Congenital hypothyroidism in cats is a rare disease with an autosomal recessive mode of inheritance. If diagnosed at a young age, this disease can be successfully treated with thyroid supplementation (3). Kittens affected with congenital hypothyroidism have disproportionate dwarfism manifested with a broad head and short neck phenotype. Examination of the oral cavity may reveal partially erupted or unerupted permanent dentition, covered with a thickened fibrous gingiva (4, 5) and persistence of deciduous teeth (Figure 1). If suspected, hypothyroidism can be confirmed by a thyroid panel that includes the total thyroid hormone (T4), free T4 (FT4), and thyroid stimulating hormone (TSH) (4).

Hyperparathyroidism is characterized by elevated blood parathyroid hormone levels that can result in hypercalcemia and other systemic consequences (5). Primary hyperparathyroidism occurs when a functional parathyroid gland tumor, usually a functional adenoma, autonomously produces excess parathyroid hormone (PTH). Excessive secretion of PTH results in persistent hypercalcemia and hypophosphatemia (5). Vomiting, polyuria, polydipsia, lethargy, and weakness represent clinical signs of hypercalcemia and should be considered in conjunction with oral lesions. In secondary hyperparathyroidism, which results from nutritional deficiencies or chronic kidney disease, plasma total calcium concentrations are either normal or slightly decreased, and, depending on the cause, plasma phosphorus concentrations are either normal or increased (5). Secondary renal hyperparathyroidism occurs in almost all dogs and cats with advanced and end stage kidney disease (6). Nutritional hyperparathyroidism is rarely seen in domestic animals because commercial diets balance calcium and phosphorus adequately.

However, obtaining a detailed diet history for every patient is still critical with the popularity of home-cooked diets that can be nutritionally unbalanced. Regardless of the primary cause of hyperparathyroidism, the action of excess PTH is calcium and phosphorus release from the bone by osteoclastic resorption, leading to osteopenia.

Oral manifestations of osteopenia include demineralization of the jaw bones with resultant painful mastication and dysphagia, teeth mobility, and gingivitis (7). In affected patients, the alveolar and cancellous bone of the mandible and maxilla are more prone to demineralization than other sites, such as long bones, and oral manifestations are therefore present before clinical signs such as lameness. As demineralized tissue is replaced by fibrous tissue, affected bones lose stability and result in a condition known as “fibrous osteodystrophy” or “rubber jaw.” Gross enlargement of the jaws is uncommon but has been documented in young dogs with advanced congenital kidney disease due to fibrous replacement of demineralized bone, as above (8, 9). The effects of osteopenia in the oral cavity, particularly mobile teeth, can easily be mistaken for severe periodontal disease, often mimicking periodontal-endodontic lesions (10). However, patients affected by hyperparathyroidism typically exhibit minimal to mild gingivitis and normal periodontal probing depths. Radiographically, the absence of the lamina dura, widened periodontal ligament space in the absence of periodontal attachment loss, and a ground glass appearance of the trabecular bone (Figure 2) should make a clinician suspicious for hyperparathyroidism and not primary periodontal disease. Secondary hyperparathyroidism due to renal disease should be suspected if uremic ulcers are detected in addition to osteopenia (Figure 2).

The ulcers are formed due to uremic vasculopathy that develops due to urea degradation into ammonia with its direct damage to endothelial cells (11). To determine if teeth truly need to be extracted in hyperparathryoid patients, extractions should be delayed until osteopenia is resolved or improved with medical management. Hence, if suspected, hyperparathyroidism should be ruled out by obtaining a complete history, physical examination, complete blood count, biochemical profile, and diagnostic imaging.

Acromegaly is a functional disturbance of growth resulting from hypersecretion of growth hormone (GH). This syndrome has been reported in dogs and cats (12). Acromegaly in cats is usually caused by excessive production of GH by a functional acidophil (somatotroph) adenoma in the pars distalis of the pituitary gland (13, 14). Excessive GH results in the downregulation of insulin receptors and resistance to insulin action at the cellular level. Somatotroph adenomas in cats are considered to be a predisposing cause of insulin-resistant diabetes mellitus, which is difficult to control in these patients (14). Recent studies suggest that acromegaly may be present in as many as 30% of insulin-resistant diabetic cats and should be considered a differential diagnosis, especially when associated clinical features are present (14, 15). In dogs, acromegaly usually results from functional GH-producing tumors in organs other than the pituitary (5).

