
Sodium (mmol/L)	70	137.5	6.7	124–156	2 (3)	50 (71)	140–150
Potassium (mmol/L)	70	6.6	1.2	3.4–9.8	60 (86)	0 (0)	4.0–5.2
Na:K ratio	70	21.6	4.6	13–39	5 (7)	65 (93)	< 27
Chloride (mmol/L)	57	106.3	8.8	84–126	4 (7)	23 (40)	109–120
BUN (mmol/L)	68	22.5	12.3	3.6–52.5	60 (88)	0 (0)	1.8–10.7
Creatinine (μmol/L)	69	190.6	91.5	68.6–587.1	53 (77)	0 (0)	53.4–137.4
Phosphorus (mmol/L)	66	2.4	0.9	0.9–5.3	43 (65)	0 (0)	0.9–2.0
Glucose (mmol/L)	66	5.2	1.3	1.4–8.6	3 (5)	7 (11)	3.6–6.2
Calcium (mmol/L)	66	2.8	0.4	2.1–3.6	27 (41)	5 (8)	2.5–2.9
Albumin (g/L)	67	31.0	7.0	14–45	5 (7)	16 (24)	25–37
Cholesterol (mmol/L)	54	4.0	1.9	1.2–11.1	1 (2)	14 (26)	3.5–7.0
HCT (%)	65	50.0	11.5	19–74	18 (28)	9 (14)	40.3–60.3
Leukocytes (× 103 cells/μL)	62	11.2	3.7	4.5–21.3	5 (8)	2 (3)	5.3–19.8
Neutrophils (× 103 cells/μL)	57	6.6	31	2.5–15.5	2 (4)	2 (4)	3.1–14.4
Lymphocytes (×103 cells/μL)	57	3.2	1.5	0.7–8.1	7 (12)	1 (2)	0.7–5.5
Eosinophils (× 103 cells/μL)	54	0.7	0.7	0.0–3.1	10 (19)	0 (0)	0.0–1.6
Lack of stress leukogram	57	—	—	—	57 (100)	—	Lymphocytes > 750 cells/μL
Urine specific gravity	40	1.027	0.010	1.010–1.049	1 (3)	4 (10)	1.015–1.045

BUN — blood urea nitrogen; HCT — hematocrit.

Table 2.

Selected clinicopathologic data in 9 soft-coated wheaten terriers (SCWTs) with normal serum electrolyte (Na and K) concentrations

Test	Number of SCWT assessed	Mean	Standard deviation	Range	Number of dogs with value greater than reference limit (%)	Number of dogs with value less than reference limit (%)	Reference interval
Sodium (mmol/L)	9	148.9	4.0	144–154	0 (0)	0 (0)	140–150
Potassium (mmol/L)	9	5.0	0.6	4.0–5.7	0 (0)	0 (0)	4.0–5.2
Na:K ratio	9	29.6	3.3	26–37	2 (22)	7 (88)	> 27
Chloride (mmol/L)	9	119	3.8	112–125	3 (33)	0 (0)	109–120
BUN (mmol/L)	9	10.5	4.1	6.0–20.4	4 (44)	0 (0)	1.8–10.7
Creatinine (μmol/L)	9	114.4	22.9	91.5–152.5	2 (22)	0 (0)	53.4–137.4
Phosphorus (mmol/L)	9	1.4	0.4	1.0–2.0	0 (0)	0 (0)	0.9–2.0
Glucose (mmol/L)	9	4.8	0.4	4.2–5.4	0 (0)	0 (0)	3.6–6.2
Calcium (mmol/L)	9	2.5	0.2	2.2–2.8	0 (0)	0 (0)	2.5–2.9
Albumin (g/L)	9	26.0	4.0	21–32	0 (0)	4 (44)	25–37
Cholesterol (mmol/L)	9	2.7	0.7	1.9–3.8	0 (0)	4 (44)	3.5–7.0
HCT (%)	8	42.0	12.5	24–60	1 (13)	3 (38)	40.3–60.3
Leukocytes (× 103 cells/μL)	8	9.1	1.5	6.4–11.8	0 (0)	0 (0)	5.3–19.8
Neutrophils (× 103 cells/μL)	8	4.8	2.2	2.5–9.3	0 (0)	1 (13)	3.1–14.4
Lymphocytes (× 103 cells/μL)	8	3.1	1.5	0.9–5.5	1 (13)	1 (13)	0.9–5.5
Eosinophils (× 103 cells/μL)	8	0.7	0.4	0.3–1.6	1 (13)	0 (0)	0.0–1.6
Lack of stress leukogram	8	—	—	—	8 (100)	—	Lymphocytes > 1000 cells/μL
Urine specific gravity	6	1.037	0.011	1.027–1.049	3 (50)	0 (0)	1.015–1.045

