Autosomal Recessive Congenital Ichthyosis in American Bulldogs Is Associated With NIPAL4 (ICHTHYIN) Deficiency.

A minority of patients with nonsyndromic autosomal recessive congenital ichthyosis (ARCI) display mutations in NIPAL4 (ICHTHYIN). This protein plays a role in epidermal lipid metabolism, although the mechanism is unknown. The study describes a moderate form of ARCI in an extended pedigree of American Bulldogs that is linked to the gene encoding ichthyin. The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin. Pedigree analysis indicated an autosomal recessive mode of inheritance. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies. Linkage analysis, performed by choosing simple sequence repeat markers and single-nucleotide polymorphisms near genes known to cause ACRI, revealed an association with NIPAL4. NIPAL4 was identified and sequenced using standard methods. No mutation was identified within the gene, but affected dogs had a SINE element 5' upstream of exon 1 in a highly conserved region. Of 545 DNA samples from American Bulldogs, 32 dogs (17 females, 15 males) were homozygous for the polymerase chain reaction fragment. All affected dogs were homozygous, with parents heterozygous for the insertion. Immunolabeling revealed an absence of ichthyin in the epidermis. This is the first description of ARCI associated with decreased expression of NIPAL4 in nonhuman species.

Dental abnormalities associated with X-linked hypohidrotic ectodermal dysplasia in dogs.

OBJECTIVES: X-linked hypohidrotic ectodermal dysplasia (XLHED) occurs in several species, including humans, mice, cattle and dogs. The orofacial manifestations of ectodermal dysplasia in humans and mice have been extensively studied, but documentation of dental abnormalities in dogs is lacking. The current study describes the results of clinical and radiographic examinations of XLHED-affected dogs and demonstrates profound similarities to findings of XLHED-affected humans. SETTING AND SAMPLE POPULATION: Section of Medical Genetics at the University of Pennsylvania, School of Veterinary Medicine. Clinical and radiographic oral examinations were performed on 17 dogs with XLHED, three normal dogs, and two dogs heterozygous for XLHED. MATERIALS AND METHODS: The prevalence and severity of orofacial and dental abnormalities were evaluated by means of a sedated examination, photographs, and full-mouth intraoral radiographs. RESULTS: Crown and root abnormalities were common in dogs affected by XLHED, including hypodontia, oligodontia, conical crown shape, decreased number of cusps, decreased number of roots, and dilacerated roots. Persistent deciduous teeth were frequently encountered. Malocclusion was common, with Angle Class I mesioversion of the maxillary and/or mandibular canine teeth noted in 15 of 17 dogs. Angle Class III malocclusion (maxillary brachygnathism) was seen in one affected dog. CONCLUSION: Dental abnormalities are common and severe in dogs with XLHED. Dental manifestations of canine XLHED share characteristics of brachyodont tooth type and diphyodont dentition, confirming this species to be an orthologous animal model for study of human disease.

The clinical and morphologic features of nonepidermolytic ichthyosis in the golden retriever.

A scaling disorder specific to Golden Retriever dogs has been recognized by both dermatologists and pathologists, but to date has not been well characterized. At the University of Pennsylvania's Laboratory of Toxicology and Pathology, 46 cases of ichthyosis were diagnosed histologically in Golden Retriever dogs from January 2004 to January 2007. A total of 22 dogs had skin lesions documented at younger than 1 year of age; 3 dogs between 1 and 2 years of age; 13 dogs developed lesions at older than 2 years; and the time of onset was unknown for 8 dogs. A total of 25 dogs were female, and 21 were male. All dogs had strikingly similar histopathologic changes that consisted of mild to moderate laminar orthokeratotic hyperkeratosis with an absence of epidermal hyperplasia and dermal inflammation. Ultrastructural analysis using a ruthenium tetroxide fixation method was performed on punch biopsy samples from 5 dogs and compared with 2 control dogs (1 clinically and histologically normal sibling of an affected dog and 1 Cairn Terrier). All affected dogs had retained and convoluted membranes with crystalline structures in the stratum corneum. Scattered keratinocytes in the granular cell layer had prominent, clear, membrane-bound, cytoplasmic vacuoles. Pedigree analysis of 14 dogs was compatible with autosomal recessive inheritance, but incomplete dominance could not be ruled out. This unique hyperkeratotic/scaling disorder in Golden Retrievers has distinctive clinical, histologic, and ultrastructural features, which are consistent with a primary cornification defect.

Cutaneous neoplasms in pet rabbits: a retrospective study.