Clinically, acromegaly is characterized by an overgrowth of connective tissue, increased appositional growth of bones, coarsening of facial features, gingival hyperplasia, separation of teeth, macroglossia, and visceral organ enlargement. In cats, reports describe enlargement of the jaws and calvarium, resulting in a broad face and mandibular prognathism (13). Excessive soft tissue growth leads to an enlarged tongue and thickening of the soft palate and pharyngeal tissues, which can cause respiratory stridor in up to 50% of affected cats (15). The uncontrolled growth of the flat bones of the skull and mandible seen in this disease results in increased interdental spaces (12). The proliferation of joint cartilage may cause degenerative arthropathy. Kidney disease also may develop as a result of periglomerular fibrosis. Diagnosis of acromegaly requires a combination of tests, including measurements of IGF-1 (Insulin growth factor-1), GH, and intracranial imaging (14).

Diabetes mellitus (DM) occurs in patients with increased cellular resistance to insulin and/or decreased production and secretion of insulin by the pancreas. In humans, the oral manifestations of DM have been extensively researched and documented. The most prevalent clinical signs in humans include salivary dysfunction (xerostomia) and increased oral infections that may result in gingivitis, periodontitis, and oral candidiasis (16). An amplified inflammatory response to the normal flora in the oral cavity is thought to precipitate periodontitis in patients with diabetes (17). Veterinary literature investigating oral manifestations of DM in dogs and cats is limited to a single case report of a diabetic cat with root retention after dental surgery that caused subsequent sepsis and a severe systemic inflammatory response (18). The author’s clinical experience indicates that patients affected with diabetes mellitus are often presented with moderate to severe periodontitis and that dental cleaning and removal of bacterial biofilm facilitate subsequent glycemic control. It is likely that significant oral inflammation and periodontitis causes insulin resistance in some patients with DM (19). As such, thorough oral evaluation and comprehensive periodontal treatment and extraction of periodontically and endodontically affected teeth may help in the overall management of DM.

Erythema multiforme (EM) is generally an entity within a spectrum of cytotoxic epidermal diseases that also include Stevens-Johnsons Syndrome (SJS; a more severe form of EM) and toxic epidermal necrolysis (TEN; the most severe form) (20). There is no uniform consensus on the classification of these diseases, and the clinician should be aware that histopathological features cannot distinguish EM/SJS/TEN reliably, since they are very similar and differ mainly in clinical severity (21). There is also uncertainty regarding what triggers these conditions. Medications, viral, and bacterial infections were documented along with idiopathic cases, in which no such associations were found. Animals with SJS/TEN are usually presented as very sick and febrile, with leukocytosis, neutrophilia, hypergammaglobulinemia, and other serum biochemical abnormalities (22). In humans, SJS and TEN cases are separated based on the degree to which the surface area is affected, with TEN represented by skin reaction over 30% of the body surface area. The skin and mucosal lesions are typically macular erythema that progress to blisters and ulcers with exudation. Nikolsky’s sign (where epidermis sloughs with minimal shear force applied) may be present adjacent to the affected areas (23). Several biopsy samples together with the application of algorithms for drug causality, such as the Assessment of Drug Causality in Epidermal Necrolysis (ALDEN), can be helpful when evaluating suspected cases of TEN (24). In humans and animals, immediate emergency attention and aggressive supportive treatment are warranted.