BUN — blood urea nitrogen; HCT — hematocrit.

The Kaplan-Meier method was used to describe the survival pattern, with median survival time (MST) taken as a key summary statistic. Death due to any cause was treated as an endpoint; dogs were considered censored at the time that they were lost to follow-up. The log rank test was used to compare the survival curves between subgroups of interest, including those with and without a normal Na and K at diagnosis and those that were ultimately diagnosed with PLN and/or end-stage renal disease. A P-value of < 0.05 was considered significant.

Results

Demographic data

Medical records of 107 client-owned SCWTs with presumptive spontaneous hypoadrenocorticism were identified; following medical record review, 82 cases met the inclusion criteria. Fifteen dogs were excluded due to insufficient medical records; 7 dogs were excluded due to ACTH stimulation test results inconsistent with hypoadrenocorticism; 2 dogs were excluded due to recent use of glucocorticoids prior to diagnosis; 1 dog was excluded due to documented presence of metastatic disease in the adrenal glands.

Forty-three of 82 dogs were castrated males (52%), 30 were spayed females (37%), 7 were intact females (9%), and 2 were intact males (2%). Six of 9 dogs with normal Na and K at diagnosis were castrated males, while the remaining 3 were spayed females. Median age at diagnosis was 3.5 y for all dogs (range: 0.5 to 14.6 y). Median age at diagnosis for females was 3.2 y (range: 0.5 to 11.4 y), compared with 3.8 y for males (range: 1.1 to 14.6 y). There was no significant difference in age between genders (P = 0.492). The median age at diagnosis for dogs that were also diagnosed with PLN (n = 18) or end-stage renal disease (n = 3) during their lifetimes was 4.0 y, compared with 3.4 y for those which did not develop PLN; this difference was not significant. Dogs presenting with normal Na and K were significantly older than those with abnormal Na and/or K (median: 7.0 y versus 3.2 y, P = 0.008).

Historical and physical examination findings

Clinical signs at diagnosis were available in 63 of 82 dogs and largely consistent with those previously reported in the general population of dogs with hypoadrenocorticism, including lethargy (48/63, 76%), anorexia (46/63, 73%), vomiting (39/63, 62%), and diarrhea (18/63, 29%); duration of signs varied (1 day to several months, with most records citing “weeks” or “months”). Other clinical signs included polyuria/polydipsia (5/63, 8%), weight loss (5/63, 8%), generalized weakness (2/63, 3%), and gait abnormalities (1/63, 2%). For 59 of 63 dogs with information pertaining to clinical signs, 2 or more of the aforementioned clinical signs were present; 4 dogs had only 1 clinical sign (lethargy in 1, diarrhea in 1, anorexia in 2). Initial physical examination findings were available in 55 of 82 dogs. Physical examinations were most commonly unremarkable (17/55, 31%), but also included numerous other findings; e.g., dehydration (14/55, 25%), depressed mentation (8/55, 15%), thin body condition (7/55, 13%), abnormal stool (3/55, 5%), and bradycardia (1/55, 2%).