Over a 16-year period, 190 tumors and tumorlike lesions from 179 pet rabbits were submitted for histopathologic examination. A total of 23 different tumor types and 1 tumorlike lesion were diagnosed. The most common diagnoses were trichoblastoma, collagenous hamartoma, and Shope fibroma. Viral-induced tumors were Shope fibroma (19) and Shope papilloma (2). Common nonviral epithelial tumors included trichoblastoma (59), squamous cell carcinoma (5), squamous papilloma (4), trichoepithelioma (3), and apocrine carcinoma (3). Common mesenchymal tumors were lipoma (10), liposarcoma (3), myxosarcoma (9), malignant peripheral nerve sheath tumor (8), fibrosarcoma (7), and leiomyosarcoma (4). Malignant melanoma was diagnosed in 8 rabbits. Collagenous hamartomas were diagnosed in 26 rabbits. Mesenchymal proliferations occurred significantly more often in male rabbits than in females. Collagenous hamartomas and myxosarcomas occurred exclusively in male animals, and 3 rabbits had multiple collagenous hamartomas. Immunohistochemistry was applied in cases in which a definite diagnosis could not be reached on hematoxylin and eosin slides. Follow-up information was received in 19 cases. Carcinomas recurred (2 of 3) or metastasized (1 of 3), whereas sarcomas frequently recurred (7 of 12). One malignant melanoma (1 of 3) and one poorly differentiated round cell neoplasm recurred (1 of 1). This is the first comprehensive retrospective analysis on skin neoplasia in pet rabbits.

Adult-onset hair loss in Chesapeake Bay retrievers: a clinical and histological study.

Ten Chesapeake Bay retriever (CBRS) dogs with hair loss were recruited in collaboration with the American Chesapeake Club. All dogs had nonpruritic, noninflammatory, regionalized hair loss affecting the same areas of the body in male and female dogs. Hormonal investigations showed increased adrenal and sex steroid concentration in seven cases. Histopathology revealed follicular hyperkeratosis and plugging, follicular atrophy, and occasional melanin clumping with malformed hair shafts. This study suggests that hair loss in CBRS is a breed syndrome in which young adult dogs have hair loss characterized by unusual histological features and abnormal steroid production. A familial predisposition seems likely and selective breeding might reduce the occurrence of this condition.

A retrospective study comparing the histopathological features and response to treatment in two canine nasal dermatoses, DLE and MCP.

Canine discoid lupus erythematosus (DLE) and mucocutaneous pyoderma (MCP) have overlapping clinical and histopathological changes, often making diagnosis difficult. Histopathological features of 27 nasal planum biopsies were scored to determine whether DLE and MCP were histopathologically distinguishable. Long-term follow-up, enabling assessment of clinical diagnoses, was available on 15 cases; 11/15 cases were immunomodulatory responsive (ImR) and 4/15 were antibiotic responsive (AbR). Clinical diagnosis, determined by response to treatment for 15/27 cases, was not predictable based on scoring of histopathological features. Distinct histopathological patterns were observed: 2/11 ImR cases had a lymphocyte-rich interface dermatitis. All other cases had the same histopathological changes: a band-like diffuse superficial plasmacytic to lymphoplasmacytic dermatitis +/- focal basal cell damage, but different clinical diagnoses (4/4 AbR, 9/11 ImR). German shepherd dogs/crosses were over-represented (44.4% of the cases) and tended to have more multifocal lesions (41.7% vs. 26.7% of all other breeds). Longer duration of disease was associated with a preponderance of plasmacytic infiltrate (P = 0.026).

The pathology of spontaneous paratuberculosis in the North American bison (Bison bison).

Gross and histopathologic examinations were performed on 70 North American bison (Bison bison) from a Mycobacterium avium paratuberculosis culture-positive herd. The bison examined were part of a breeding herd totaling 2,800 animals. Eight of 70 (11%) animals had gross findings of intestinal mucosal thickening, and 16 of 70 (23%) of the animals had enlarged mesenteric lymph nodes. Histologic lesions compatible with Johne's disease were diagnosed in 30 of 70 (43%) bison on the basis of the demonstration of noncaseating granulomatous inflammatory infiltrates and of one or more acid-fast bacilli characteristic of Mycobacterium avium paratuberculosis. A suspicious diagnosis of Johne's disease was obtained in 11 of 70 (16%) bison on the basis of the observation of noncaseating granulomatous inflammatory infiltrates without demonstrable acid-fast bacteria. Twenty-nine of 70 (41%) animals were assessed as histologically paratuberculosis free. Histologic results were compared to Johne's disease tests such as culture, serology, and polymerase chain reaction, which were performed on some of the cohort animals.

Primary osteosarcoma of the synovium in a dog.

