Introduction

Since 1983 a number of familial diseases in the Soft-Coated Wheaten Terrier breed have been recognized that may be described under the umbrella of hypersensitivity, immune-mediated, or inflammatory diseases. These include food allergies, inflammatory bowel disease (IBD), protein-losing enteropathy (PLE), protein-losing nephropathy (PLN), and Addison's disease (AD). The breed is also predisposed to renal dysplasia (juvenile renal disease, RD).

We first described 33 SCWT dogs with PLE and/or PLN in 1990. The dogs were related to a common male ancestor that died with evidence of a saddle thrombus, a thromboembolic event which suggests the dog may have been affected with PLE and/or PLN which can cause hypercoagulopathy. By 2000, the number of SCWT dogs described with the syndrome PLE and/or PLN reached 222 dogs. By August 2009, consultations for diagnosis and management of sick Wheatens (requested by FAX, email/mail, phone, or visit at Penn) documented more than 1000 Wheatens to be affected with PLN (460 dogs), IBD or PLE (249 dogs), sequential or combined PLE/PLN (226 dogs), Addison's disease (80 dogs), renal dysplasia (51 dogs), or incompletely characterized renal failure (RF) before 8 years of age (41 dogs). Veterinarians need to be aware of the genetic predispositions in the breed, especially the immunodysregulation disorders which comprised more than 90% of the requested consultations. Currently there are no genetic markers or predictive tests so annual screening tests are recommended, to find early warning signs before dogs become ill, so that interventions can be started (diet and medication). Since the clinical signs of these diseases may mimic one another at presentation of a sick dog, characterization of the specific diagnosis by further testing is important.

Methods

The clinical diagnosis for IBD/PLE, PLN, RD, Addison's disease and/or incompletely diagnosed renal failure (RF) at a relatively young age (8 yrs or less) was based on the clinical findings including history, physical examination, and diagnostic tests, e.g., clinical pathology, adrenal function tests, histopathology, ± serology/imaging/etc., as necessary. Criteria for inclusion of an affected dog on the Open Registry required permission from the owner(s) and documentation by blood (Bl), urine (U), and/or histopathology (Bx) of abnormalities as follows:

Ple: Protein-Losing Enteropathy

 Bl: panhypoproteinemia without evidence of hemorrhage or other causes.

 U: absence of proteinuria.

 Bx: intestinal lesions characteristic of PLE (e.g., inflammatory bowel disease, lymphangitis, lymphangiectasia).

Ibd: Inflammatory Bowel Disease

 Bx: changes as for PLE but without panhypoproteinemia (if bloodwork available).

PLN: Protein-losing nephropathy

 Bl: hypoalbuminemia without hypoglobulinemia, ± azotemia.

 U: proteinuria (by urinalysis, SSA, microalbuminuria, or urine protein/creatinine ratio). inactive sediment, and no other cause for proteinuria other than glomerular leakage.

 Bx: renal lesions characteristic of PLN (e.g., glomerulonephritis, glomerulosclerosis).

PLE/PLN

 Including criteria of both PLE and PLN, i.e., panhypoproteinemia, proteinuria, and/or characteristic intestinal and renal histopathologic lesions.

RD: Renal dysplasia or juvenile renal disease

 Bl: changes of renal failure without hypoalbuminemia.

 U: decreased urine specific gravity.

 Bx: renal lesions associated with RD (fetal glomeruli, fetal mesenchyme).

 R: (Radiograph or ultrasound): small kidneys at a very young age.

RF: Renal failure, incompletely diagnosed, aged 8 years or less

 Bl: changes of renal failure without hypoalbuminemia.

 U: decreased urine specific gravity.

 Bx: abnormal but not classic for PLN or RD (possibly end-stage kidneys).

Addison's Disease

 Bl: low Na/K ratio (typical), flat/low ACTH stimulation test results.

Clinical features of the most common of these diseases are compared in Table 1.