Clinicopathologic findings

Variable clinicopathologic data at diagnosis were available in 79 of 82 dogs (Tables 1, 2). Abnormalities on CBC included hemoconcentration (19/73, 26%), anemia (12/73, 16%), neutropenia (4/66, 6%), neutrophilia (2/66, 3%), lymphopenia (2/65, 3%), lymphocytosis (8/65, 12%), and eosinophilia (11/62, 18%). No dog had a stress leukogram. The lymphocyte count was > 750 cells/μL in 64 of 65 dogs for which a lymphocyte count was available (98%), including > 1000 cells/μL in 63 dogs (97%), > 2400 cells/μL in 48 dogs (74%), > 5000 cells/μL in 8 dogs (12%), and > 6000 cells/μL in 3 dogs (5%). There were no significant differences in CBC parameters between those dogs with normal Na or K and those with an abnormal Na or K.

Hyponatremia, hyperkalemia, or both were identified in 70 of 79 dogs (89%); 9 dogs (11%) had normal serum Na and K values. Additional abnormalities on serum chemistry panels included increased blood urea nitrogen (BUN) (64/77, 83%), increased creatinine (55/78, 71%), hyperphosphatemia (43/75, 57%), hypercalcemia (27/75, 36%), hypochloremia (23/66, 35%), hypocholesterolemia (18/63, 29%), hypoalbuminemia (20/76, 26%), hypoglycemia [7/75, 9%; of these 7 dogs, only 2 displayed clinical signs which could potentially be ascribed to such (generalized weakness); the remaining 5 were asymptomatic], and hypocalcemia (5/75, 7%). In comparing the 9 dogs with normal Na and K to the 70 with abnormal Na and/or K, those with abnormal Na and/or K were significantly more likely to have an increased BUN (P = 0.005), increased creatinine (P = 0.002), hyperphosphatemia (P = 0.0002), and hypercalcemia (P = 0.01). There was no significant difference in albumin at presentation between those dogs which ultimately were diagnosed with PLE or PLN and those which were not (P = 0.69).

Seventy-six of 79 dogs (96%) had a sodium to potassium (Na/K) ratio of ≤ 30; it was < 27 in 67 dogs (85%), and ≤ 24 in 54 dogs (68%). Of the 9 SCWTs with normal Na and K values, only 2 (22%) had a Na/K ratio < 27 (26.0 and 26.8). Of the 70 SCWTs with an abnormal Na and/or K, only 5 (7%) had a Na/K ratio ≥ 27.

Urine specific gravity (USG) prior to fluid administration was available for 46 dogs. The median USG was 1.027 (range: 1.010 to 1.049). Only 4 dogs were isosthenuric at presentation (9%).

Concurrent disease and survival data

Reported concurrent diseases (diagnosed before or after hypoadrenocorticism) included PLN (n = 18) or uncharacterized end-stage renal disease (n = 3) in a total of 21 dogs (26%, including 3 dogs that had both PLN and PLE), hypothyroidism in 6 (7%), suspected allergies (atopy and/or food allergies) in 6 (7%), PLE in 5 (6%, including 3 dogs that had both PLN and PLE), urinary incontinence in 2 (2%), anxiety in 1 (1%), and transitional cell carcinoma in 1 (1%). The 6 dogs reported to be hypothyroid were diagnosed on the basis of total thyroxine value (2 were diagnosed with hypothyroidism concurrent with the diagnosis of hypoadrenocorticism and 4 were diagnosed with hypothyroidism prior to diagnosis of hypoadrenocorticism); records did not reflect an effort to exclude nonthyroidal illness. Survival data available for 82 dogs included 16 dogs still alive at this writing, 50 dogs deceased, and 16 lost to follow-up at variable times after diagnosis. Death was attributed to hypoadrenocorticism in only 2 cases (4%); other causes of death included progressive PLN alone in 16 dogs (32%), neoplasia in 5 dogs (10%), a combination of progressive PLE/PLN in 3 dogs (6%), thromboembolic events in 2 dogs (4%), and poisoning, heart failure, mesenteric torsion, or complications of a water deprivation test (1 dog each). The cause of death was unknown or non-specific in 18 dogs (36%). The overall MST for all dogs was 5.4 y. Among the 50 dogs that died, median survival was 4.5 y (range: 0 to 11.6 y). Survival times were shorter for dogs with normal Na and K versus those with an abnormal Na and/or K (MST: 4.2 versus 5.6 y; P = 0.044; Figure 1). However, the dogs with normal Na and K were older at diagnosis (median: 7.0 y versus 3.2 y), a potential explanation for the difference in survival patterns. The survival times were shorter for dogs with subsequent PLN versus non-PLN (MST: 4.2 versus 6.4 y; P = 0.014; Figure 2). There was no significant difference in age at diagnosis between these sub-groups (P = 0.90) so this would not explain shorter survival times.