An eight-year-old, spayed female Labrador retriever was presented for evaluation of left thoracic limb lameness. Radiographs of the left elbow revealed mineralization of the soft tissues surrounding the joint, with no evidence of periarticular bony lysis. Biopsy of the synovial tissues of the left radiohumeral joint yielded a diagnosis of osteosarcoma (OSA). The dog was treated with palliative radiotherapy, piroxicam, and carboplatin chemotherapy, which resulted in excellent pain control for approximately eight months. Amputation of the affected limb was then performed. Six months later, the dog developed multiple subcutaneous OSA metastases, and the dog was euthanized 15 months after diagnosis due to refractory vomiting. This report documents the first known case of primary OSA of the synovium in any species.

Canine orbital meningiomas: a review of 22 cases.

Clinical and pathologic features of primary orbital meningiomas in the dog were reviewed. Twenty-two meningiomas, confined to the orbit, were identified from the Comparative Ophthalmic Pathology Laboratory of Wisconsin from 1981 to 1997. The dogs ranged in age from 3 to 17 years (mean = 9.2 years). The clinical presentation, reported in 20 cases, was indicative of a retrobulbar mass and included exophthalmos and orbital swelling (18/20), and papilledema or abnormalities of the posterior segment (7/20). Visual acuity was reported in 15 cases; of those, 12 dogs were blind in the affected eye. Follow-up information was obtained on 17 cases; six dogs developed local recurrence of the neoplasm. Two dogs with recurrent neoplasms simultaneously developed blindness in the opposite eye. Extension along the optic nerve to the optic chiasm was suspected. No metastasis was found at the time of the study. Enucleation with excisional biopsy was effective therapy to date in 11 cases (0.2-4.5 years follow-up time). All neoplasms were located within the vicinity of the optic nerve and, when sectioned through the optic nerve head, appeared to completely envelope the nerve. The neoplastic cells were arranged in tight whorls and bundles characteristic of meningiomas. Most tumors had islands of chondroid and osseous metaplasia (17/22). Ocular invasion was limited to small foci in the posterior choroid or optic nerve head of six dogs. Immunoperoxidase stains on 10 cases were positive for vimentin and S-100, but negative for cytokeratin. Electron microscopy revealed complex interdigitations between cell membranes and few desmosomal intercellular attachments. Primary orbital meningiomas have a characteristic histologic appearance and may recur locally after surgical excision.

Prednisone and vinblastine chemotherapy for canine mast cell tumor--41 cases (1992-1997).

Forty-one dogs with mast cell tumors (MCTs) were treated with oral prednisone and injectable vinblastine (VBL), both in the adjuvant setting (23 dogs) and in dogs with gross disease (18 dogs). Adverse effects were noted in 20% (8/41) of the patients, usually after the 1st dose of VBL. Adverse effects were considered mild in 6, and severe, necessitating treatment discontinuation, in 2 (5%). Overall response rate in the evaluable dogs with gross disease was 47% (7/15), consisting of 5 complete responses and 2 partial responses. Median response duration was 154 days (24 to >645 days). As adjuvant therapy to incomplete surgical resection, prednisone and VBL conferred a 57% 1- and 2-year disease-free rate. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade III MCT was 331 days, with 45% of dogs alive at 1 and 2 years. This is an apparent improvement over historical survival data employing surgery alone. Upon univariate analysis, significant prognostic factors (P < .05) for survival included presence of a locally recurrent tumor, presence of gross disease, argyrophilic nucleolar organizer region frequency, lymph node status, histologic grade, previous chemotherapy, and ulceration of the tumor. Similar criteria were significant when analyzed for time to treatment failure. Response to therapy was also predictive of survival in the gross disease group. Upon multivariate analysis, histologic grade (P = .012) and presence of a locally recurrent tumor (P < .001) were significant factors for survival.

Evaluation of somatostatin analogues for the detection and treatment of gastrinoma in a dog.

Gastrinomas in dogs are difficult to diagnose, localise and treat. In humans, somatostatin analogues have improved localisation and treatment of gastrinomas. The somatostatin analogues pentetreotide and octreotide were evaluated for the detection and treatment of gastrinoma in a dog. 111indium-pentetreotide scintigraphy revealed multiple areas of activity in the patient's mid-ventral abdomen which were consistent with masses in the pancreas and liver at laparotomy. Immunohistochemistry, electron microscopy and binding of 125I-[Tyr3]-octreotide in vitro confirmed the lesion as a gastrinoma which expressed somatostatin receptors. Octreotide at doses of 2, 4 and 8 micrograms/kg caused transient decreases in circulating gastrin. Plasma somatostatin peaked at one hour after octreotide and was still detectable at four and six hours after administration of octreotide. Combination therapy with famotidine, omeprazole, sucralfate and increasing doses of octreotide allowed patient survival for 14 months.