A large deletion in the Plasminogen gene is associated with ligneous membranitis in a Maltese dog.

Ligneous membranitis/conjunctivitis (LM, OMIM 217090) is a hereditary disorder caused by a congenital plasminogen (PLG) deficiency. In veterinary medicine, LM (OMIA 002020-9615) has rarely been reported in Golden Retrievers, Yorkshire Terriers, Doberman Pinschers and Scottish Terriers. In the latter breed, an A>T variation in an intron donor site of the PLG gene (PLG, c.1256+2T>A) has been found to be the sole causative molecular defect reported to date in dogs. Owing to the absence of plasmin enzymatic clearance which in turn depends on the lack of its proenzyme plasminogen, fibrin deposits tend to accumulate in viscous membranes on the eyes, triggering and sustaining an intense inflammatory response. A case of LM was diagnosed in a 7-month-old male Maltese dog. The dog was examined for severe recurrent conjunctivitis. A diagnosis of ligneous conjunctivitis was made by an ophthalmologist after a thorough eye examination and was confirmed by a complete lack of plasma activity of plasminogen. The main local signs were redness of the conjunctiva with persistent membranes having ligneous (wood-like) membranes on the eyes. The disease was associated with a complex rearrangement involving the plasminogen gene loci, causing the complete deletion of exon 1. This study provides a spontaneous animal model for LM associated with complete plasminogen deficiency and provides a method for detecting affected or carrier dogs.

Primary isolated osteoma cutis causing eyelid deformation and strabismus in a dog.

Osteoma cutis describes bone formation in skin and is well documented in the medical literature, but veterinary reports are few. We report a single case of a juvenile samoyed that was referred for assessment of a superior eyelid anomaly. Exploratory surgery and histopathology revealed the presence of mature, lamellar bone within the superior eyelid. The histologic appearance was consistent with primary osteoma cutis. The presence of the ossification within the deep dermis of the eyelid was associated with an abnormal conformation causing trichiasis, keratitis and dorsal strabismus. Identification of the osseous lesion during surgery and its removal was curative with no recurrence of disease during the 32 month follow-up period.

Localized parakeratotic hyperkeratosis in sixteen Boston terrier dogs.

BACKGROUND: Although zinc responsive dermatosis is typically a disorder of Arctic breed dogs, this study identifies similar cutaneous lesions on the face and pressure points of Boston terrier dogs. HYPOTHESIS/OBJECTIVES: To document the clinical and histological features of localized parakeratotic hyperkeratosis of Boston terrier dogs, to determine if the lesions respond to zinc supplementation and to determine whether tissue zinc levels were decreased in affected versus unaffected dogs. MATERIAL AND METHODS: Sixteen Boston terrier dogs with similar gross and histological findings were identified retrospectively from two institutions. Follow-up information for nine dogs from one institution was obtained from referring veterinarians using a questionnaire. Tissue zinc levels were measured from formalin-fixed paraffin-embedded skin biopsy samples of affected and unaffected dogs using inductively coupled plasma mass spectrometry. RESULTS: Mild to severe parakeratotic hyperkeratosis with follicular involvement was present in all 16 cases. Of the nine dogs for which follow-up information was available, five dogs received oral zinc supplementation and four dogs had documented clinical improvement or resolution of dermatological lesions. The median skin zinc levels were not significantly different between affected and unaffected dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge this is the first report of localized parakeratotic hyperkeratosis in Boston terrier dogs, some of which improved with oral zinc supplementation. Prospective studies in Boston terrier dogs are warranted to document potential zinc deficiency (serum and/or tissue levels, pre- and post-treatment) and to objectively assess response to zinc supplementation and other therapies.

Features and outcome of a glomerulonephropathy associated with ligneous conjunctivitis in a Doberman pinscher dog.

This report describes a 3-year-old female Doberman pinscher dog with ligneous conjunctivitis and a protein-losing nephropathy not associated with underlying plasminogen deficiency. Glomerulonephropathy in this circumstance had a positive outcome.