Erythema multiforme is a less severe rare vesiculobullous and ulcerative skin condition that affects mucocutaneous junctions, including those in the oral cavity. Patients with EM-related oral lesions develop severe ulcerative stomatitis and glossitis (25). Based on the limited research available, approximately 30% of dogs with EM may have oral involvement (26), and there have been no reported cases of EM that are limited only to the oral cavity (27). Commonly affected areas of skin in the body with EM classically include the ventral abdomen and axillae, mucocutaneous junctions, footpads, and pinnae. EM is thought to be a hypersensitivity reaction, and the most common reported trigger in the dog has been drug therapy, including, but not limited to, penicillins and sulfonamides (28). Other suspected triggers include adverse food reactions, infection (i.e., bacterial skin infection, parvovirus), or neoplasia (i.e., splenic sarcoma, thymoma) (29). Chronic EM in old dogs is often idiopathic (30). Definitive diagnosis of EM can be challenging but is typically based on a compatible history of a known trigger, compatible clinical findings, and histopathological findings that include lymphohistiocytic lichenoid infiltrates and keratinocyte necrosis with lymphocytic satellitosis at all levels of the epidermis (25). Depending on the severity, important clinical differentials of this condition include SJS, TEN, thermal or caustic burns, epitheliotropic lymphoma, and other immune-mediated dermatoses.

Pemphigus is a group of autoimmune bullous skin diseases affecting multiple species, including dogs and cats. Pemphigus Vulgaris (PV), Pemphigus Foliaceous (PF), and Paraneoplastic Pemphigus (PNP) result from an autoimmune attack on desmosomes, leading to the breakdown of cell-to-cell adhesion in the mucosa and epidermis through acantholysis (31). When these connections are destroyed, the epithelial tissue layers separate, forming pustules, vesicles, bullae, erosions, and ulcers on the mucosa, haired skin, and mucocutaneous junctions.

Lupus Erythematosus (LE) occurs in various forms, and each specific form differs by the tissues involved and the localization and distribution of lesions. This spectrum of inflammatory disorders ranges from mild skin-limited conditions to life-threatening systemic disease (systemic LE). The classification of Lupus erythematosus is complex and includes discoid lupus (DLE), systemic lupus (SLE) and variants of cutaneous lupus erythematosus (CLE) (39). The forms most commonly affecting the oral cavity in dogs are DLE and SLE. Classically, DLE is presented with depigmentation, erythema, and scaling frequently restricted to the face, particularly the nasal planum, symmetrically around the eyes, pinnae, lips, and vulva. The lesions may progress from erythema to erosions, ulcerations and scars. Oral lesions, manifested as focal ulcers, are rare in discoid lupus erythematosus (DLE) and mucocutaneous lupus erythematosus (MCLE), with perioral lesions being more common than intraoral lesions (25). In one study of 21 dogs with MCLE, only three showed mild ulcerations in the oral cavity on the gingiva or palate (40). DLE is most commonly diagnosed in the skin, and lesions are aggravated by sun exposure. Given this, cutaneous lesions typically appear before oral lesions (25). Thus, the timing of lesion development, with skin lesions preceding oral lesions, may help in DLE diagnosis when other associated features are present. With SLE, polyarthritis, thrombocytopenia, fever of unknown origin, anemia, stomatitis, and glomerulonephritis are common manifestations, while skin lesions are actually rare (20).

Autoimmune subepidermal blistering diseases are rare chronic skin conditions in humans and companion animals. In this group of diseases, vesicles and bullae form due to antibodies targeting the adhesions between the epithelium and the basement membrane; these lesions rupture to form deep erosions and ulcers (41, 42). AISBD in dogs and cats include mucous membrane pemphigoid, epidermolysis bullosa aquisita, and bullous pemphigoid. These can be diagnosed via recognition of histopathologic features, detailed medical history, and distribution of lesions.

Feline calicivirus (FCV) is a highly contagious virus that is a common cause of upper respiratory tract infections and oral disease in cats. Outdoor cats and cats in shelters are more likely to contract the virus as it is transmitted via direct contact with saliva, respiratory secretions, and fomites (48). FCV is known to cause ulcerative lesions in the oral cavity, specifically the tongue, by inducing necrosis of the epithelial cells (49). FCV’s role in feline chronic gingivostomatitis (FCGS) is widely accepted, but a direct causal relationship has not been definitively established (50). FCGS is diagnosed based on examination of the oral cavity and distribution of lesions, which include oral pain, halitosis, and bilateral inflammation to ulceration of the gingiva, alveolar, buccal, and caudal oral mucosa, lateral to the palatoglossal arches (50, 51) (Figure 4). The diagnosis can be confirmed histologically in the lesions with feline calicivirus immunohistochemical staining using a monoclonal antibody to FCV (52). The definitive association between FCV and FCGS is difficult to demonstrate because many cats with FCV will not develop any oral lesions or may have acute manifestations with a resolution of clinical signs and lesions within a month.

Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are retroviruses that are endemic worldwide in domestic cats. Transmission of FIV occurs primarily through bite wounds from infected cats and can lead to immunodeficiency in some patients. The feline leukemia virus is spread via saliva and other secretions and may be passed from queen to offspring. Infection may result in neoplasia, myelosuppression, and immunosuppression (53). FIV and FeLV are both reported to be associated with periodontitis and stomatitis (53). Specifically, retrovirus seropositivity rates are significantly higher in cats with oral cavity inflammation than in cats with healthy oral cavities (53).

Furthermore, FIV has been found to be significantly associated with gingivitis and feline resorptive lesions compared to virus-free cats (54). It is critical to determine the viral status of cats diagnosed with FCGS as viral status negatively affects prognosis for improvement following dental extractions; cats with FeLV were 7.5 times more likely to have no improvement after extractions than virus-free cats (55). In the same study, cats with lingual ulcers were 2.7 times more likely to have a decreased response to dental extractions (55). In cats with FCGS, knowing the viral status will allow clinicians to inform clients of potential outcomes following dental extraction more accurately and prepare them for the increased likelihood of needing long-term medical management.

Bartonella is an intracellular bacteria transmitted by fleas, sandflies, or ticks to the cat. It is zoonotic and the causative agent of cat scratch fever in humans. Bartonella has been implicated in stomatitis and gingivitis, but study results have not consistently linked Bartonella seropositivity with gingivostomatitis in cats (51, 56). Currently, Bartonella is not widely believed to play a significant role in stomatitis in cats, and more research is warranted. Western blot is the diagnostic test of choice, and screening cats with stomatitis for Bartonella may be warranted, given its zoonotic potential.

Several species-specific types of Papillomaviruses infect dogs and cats. Papillomaviruses infect keratinocytes in both the haired skin and mucosa. Most infections are subclinical but may result in epithelial cell proliferation. The role of papillomavirus in the development of papillary squamous cell carcinoma has been debated in dogs and implicated in cancerogenesis in humans (57). There are currently 20 known types of canine papillomavirus (CPV). CPV3 and CPV16 strains, both Chipapillomaviruses, have been implicated in the development of squamous cell carcinoma in dogs (58). CPV-1 was once considered relatively benign, but one study demonstrated the malignant transformation of oral papillomas caused by CPV-1 into squamous cell carcinomas in multiple dogs (58). Oral manifestations of CPV include wart-like growths on mucosal surfaces in the oral cavity and the lesions can be localized anywhere from the lip margins to the pharynx. In the case of malignant transformation, there may be an invasion into the bone, leading to loss of teeth and a more considerable mass-like proliferation of tissue (Figure 5). Oral biopsies and imaging with dental radiographs and computed tomography are essential in patients with non-self-limiting or persistent lesions, especially if the lesions appear atypical for benign papillomas.

Canine distemper virus (CDV) is a Morbillivirus that affects dogs and is spread through oronasal contact via secretions and aerosol transmission. Infection in puppies prior to the eruption of permanent dentition typically leads to damage to the tooth roots, enamel, and dentin (59). Diffuse enamel hypoplasia typically results from a systemic infection, like CDV, resulting in a high fever and direct infection of the ameloblasts during enamel production. In dogs, hard tissue formation of permanent teeth occurs between birth and 8 weeks of age (60). Possible presentations include pits, fissures, and, the most commonly seen with CDV, enamel hypoplasia of the entire circumference of the crown (60). Enamel hypoplasia results in thinner than normal enamel that may appear stained tan to dark brown; an exposed area of dentin may be present, and there is often increased plaque retention due to the rough surface of the tooth (61) (Figure 6). These patients may also have missing and impacted teeth (62). All patients exhibiting enamel hypoplasia should receive cone beam CT or dental radiographs and charting. Missing teeth and malformed teeth also warrant cone beam CT or dental radiographs to detect unerupted teeth or evidence of endodontic disease.