Figure 1.

Kaplan-Meier survival curve comparing SCWT with hypoadrenocorticism and abnormal Na and/or K at presentation to those with normal Na and K.

Figure 2.

Kaplan-Meier survival curve comparing SCWT with hypoadrenocorticism and subsequent PLN or end-stage renal failure to those without PLN or renal failure.

Discussion

Hypoadrenocorticism is an uncommon illness in dogs, with an incidence ranging from 0.36% to 0.5%; the SCWT has been previously identified to be at increased risk for this condition (1,20). In the present study, we examined the clinical features of naturally occurring hypoadrenocorticism in SCWTs, and identified several interesting differences between the condition in this population compared to the general canine hypoadrenocorticoid population and to other predisposed breeds.

Peterson et al (5), showed that in the general canine population intact females were at greatest risk for developing hypoadrenocorticism, followed by neutered males, spayed females, and finally intact males. In contrast, in this study there was no significant gender predilection, though neutered males represented 52% of the study population. Interestingly, each of the breed-specific studies also failed to identify a gender predilection in BRDC, Leonberger, NSDTR, POWD, and SPOO (11–16).

The median age at diagnosis of 3.5 y in this study was similar to that in the general population (4 to 5 y) (5), the NSDTR (2.6 y) (16), and the BRDC, in which most (82%) of the population was diagnosed at ≥ 5.0 y of age (11). Clinical signs, ranging from none to mild/episodic/chronic to acute/severe, were similar to those in previous reports, as were physical examination findings, which ranged from unremarkable to those consistent with hypovolemic shock and hyperkalemia. Most dogs lacked a stress leukogram, consistent with previous reports involving the general population (27).

In 1 study of the general canine hypoadrenocorticoid population, 83% of dogs were hyponatremic and 97% were hyperkalemic at presentation (5), but this study was done at a time when presentations with normal electrolytes were poorly recognized; subsequent investigations found normal electrolytes to be a more common feature of hypoadrenocorticism than previously thought (6,16). In our SCWT population, only 63% were categorized as hyponatremic, 76% were hyperkalemic, and 11% had no electrolyte abnormalities; of 9 dogs with normal electrolytes at presentation, the date of diagnosis was after January 1, 2001 in 7, which may be a reflection of heightened awareness of presentations with normal electrolytes. In the 2007 assessment of hypoadrenocorticism in NSDTR, 32% had normal electrolytes at presentation; several dogs subsequently developed electrolyte abnormalities while others did not. This suggests that some dogs may have been diagnosed at an early stage in their disease prior to the development of hypoaldosteronism, whereas others may have had selective destruction of the zona fasciculata or secondary hypoadrenocorticism resulting from inadequate ACTH release from the pituitary gland (16). Selective destruction of functional layers of the adrenal cortex was investigated by Frank et al (8), who identified selective sparing of the zona glomerulosa in dogs which had diffuse atrophy of both the zonae fasciculata and reticularis. In 1 study, serum aldosterone concentrations were low in most dogs with hypoadrenocorticism, independent of the degree of Na and K abnormalities (7). The authors postulated that normal K is maintained in some dogs due to high renal tubular flow rate with corresponding high delivery of K to the collecting duct, an increased tubular sensitivity to aldosterone, or a combination thereof. They also discussed the possibility that a diet sufficiently high in Na might allow for maintenance of extracellular fluid volume and distal tubular flow rate (7). In our study there was insufficient follow-up data on 6 of 9 dogs which did not have electrolyte abnormalities to know if they subsequently developed evidence of hypoaldosteronism. Of the remaining 3 dogs, 1 died at diagnosis (Na/K = 26.0), 1 was treated with mineralocorticoid supplementation (Na/K = 28.8), and 1 was subsequently treated when the Na/K ratio was “low,” almost 3.5 y after initial diagnosis.