Caractéristiques et résultats d'une glomérulonéphropathie associée à une conjonctivite ligneuse chez un chien Doberman. Ce rapport décrit une chienne Doberman pinscher âgée de 3 ans souffrant de conjonctivite ligneuse et de néphropathie avec perte de protéines non associée à une carence de plasminogène sous-jacente. Dans cette circonstance, la glomérulonéphropathie a eu une résolution favorable.(Traduit par Isabelle Vallières).

Dermatological and morphological findings in quarter horses with hereditary equine regional dermal asthenia.

BACKGROUND: Hereditary equine regional dermal asthenia (HERDA) is an autosomal recessive disorder affecting quarter horses (QHs); affected horses exhibit characteristic skin abnormalities related to abnormal collagen biosynthesis. HYPOTHESIS/OBJECTIVES: To characterize the thickness and morphological abnormalities of the skin of HERDA-affected horses and to determine the interobserver agreement and the diagnostic accuracy of histopathological examination of skin biopsies from horses with HERDA. ANIMALS: Six affected QHs, confirmed by DNA testing, from a research herd and five unaffected QHs from a stud farm. METHODS: The skin thickness in 25 distinct body regions was measured on both sides in all affected and unaffected horses. Histopathological and ultrastructural evaluation of skin biopsies was performed. RESULTS: The average skin thickness in all of the evaluated regions was thinner in the affected horses. A statistically significant difference between skin thickness of the affected and unaffected animals was observed only when the average magnitude of difference was ≥38.7% (P = 0.038). The interobserver agreement for the histopathological evaluation was fair to substantial. The histopathological sensitivity for the diagnosis of HERDA was dependent on the evaluator and ranged from 73 to 88%, whereas the specificity was affected by the region sampled and ranged from 35 to 75%. CONCLUSIONS AND CLINICAL IMPORTANCE: Despite the regional pattern of the cutaneous signs, skin with decreased thickness was not regionally distributed in the HERDA-affected horses. Histopathological evaluation is informative but not conclusive for establishing the diagnosis. Samples of skin from the neck, croup or back are useful for diagnosis of HERDA. However, the final diagnosis must be confirmed using molecular testing.

Heritable equine regional dermal asthenia.

Hereditary equine regional dermal asthenia is a form of Ehlers-Danlos syndrome, and has an autosomal recessive mode of inheritance. Affected horses are typically born normal and develop lesions within the first 2 years of life. The most common symptoms of the disease include stretchy, loose skin that feels doughy or mushy. More severely affected horses experience spontaneous skin sloughing and extensive lacerations, hematomas, and seromas from minor trauma. Affected horses have a higher than expected incidence of corneal ulcers. DNA testing can normal, establish carrier and affected status. Palliative therapy is available, but no curative treatment exists.

A premature stop codon in the ADAMTS2 gene is likely to be responsible for dermatosparaxis in Dorper sheep.

We have used polymerase chain reaction-single-strand conformational polymorphism analysis to investigate variation in exon 2 of the ADAM metalloproteinase with thrombospondin type I motif, 2 (ADAMTS2) gene in 598 sheep, including three white Dorper lambs that had a pathology consistent with dermatosparaxis. Four sequence variants (A, B, C and D) were identified at this exon, with the lambs having the dermatosparaxis phenotype being uniquely B homozygous and their mothers being B-containing heterozygous for ADAMTS2. Analysis of the amplified exon 2 sequences revealed the B variant had a nucleotide substitution that creates a premature stop codon and would notionally abbreviate the ADAMTS2 peptide. The B variant was not found in any other breed aside from the white Dorper sheep that were studied.

Prevalence of the mutation in cyclophilin B (PPIB), a causal candidate gene for HERDA, among Quarter Horses in France.