Cryptococcosis is the most common systemic fungal infection in cats. Inhalation of spores from the environment allows the fungus to colonize the nasal passages of susceptible cats and can cause severe rhinitis (59). The nose is the most commonly affected part of the body in infected cats, with nasal discharge and facial swelling often noted on physical examination. Ulcers in the oral cavity and pharynx may also be noted along with proliferative lesions (63). Lesions on the tongue or gingiva may suggest a hematogenous spread of the infection (64). In one case report, the cat presented with oral bleeding from a proliferative and friable mass on the buccal and palatal aspect of the right maxilla. This mass closely resembled a squamous cell carcinoma in clinical presentation. However, histopathological evaluation was consistent with a fungal infection, and Cryptococcus was confirmed with PCR. Additionally, ulcerations were found on the palate of this cat, and on radiographs, there was loss of the periodontal ligament space and alveolar bone under the soft tissue proliferation (65). Diagnosis of cryptococcus in cats can be obtained with a rapid agglutination test on serum or culture of biopsied tissue from the nasal or oral cavity. A thorough fundic examination should be performed in any patient with oral manifestations of disease, especially in patients with suspected fungal disease, as associated chorioretinal lesions can commonly be present in these patients. With early detection and appropriate treatment, the prognosis for cryptococcosis is good (63).

Mucocutaneous pyoderma (MCP) is a bacterial infection that can affect mucocutaneous junctions around the mouth, eyes, nose, genitals, and anus in both dogs and cats. The only way to confirm the diagnosis is by response to antibacterial therapy. Clinically, the lesions manifest as erythema, with erosions, depigmentation, and crusting. Histologically, the inflammation is concentrated in the superficial dermis and can be pleomorphic but classically predominated by plasma cells. MCP should not have evidence of basal cell degeneration, but this cellular change may occur due to inflammation, making the distinction from DLE more challenging (25).

Von Willebrand’s disease (vWD) is the most common heritable bleeding disorder in dogs and is caused by a deficiency in von Willebrand’s Factor (vWF) (66). vWF is a glycoprotein in the endothelium that plays an essential role in primary hemostasis and platelet adhesion during blood clot formation. Three types of vWD exist, with Type 1 (normal protein structure but variably low levels) being the most common. Doberman pinschers, German shepherd dogs, and Golden retrievers are some of the breeds that are over-represented (66). Clinical signs range from absent to severe. Type II vWD is severe and has only been noted in German shorthair pointer dogs. Type III is uncommon and severe as there is a complete or near complete absence of vWF; Scottish terriers and Chesapeake Bay retrievers are overrepresented (67). Dogs with a deficiency may exhibit gingival bleeding, prolonged bleeding during oral surgery, and petechia and/or ecchymoses (67) (Figure 7).

Immune mediated hemolytic anemia (IMHA) is caused by the destruction of circulating red blood cells by the animal’s immune system and is one of the most common causes of anemia in small animals (68). IgG or IgM antibodies binding to the erythrocytes leads to immune destruction. There are many known underlying disorders and triggers for IMHA, including medications (sulfonamides, vaccines), neoplasia, infectious agents (viral, parasitic, and bacterial), and genetic predisposition (American cocker spaniel) (69). Oral symptoms associated with IMHA in dogs and cats include pallor and icteric mucous membranes. Immune-mediated thrombocytopenia is caused by immune destruction of circulating platelets by macrophages. Immune mediated thrombocytopenia (ITP) may be idiopathic or secondary to neoplasia, infectious disease, or medications (70). An increased risk of spontaneous hemorrhage occurs when the platelet count is <30,000 cells/μL (71). Oral lesions include petechia and ecchymoses on mucous membranes, pallor, and gingival bleeding that occur when platelet function or the total number in the bloodstream is affected.