The incidence of hypoalbuminemia in this population was 26%, which is higher than that in an early study (6% in the general population) (5), although a subsequent study identified an increased risk of hypoalbuminemia, particularly in dogs with normal electrolytes at presentation (6). In the present study, dogs with normal electrolytes did not display an increased tendency to be hypoalbuminemic, nor was there a significant difference in albumin at presentation between dogs that subsequently were diagnosed with PLE and/or PLN and dogs which were not, though we had initially hypothesized that there would be a difference, given the risk of developing these conditions (PLE and/or PLN) in SCWTs (26).

The overall MST (5.4 y, range: 0 to 11.6 y) in SCWTs was similar to that in the general hypoadrenocorticoid population (4.7 y, range: 7 d to 11.8 y) (28). Median survival time after diagnosis for 4 NSDTRs that died or were euthanized as a result of medical causes was 1.6 y (16) versus 4.5 y for 50 SCWTs which died. Other studies of canine hypoadrenocorticism have found that most of the dogs expire for reasons other than hypoadrenocorticism; this was true in this population of SCWTs, though 36% of dogs which died during this study period had an unknown or non-specific cause of death, which does not exclude hypoadrenocorticism as a contributing factor in death. In this population, dogs with normal electrolytes at presentation had a significantly shorter survival time than those which had an abnormal Na and/or K; however, this may be influenced by the older age of those patients with normal Na and K at presentation, and the fact that 1 dog with normal Na and K died on the day of presentation, though the cause of death could not be ascertained. The overall MST may be influenced by the guarded prognosis associated with other conditions for which the SCWT are at increased risk, particularly PLN (26). In this population, survival times were significantly shorter among those that developed PLN (P = 0.014). Interestingly, 21/82 (26%) of the SCWT hypoadrenocorticoid population was diagnosed with PLN or presumed PLN causing end-stage renal failure; this is higher than the estimated prevalence of PLN (10% to 15%) in the general SCWT population (26). This could be a reflection of a genetic linkage of the traits, or merely a reflection of the relatively isolated gene pool. A DNA test for the PLN-associated variant alleles found in SCWT is available to identify dogs at high risk for developing PLN (23,29).

Given the delayed onset of adrenal failure and non-specific clinical signs of the condition, hypoadrenocorticism is often not identified until later in life; in this population, half the dogs were older than 3.5 y of age. Late onset is particularly problematic because breeding animals may have produced several litters prior to diagnosis. Hypoadrenocorticism left unrecognized can have devastating effects for the affected animal and lifetime costs of therapy can be substantial. Thus, identification of a genetic test in order to screen potential breeding animals and to arrive at a more timely diagnosis is desirable. The removal of animals carrying at-risk alleles from the breeding pool must be balanced with the need to maintain genetic diversity. Genome-wide association studies and sequencing of candidate genes may help identify genetic markers in dogs carrying at-risk alleles. Banking DNA samples from dogs with properly characterized phenotypes is a first step toward this goal.

A mode of inheritance for familial hypoadrenocorticism has been proposed in each of the breed-specific studies to date. In the BRDC, evaluation of pedigrees did not support a Mendelian autosomal dominant mode of inheritance; in the NSDTR, POWD, and SPOO, pedigree analyses fit best with autosomal recessive loci (11–16). This study involved isolated cases seen at independent practices. Phenotypic information on members of affected dogs’ pedigrees was sought from breeders; however, the reported information was incomplete and anecdotal; therefore, it was not possible to determine a specific mode of inheritance. Among 59 available pedigrees of affected dogs, only 3 litters were known to include 2 affected siblings, and only 1 parent was known to be affected. These findings argue against a simple dominant or an X-linked recessive mode and suggest a simple recessive or complex (multigenic) mode of inheritance.