Hereditary equine regional dermal asthenia (HERDA) in Quarter Horses is an inherited degenerative skin disease. Initially reported as hyperelastosis cutis, HERDA has a phenotype of hyperextensible, fragile skin, with secondary seromas, haematomas, ulcers and scarring. It primarily affects the dorsal aspect of the body. An autosomal recessive mode of inheritance is considered likely, with affected horses more at risk to produce affected offspring. A mutation in cyclophilin B (PPIB) as a novel, causal candidate gene for HERDA has been described, and verified as segregating with carriers and affected horses. Screening of control Quarter Horses in the USA has indicated a 3.5% carrier frequency. The prevalence of this mutation among Quarter Horses in France was determined to be 1.6%.

Ocular findings in Quarter Horses with hereditary equine regional dermal asthenia.

OBJECTIVE: To compare ocular structures of Quarter Horses homozygous for hereditary equine regional dermal asthenia (HERDA) with those of Quarter Horses not affected by HERDA (control horses) and to determine the frequency of new corneal ulcers for horses with and without HERDA during a 4-year period. DESIGN: Cohort study of ocular structures and retrospective case series of horses with and without HERDA. ANIMALS: The cohort portion of the study involved 10 Quarter Horses with HERDA and 10 Quarter Horses without HERDA; the retrospective case series involved 28 horses with HERDA and 291 horses without HERDA. PROCEDURES: Ophthalmic examinations, Schirmer tear tests, tonometry, corneal pachymetry, histologic examinations, and scanning electron microscopy (SEM) were performed in cohorts of Quarter Horses with and without HERDA. Records were reviewed to determine the incidence of corneal ulcers in horses with and without HERDA during a 4-year period. RESULTS: Corneal thickness of horses with HERDA was significantly less than that of control horses, but tear production of horses with HERDA was significantly greater than that of control horses. Results of SEM revealed zones of disorganized, haphazardly arranged collagen fibrils in corneas of horses with HERDA that were not evident in corneas of control horses. The incidence of corneal ulcers was significantly greater for horses with HERDA than for horses without HERDA during the 4-year period. CONCLUSIONS AND CLINICAL RELEVANCE: Alterations in corneal thickness, arrangement of collagen fibers, and incidence of corneal ulcers indicated that abnormalities in horses with HERDA were not limited to the skin.

Bilateral osteoma cutis in a Peach-Faced Lovebird (Agapornis roseicollis).

An osteoma is an infrequent tumor documented in avian species. An adult female Peach-Faced Lovebird (Agapornis roseicollis) with a history of previous trauma was examined due to the presence of bilateral hard and yellowish-white masses in the radio-cubital humerus junction. Histopathological dermal examination revealed a non-neoplastic process of mesenchymal origin, characterized by the formation of well-differentiated trabecular bone, multiple areas of medullary bone and loose connective tissue and coagulation of the necrosis foci. Based on the histological findings and the medical history, the masses were diagnosed as bilateral secondary osteoma cutis. To our knowledge, this is the first report of this pathology with an acute course in this exotic pet bird. The previous trauma could be the initiating cause.

Distribution of the Warmblood Fragile Foal Syndrome Type 1 Mutation (PLOD1 c.2032G>A) in Different Horse Breeds from Europe and the United States.

