LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa.

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin ß3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals.

Scleromyxoedema in a dog.

BACKGROUND: In humans, scleromyxoedema is a chronic progressive skin condition traditionally characterized by deposits of mucin, increased number of fibroblasts and fibrosis in the skin, and by systemic disease. Thyroid disease is typically absent. A monoclonal gammopathy is usually present, as are other comorbidities. Descriptions of scleromyxoedema in the veterinary literature are limited to a single feline case. One dog, previously reported as having papular mucinosis, exhibited features that matched the more current diagnostic criteria of scleromyxoedema. OBJECTIVES: To describe generalized papular mucinosis in a dog with systemic illness and to compare the signs with those of human lichen myxoedematosus conditions, specifically scleromyxoedema. RESULTS: A nine-year-old female, spayed English springer spaniel dog presented with generalized papules and nodules (0.5-5 cm) on the body and proximal fore and hind limbs, sparing the face and distal limbs distal to carpi/tarsi. Larger nodules were erythematous. Nodules occurred in proximal limb muscles. The dog had concurrent osteoarthritis of the elbows and coxofemoral joints, developed generalized weakness, declined in health and was euthanized. Thyroid disease was lacking and a monoclonal gammopathy was not present. Histopathological evaluation revealed the classic triad of mucin, fibroblast proliferation and fibrosis with very mild inflammation, as described for humans. CONCLUSION AND CLINICAL IMPORTANCE: We document scleromyxoedema in a dog with significant morbidity and features of the human disease. Recognizing the typical histopathology is important for identifying cases and to establish a diagnosis. Systemic evaluation is important to identify evidence of internal disease and associated comorbidities, which are common, variable, and impact classification and prognosis in humans.

Is CCNU (lomustine) valuable for treatment of cutaneous epitheliotropic lymphoma in dogs? A critically appraised topic.

BACKGROUND: CCNU and other treatment protocols are commonly offered to owners for the treatment of dogs diagnosed with cutaneous (epitheliotropic) T-cell lymphoma (CTCL). Chemotherapy protocols provide variable benefits; they have different side-effects, and they typically require monitoring to detect drug toxicity at a non-negligible cost to the owner. At this time, even though CCNU is most often recommended to treat dogs with CTCL, there is no clear consensus on the benefit of this drug. Knowing which chemotherapy protocol yields the highest rate of complete remission and longest survival times would help veterinarians and pet owners select treatment options based on the best evidence available. Our objective was to review the literature to compare the complete remission rates and survival times of CCNU-based protocols to those of other interventions. We critically assessed the data included in articles reporting treatment outcome in at least five dogs with CTCL. Single case reports and case series with less than five patients were not reviewed to avoid anecdotal evidence of lower quality. RESULTS: The search for, and review and analysis of, the best evidence available as of February 8, 2017, suggests that CCNU and pegylated liposomal doxorubicin appear to yield the highest rate of complete remission in approximately one-third of dogs with CTCL. Other treatment protocols did not report usable information on remission rates. Without any treatment, the mean/median survival time in dogs with CTCL varied between 3 and 5 months. With CCNU protocols, the median survival time was 6 months and the one with retinoids (isotretinoin and/or etretinate), PEG L-asparaginase or prednisolone monotherapy was 11, 9 and 4 months, respectively; all these durations were obtained from small numbers of dogs, however. CONCLUSIONS: CCNU leads to a complete remission of signs in approximately one-third of dogs with CTCL, but such remissions are of short duration. The median survival time after CCNU appears longer than that without treatment, but other drugs appear to provide a better long-term prognosis. Further studies are required to investigate the effect of CCNU, alone or in combination, on remission rates, survival times and impact on quality of life.

Evaluation of intraepidermal nerve fibres in the skin of normal and atopic dogs.

BACKGROUND: Interest in intraepidermal nerve fibres (IENFs) is rising in human medicine, because variations in fibre density occur in some diseases and these neurites might contribute to disease pathogenesis. An increase in IENF density is seen in human atopic dermatitis (AD); there are no such data in atopic dogs. OBJECTIVES: To compare the prevalence of IENFs in normal and atopic canine skin. METHODS: Eight millimetre skin punch biopsies were taken from six sites of 25 healthy dogs without dermatitis and compared to lesional and nonlesional skin samples of dogs with AD (23 and 14 dogs, respectively). Thirty micrometre-thick paraffin-embedded sections were stained by indirect immunofluorescence for neuronal beta-3 tubulin. Only sections with detectable dermal nerves were then screened for the presence of IENFs. RESULTS: IENFs were identified in all 25 normal nasal planum sections, but in only one biopsy collected from each of the normal canine haired skin (NCHS) sites. As there was no significant difference in IENF prevalence between NCHS areas, they were grouped together. The rate of detection of IENFs was significantly higher (one-tailed Fisher's test, P = 0.004) in lesional AD specimens (18 of 23; 78%) than in nonlesional AD (four of 14; 29%) and NCHS specimens (four of 111; 4%, P < 0.0001). The prevalence of IENF detection in nonlesional AD samples was significantly higher than in normal canine skin (P = 0.006). CONCLUSIONS AND CLINICAL IMPORTANCE: IENFs are detected more commonly in canine AD than in normal haired skin; these results are comparable to those seen for human AD.

Autosomal recessive congenital ichthyosis due to PNPLA1 mutation in a golden retriever-poodle cross-bred dog and the effect of topical therapy.

BACKGROUND: Ichthyoses represent a genetically and phenotypically heterogeneous syndrome of abnormal epidermal cornification. Although the clinical presentation, histopathological findings and genetic cause of autosomal recessive congenital ichthyosis (ARCI) in golden retriever dogs have been well investigated, the optimal management of this disease remains uncharacterized. OBJECTIVES: In this report we describe the beneficial effect of oral and topical fatty acids for management of a golden retriever and poodle cross-bred dog (goldendoodle) with ARCI due to a PNPLA1 (Patatin-like phospholipase domain containing 1) mutation. CASE REPORT: A six-month-old, intact female, second generation golden retriever and poodle cross-bred dog presented with a history of generalized scaling since the age of 6 weeks. Histopathology showed diffuse, laminated-to-compact hyperkeratosis with a single small perinuclear vacuole in occasional stratum granulosum keratinocytes. Genetic testing revealed a homozygotic insertion/deletion mutation in the gene PNPLA1. Daily oral fatty acid supplementation and humectant rinse, following weekly moisturizing shampoo, resulted in only mild improvement after two months. Weekly application of a topical essential oils and fatty acid product was then added. Thirteen months after the initial presentation the dog exhibited a marked improvement in clinical signs. The temporal discontinuation of topical therapy resulted in the worsening of scaling, which improved again after resuming this combination. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case report of ARCI with homozygous PNPLA1 mutation in a golden retriever-poodle cross-bred dog. The long-term combination of oral fatty acids and topical therapy appeared to be beneficial in this case.