Open Registry

At the request of the SCWT Club of America and SCWT Association of Canada, an Open Registry (OR) was started in 1997. Normalcy cannot be predicted (there is no age limit), so the OR only lists affected dogs. Owners of affected dogs having confidential consultations at Penn were asked to give permission to have their dogs listed. By August 2009, the OR listed 856 affected dogs (see Table 2). The SCWT Open Registry lists dogs affected with IBD, PLE, PLN, PLE/PLN, Addison's disease, renal dysplasia, or uncharacterized renal failure at a relatively young age (8 yrs or less), based on documentation from blood (Bl), urine (U), and/or histopathology (Bx) results. Listed are the dog's registration name/number, call name, sire/dam, dates of birth/death, age of onset, sex, diagnosis, and methods of documentation. Comments note if a littermate, sire, dam, or offspring is also listed. The OR was started in an effort to share health information among breeders, to stop rumors about which dog had what disease, to have standardization of criteria for diagnosis, to educate breeders/owners/veterinarians about these diseases and their prevalence in the breed, to study patterns of inheritance, and to find informative families for study. The mode of inheritance of PLE/PLN appears complicated. Multiple genes, variable expression, and possibly environmental triggers are suspected. The increased risk for female Wheatens for PLE, PLN, PLE/PLN and Addison's disease agrees with the finding of higher female risk in other species for immune-mediated diseases.

DNA Bank

Penn's SCWT DNA bank was begun in 2000 and now has more than 500 samples. Included are frozen whole blood or tissue samples from affected dogs, members of several informative families including Dr. Shelly Vaden's Wheagle colony at NCSU, frozen puppy tails/declaws saved by conscientious breeders, and geriatric non-affected Wheatens. Samples sent in from puppies or normal dogs less than 14 yrs of age will not be used for study until their phenotype is known. Such dogs need to be followed carefully throughout their lives, with proper documentation of diagnosis, so that the correct phenotypic characterization can be eventually associated with each dog's DNA sample. Geriatric dogs are considered phenotypically normal for the diseases of interest based on blood, urine, and/or biopsy, and having reached their 14^th year of life. Ongoing studies of the genetic areas of interest include especially the immunity-related genes (MHC, DLA, DQA), SNP chip analysis, and karyotype of affecteds vs. geriatrics.

Table 1: Comparisons of Clinical Features of Genetic Diseases in SCWT Dogs

Table 2: SCWT Open Registry Statistics (as of August 2009)

References

1.  Littman MP, Giger U: Familial protein-losing enteropathy (PLE) and/or protein-losing nephropathy (PLN) in Soft-coated Wheaten Terriers (SCWT). ACVIM Abstr, 1990;1135 and J Vet Int Med 1990;4(2):133.

2.  Littman MP: Wheaten PLE-PLN. Proceedings of the 17^th Annual Veterinary Medical Forum, ACVIM 1999;554-556.

3.  Littman MP, Dambach DM, Vaden SL, Giger U: Familial protein-losing enteropathy and protein-losing nephropathy in Soft Coated Wheaten Terriers: 222 cases (1983-1997). J Vet Intern Med 2000;14(1):68-80.

4.  Littman MP: SCWT Open Registry. Started in 1997, with updates every 1-2 years-See website http://www.scwtca.org/openregistry/index.htm.

5.  Annual screening tests recommended for all Wheatens-See website http://www.scwtca.org/health/protocol-vet.htm.

6.  Request for DNA and histopathology samples from normal geriatric Wheatens-See website http://www.scwtca.org/health/geriatric.htm.

7.  Vaden SL, Sellon RK, Melgarejo LT, Williams DA, Trogdon MM, VanCamp SD, Argenzio RA. Evaluation of intestinal permeability and gluten sensitivity in Soft-Coated Wheaten Terriers with familial protein-losing enteropathy, protein-losing nephropathy, or both. Am J Vet Res 2000;61(5):518-524.

8.  Vaden S, Giger G, Spaulding K, Sellon R, Littman M, Harris T, Afrouzian M, Jennette J, Williams D, VanCamp S. Inheritance of protein-losing enteropathy and nephropathy of Soft Coated Wheaten Terriers. ACVIM Abstr 2002:786 and J Vet Intern Med 2002;16(3):352.