Warmblood fragile foal syndrome (WFFS) is an autosomal recessive disorder caused by a single nucleotide variant in the procollagen-lysine-2-oxoglutarate-5-dioxygenase 1 gene (PLOD1:c.2032G>A, p.Gly678Arg). Homozygosity for the PLOD1 variant causes an Ehler-Danlos-like syndrome, which has to date only been reported in warmblood breeds but the WFFS allele has been also detected in the Thoroughbred. To investigate the breed distribution of the WFFS allele, 4081 horses belonging to 38 different breeds were screened. In total, 4.9% of the horses representing 21 breeds carried the WFFS allele. The affected breeds were mainly warmbloods, with carrier frequency as high as 17% in the Hanoverian and Danish Warmblood. The WFFS allele was not detected in most non-warmblood breeds. Exceptions include WFFS carriers in the Thoroughbred (17/716), Haflinger (2/48), American Sport Pony (1/12), and Knabstrupper (3/46). The origin of the WFFS allele remains unknown. The Arabian breed and specifically the stallion Bairactar Or. Ar. (1813), whose offspring were reported to have a similar phenotype in the 19th century, were hypothesized as the origin. DNA from a museum sample of Bairactar Or. Ar. showed that he did not carry the mutated allele. This result, together with the genotypes of 302 Arabians, all homozygous for the reference allele, does not support an Arabian origin of the WFFS allele. Our extensive survey shows the WFFS allele to be of moderate frequency and concern in warmbloods and also in breeds where it may not be expected.

Primary Osteoma Cutis in the Interscapular Region of a Dog.

A 9-year-old neutered male Shih Tzu was presented with three contiguous firm nodules in the subcutaneous tissue of the interscapular region. Histopathological examination revealed that the nodules consisted of mature lamellar bone with a Haversian system, with no apparent lesion around the bone. Clinical examination revealed that the dog had no underlying disease and no history of trauma at the lesion site. Based on these findings and on the medical history, a diagnosis of primary osteoma cutis was made. Osteoma cutis is rare in both human and veterinary medicine, and most dogs reported to have secondary osteoma cutis. To our knowledge, this case is only the second report of primary osteoma cutis in a dog.

Using an Inbred Horse Breed in a High Density Genome-Wide Scan for Genetic Risk Factors of Insect Bite Hypersensitivity (IBH).

While susceptibility to hypersensitive reactions is a common problem amongst humans and animals alike, the population structure of certain animal species and breeds provides a more advantageous route to better understanding the biology underpinning these conditions. The current study uses Exmoor ponies, a highly inbred breed of horse known to frequently suffer from insect bite hypersensitivity, to identify genomic regions associated with a type I and type IV hypersensitive reaction. A total of 110 cases and 170 controls were genotyped on the 670K Axiom Equine Genotyping Array. Quality control resulted in 452,457 SNPs and 268 individuals being tested for association. Genome-wide association analyses were performed using the GenABEL package in R and resulted in the identification of two regions of interest on Chromosome 8. The first region contained the most significant SNP identified, which was located in an intron of the DCC netrin 1 receptor gene. The second region identified contained multiple top SNPs and encompassed the PIGN, KIAA1468, TNFRSF11A, ZCCHC2, and PHLPP1 genes. Although additional studies will be needed to validate the importance of these regions in horses and the relevance of these regions in other species, the knowledge gained from the current study has the potential to be a step forward in unraveling the complex nature of hypersensitive reactions.

Inheritance of hereditary equine regional dermal asthenia in Quarter Horses.

OBJECTIVE: To assess heritability and mode of inheritance for hereditary equine regional dermal asthenia (HERDA) in Quarter Horses. ANIMALS: 1,295 horses with Quarter Horse bloodlines, including 58 horses affected with HERDA. PROCEDURE: Horses were classified as affected or unaffected or as undetermined when data were insufficient to assess phenotype. Pedigree data were analyzed to determine the probable mode of inheritance. Heritability was estimated by use of Bayesian statistical methods. RESULTS: Heritability (mean+/-SD) of HERDA was estimated to be 0.38+/-0.13, with both sexes having an equal probability of being affected. Results for evaluation of the pedigrees were consistent with a single Mendelian autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL RELEVANCE: HERDA in Quarter Horses is an inherited disease, and affected horses are more likely to produce affected offspring. An autosomal recessive mode of inheritance should be considered by people making breeding decisions involving Quarter Horses when a first-degree relative has been confirmed with HERDA or has produced affected offspring. In addition, breeders whose horses have produced affected offspring can reduce the likelihood of producing affected horses in the future by avoiding inbreeding.