In humans, HLA-DRB1 has been identified as the main risk factor for hypoadrenocorticism, with smaller contributions by other loci both within the HLA region (such as MICA*5.1) and outside of the HLA region (CTLA4 and CLEC16A) (30–34). In the POWD the MHC region on chromosome 12 and the CTLA4 gene region on chromosome 37 were identified as potential genetic risk factors for hypoadrenocorticism (17). In the NSDTR there was no evidence of linkage between hypoadrenocorticism and multiple candidate genes which are associated with hypoadrenocorticism in humans (AIRE, BAFF, Casp10, CD28, FASL, PTPN22, TNFRSF6B); CTLA-4 was not completed excluded (21). Demonstration of an MHC II class association for hypoadrenocorticism in NSDTR (risk haplotype DLA-DRB1*015:02 — DQA1*006:01 — DQB1*023:01) (18) was later questioned as spurious (22). Recently, MHC II class associations were reported in 6 breeds, including BRDC, cocker spaniel, Jack Russell terrier, Labrador retriever, springer spaniel, SPOO, and WHWT; however, an association could not be identified in SCWTs (19). The authors surmised that this might be a reflection of a non-immune mediated etiology in the SCWT breed, or perhaps a greater role for other genetic risk factors. In Labrador retrievers, cocker and springer spaniels, but not in SCWT, 8 alleles in 5 of 42 candidate genes associated with hypoadrenocorticism in humans (COL4A4, OSBPLL9, STXBP5, CTLA4, and PTPN22; the latter 2 genes are immune response genes) have been identified (20). Our SCWT pedigree data suggest an autosomal recessive or complex mode of inheritance. Preliminary findings in SCWTs show that at least 1 DLA locus is nearly fixed in the breed (P. Henthorn, 2014, University of Pennsylvania, personal communication) and that a single nucleotide polymorphism (SNP) is found in DNA samples of affected SCWTs (but not in that of geriatric unaffected SCWTs) within a human hypoadrenocorticism candidate gene (TAF5L) (P < 0.05) (35).

There are several limitations to this study, largely owing to its retrospective nature and long period of time over which subjects were identified. We frequently encountered records lacking information on clinical signs and physical examination findings that originally led to the suspicion of hypoadrenocorticism, although subsequent confirmatory laboratory test results were available. Follow-up data relative to outcome and subsequent diagnoses were unavailable in some cases, particularly those from earlier in the study period. The fact that clinicopathologic data were derived from multiple reference laboratories affected assessment of absolute values, though reference ranges were generally similar between laboratories. Lastly, there was variation in the manner in which ACTH stimulation tests were performed, largely owing to changes in standards over the study period.

Future studies to test resting endogenous ACTH, renin, and aldosterone levels at diagnosis in affected dogs, particularly those with atypical presentations (such as normal electrolytes), and to obtain more detailed follow-up on dogs with atypical presentations will help characterize the underlying etiology of hypoadrenocorticism in SCWTs. Identification of the genetic mutation(s) responsible for hypoadrenocorticism in SCWTs and subsequent development of a genetic test to identify carriers of at-risk alleles and to aid breeders with genetic counseling are warranted.

In summary, this study found that while SCWTs diagnosed with spontaneous hypoadrenocorticism tend to have histories and physical examination findings similar to those in the general hypoadrenocorticoid population, there is no gender predilection, and there is a greater likelihood of identifying normal serum Na and K at presentation, relative to previous general studies, possibly because presentations with normal Na and K are now better recognized. Concurrent or subsequent PLN is an important finding in SCWTs and has an impact on survival. Screening for PLN-associated variant alleles and monitoring for proteinuria and subsequent renal failure are vital in the management of hypoadrenocorticism in SCWTs.