Vitamin K is a fat-soluble vitamin found in green leafy vegetables, meat, eggs, and milk. It is also synthesized by microflora in the GI tract (72). The daily requirement is relatively small, and the liver is responsible for storing a few days’ worth of Vitamin K. Vitamin K is required to activate coagulation factors II, VII, IX, and X (72, 73), and deficiency results in an inability to clot the blood and subsequent hemorrhage. Anticoagulant rodenticide ingestion is in the top 10 toxicities seen in dogs (74). This toxin inhibits the recycling of vitamin K, resulting in hemorrhage within 3–5 days when the body runs out of activated coagulation factors (73). In one retrospective study of clinical bleeding in dogs that were exposed to anticoagulant rodenticide, 73% of dogs had evidence of cutaneous or mucosal hemorrhage, and 13% of dogs had bleeding in the oral cavity (73). Oral signs associated with Vitamin K deficiency include oral hemorrhage and pale mucous membranes. Other causes of deficiency include liver disease and nutritional deficiency, though this is rare considering most dogs are fed a commercial diet.

While lymphoma is one of the most common cancers in dogs, it is infrequently diagnosed in the oral cavity. In the rare cases when lymphoma does affect the oral cavity, clinical presentation may range from a single tumor to diffuse ulceration, hypopigmentation, and erythema (Figure 8). Horizontal alveolar bone loss, with near complete loss of alveolar bone, may be seen on radiographs in some cases (75). Cutaneous epitheliotropic T-cell lymphoma is an uncommon cancer seen in dogs with a highly variable clinical presentation. Lesions are standard on the skin but may also be present at mucocutaneous junctions and in the oral cavity in up to 50% of cases (76). Oral manifestations of epitheliotropic T-cell lymphoma include erosion and hemorrhage of oral mucous membranes, and lesions affecting the gingiva, tongue, and hard and soft palate (27, 76). The clinical presentation may be similar to autoimmune diseases that affect the oral cavity; thus, lymph node aspiration and cytology, biopsy, and histopathology are recommended for differentiation and prognostication.

Gingival hyperplasia is the benign overgrowth of gingival tissue in response to trauma, inflammation, certain medications, or idiopathic causes. The medications reported to cause gingival hyperplasia include immunosuppressants (cyclosporin), calcium channel blockers (amlodipine, diltiazem), and anti-seizure medications (phenytoin) (77, 78). Enlargement of the gingiva typically begins within a few months of starting medication and can be widespread throughout the oral cavity. Overgrowth of the gingiva may sometimes be relieved by adjusting the dosage or discontinuing the medication when possible (79). Medical management with azithromycin was shown to be successful in treating gingival hyperplasia secondary to cyclosporin administration in one case series (79). Otherwise, periodic periodontal treatment and gingivoplasty may be required to control the gingival hyperplasia. A biopsy of the gingival tissue is needed for a definitive diagnosis to rule out other causes of gingival enlargement. Histologically, with gingival enlargement due to cyclosporine, a band of lymphoplasmacytic infiltration in the superficial dermis is accompanied by dermal edema and fibroplasia. The gingival epithelium can be hyperplastic to eroded with prominent rete pegs and individual apoptotic keratinocytes without satellitosis. In contrast, enlargement of the gingiva as a result of other medications is predominantly fibrotic (80).

Xerostomia, or dry mouth, may be caused by commonly prescribed medications, including beta-blockers, tricyclic antidepressants, benzodiazepines, and antihistamines (81). Xerostomia is known to cause halitosis and periodontal disease in humans (82, 83).

Osteonecrosis of the jaw (ONJ) is characterized by chronically exposed and necrotic bone of the maxilla and mandible. ONJ can further be divided into osteoradionecrosis of the jaw (ORNJ) and bisphosphonate-associated osteonecrosis of the jaw (BRONJ) or medication-related osteonecrosis of the jaw (MRONJ). A history of radiation for the treatment of oral tumors is a risk factor for developing necrosis of the jaw bones (84). Administration of bisphosphonate medications, like zoledronate or anti-angiogenic agents, is associated with the development of jaw osteonecrosis in humans, dogs and cats (85–87). Regardless of the cause, ONJ can lead to exposed necrotic bone in the mouth, draining tracts, swelling, halitosis, oral pain, and dysphagia (84, 85, 88).

Maintaining good oral health in animals requires a balanced diet. Gingivitis and periodontitis have been linked to and periodontal disesase has been associated with nutritional deficiencies of vitamins A, B, C, D and E (89). There is a likely decrease in the incidence of malnutrition among domesticated dogs and cats with the availability of nutritionally balanced commercial pet food diets.