The epitheliogenesis imperfecta locus maps to equine chromosome 8 in American Saddlebred horses.

Epitheliogenesis imperfecta (EI) is a hereditary junctional mechanobullous disease that occurs in newborn American Saddlebred foals. The pathological signs of epitheliogenesis imperfecta closely match a similar disease in humans known as Herlitz junctional epidermolysis bullosa, which is caused by a mutation in one of the genes (LAMA3, LAMB3 and LAMC2) coding for the subunits of the laminin 5 protein (laminin alpha3, laminin beta3 and laminin gamma2). The LAMA3 gene has been assigned to equine chromosome 8 and LAMB3 and LAMC2 have been mapped to equine chromosome 5. Linkage disequilibrium between microsatellite markers that mapped to equine chromosome 5 and equine chromosome 8 and the EI disease locus was tested in American Saddlebred horses. The allele frequencies of microsatellite alleles at 11 loci were determined for both epitheliogenesis imperfecta affected and unaffected populations of American Saddlebred horses by genotyping and direct counting of alleles. These were used to determine fit to Hardy-Weinberg equilibrium for control and EI populations using Chi square analysis. Two microsatellite loci located on equine chromosome 8q, ASB14 and AHT3, were not in Hardy-Weinberg equilibrium in affected American Saddlebred horses. In comparison, all of the microsatellite markers located on equine chromosome 5 were in Hardy-Weinberg equilibrium in affected American Saddlebred horses. This suggested that the EI disease locus was located on equine chromosome 8q, where LAMA3 is also located.

Tensile properties in collagen-rich tissues of Quarter Horses with hereditary equine regional dermal asthenia (HERDA).

REASONS FOR PERFORMING STUDY: Hereditary equine regional dermal asthenia (HERDA) is an autosomal recessive disorder of Quarter Horses characterised by skin fragility. Horses with HERDA have a missense mutation in peptidyl-prolyl cis-trans isomerase B (PPIB), which encodes cyclophilin B and alters folding and post translational modifications of fibrillar collagen. OBJECTIVES: The study aimed to test the hypothesis that tendons, ligaments and great vessels, which, like skin, are rich in fibrillar collagen, will also have abnormal biomechanical properties in horses with HERDA. STUDY DESIGN: Ex vivo biomechanical study comparing horses with and without a diagnosis of HERDA. METHODS: Forelimb suspensory ligament, superficial and deep digital flexor tendons; withers, forelimb and abdominal skin; the main pulmonary artery and the aortic arch were harvested from 6 horses with HERDA and 6 control horses without the HERDA allele. Tissues were distracted to failure. Tensile strength (TS), elastic modulus (EM) and energy to failure (ETF) were compared. RESULTS: Horses with HERDA had significantly lower TS and EM in tendinoligamentous tissues and great vessels, respectively. The TS, EM and ETF were significantly lower in skin from horses with HERDA. Differences in TS and ETF were more extreme at the withers than at the forelimb or abdomen. CONCLUSIONS: Tendinoligamentous tissue, great vessels and skin are significantly weaker in horses with HERDA than in horses lacking the PPIB mutation, substantiating that diverse tissues with high fibrillar collagen content are abnormal in HERDA and that the HERDA phenotype is not limited to the integument.

Allele frequency of hereditary equine regional dermal asthenia in American Quarter horses in Brazil determined by quantitative real-time PCR with high resolution melting analysis.

Hereditary equine regional dermal asthenia (HERDA) is a genetic disorder that occurs in the American Quarter horse (AQH) and is caused by a c.115G>A missense mutation in the peptidylprolyl isomerase B (PPIB) gene. Using a quantitative real-time PCR high resolution melting analysis genotyping assay for the PPIB mutation, the estimated HERDA allele and carrier frequencies in a sample of Brazilian AQHs were 2.9% and 5.8%, respectively.