The oral cavity plays a critical role in numerous physiologic processes, including digestion, respiration, and speech. It is also unique for the presence of teeth and mucosa. The mouth is frequently involved in conditions that affect the skin, but it is also affected by many systemic diseases. Oral involvement may precede or follow the appearance of findings at other locations.
This article is intended as a general overview of conditions with oral manifestations of systemic diseases. It is not intended to provide details about the diagnosis and management of these conditions. Many of these conditions have excellent full-length Medscape Drugs & Diseases articles, which are linked herein.
The oral cavity is the portal of entry to the GI tract and is lined with stratified squamous epithelium. The oral cavity is often involved in conditions that affect the GI tract. Both ulcerative colitis (UC) and Crohn disease are classified as inflammatory bowel disease (IBD). While Crohn disease can affect any part of the GI tract (from the oral cavity to the anus), inflammation in UC is generally restricted to the colon and is specifically limited to the mucosa and submucosa.
UC is characterized by periods of exacerbation and remission, and, generally, oral lesions coincide with exacerbations of the colonic disease. Lesions in the colon consist of areas of hemorrhage and ulceration, along with abscesses. Cutaneous involvement consists of similar ulcerations that may arise on the buttocks, abdomen, thighs, and face, although in rare cases patients may develop pyoderma vegetans. [1, 2] In the oral cavity, aphthous ulcers or angular stomatitis occurs in as many as 5-10% of patients, although hemorrhagic ulcers can occur.  Rarely, patients can develop pyostomatitis vegetans (PSV), the oral counterpart of pyoderma vegetans.
Also see Ulcerative Colitis.
Crohn disease is an idiopathic inflammatory disorder that can involve the entire GI tract with transmural inflammation and noncaseating granulomas. The prevalence of Crohn disease varies significantly between populations. In North America, the incidence of Crohn disease can be as high as 20.2 cases per 100,000 population.  Although formerly considered a disease of Western nations, the incidence is rising in Asia. Similarly, it has long been observed that the incidence of Crohn disease is higher at northern latitudes than at southern latitudes.  There is a well-documental bimodal age distribution associated with the onset of Crohn disease: the peak incidence occurs in the second and third decades of life, with a second, smaller peak in the sixth and seventh decades.  Genetics have also been implicated in the development of the disease since certain populations (ie, Ashkenazi Jewish populations) have a much higher risk for the development of the disease; more recently, Crohn disease‒associated genetic loci have been identified.  Changes to the gut microbiome and various environmental risk factors (including smoking, hygiene, and dietary practices) have also been implicated in the disease’s onset or progression. 
Symptoms of Crohn disease include intermittent attacks of diarrhea, constipation, abdominal pain, and fever.  Patients may develop malabsorption and subsequent malnutrition.  Systemic features of Crohn disease include arthritis, clubbing of the fingers, and sacroiliitis. 
Skin findings include knifelike fissures and ulcerations, as well as fistulae. Vulvar manifestations, such as fissures, edema, tenderness to palpation, and nonspecific aphthae, have also been reported.  Cutaneous manifestations of Crohn disease may also be noncontiguous: metastatic Crohn disease is defined as a granulomatous inflammation of the skin that is not contiguous with the GI tract. Although well described, metastatic Crohn disease may present a diagnostic challenge since its clinical presentation is quite variable and may occur without a history of GI disease.  Nonspecific, reactive skin findings in patients with Crohn disease include erythema nodosum, pyoderma gangrenosum, and Sweet syndrome. 
Intraoral involvement occurs in up to 50% of patients with Crohn disease and may precede intestinal involvement.  Oral manifestations can prove crucial in diagnosis and usually parallel the intestinal disease course.  The severity of oral lesions may indicate the severity of the systemic disease and, as such, may be used as a marker for intestinal impairment.  However, oral lesions identified following the diagnosis and control of Crohn disease may not always reflect recurring intestinal disease, but rather treatment adverse effects. [7, 10]
Specific oral findings of Crohn disease include diffuse lip, gingival, or mucosal swelling; cobblestoning of the buccal mucosa and gingiva; mucosal tags; and fissures at the angles of the mouth. [11, 12] These lesions are considered specific, because histologic examination reveals evidence of noncaseating granulomatous change. [2, 11, 12] For example, lip fissures may initially resemble angular cheilitis, but often is identified by histology as granular cheilitis.
Oral granulomas may occur in isolation, without GI involvement. However, the term orofacial granulomatosis is not specific to Crohn disease, but rather encompasses a variety of other disorders, including sarcoidosis, Melkersson-Rosenthal syndrome, and tuberculosis.  Thus, it is not surprising that some patients with orofacial granulomatoses may subsequently develop intestinal manifestations of Crohn disease, but histologic similarities between the oral lesions and the intestinal lesions are evident.
Nonspecific oral findings of Crohn disease (ie, lesions for which histology does not reveal granulomatous change) are more common than the specific oral findings.  They include PSV, which is discussed in a separate section below, and aphthous ulcers. Approximately 5% of patients with Crohn disease have aphthous ulcers, which are indistinguishable from classic aphthae.  Of note, patients may also develop dental caries. 
Patient-reported symptoms may include significant pain, impaired speech, or difficulty eating secondary to gingival and mucosal swelling, ulcers, or fissures. Patients who present with oral findings suggestive of Crohn disease warrant a full systemic evaluation, including referral for colonoscopy and biopsy with histopathologic correlation. The most common histologic findings in both oral and intestinal Crohn disease are noncaseating granulomas and both acute and chronic inflammation with lymphocytic and giant cell perivascular infiltrates.
Also see Crohn Disease.
Although relatively rare, most PSV cases occur concurrently with either Crohn disease or UC.  As such, PSV is considered a specific finding of IBD, and its presence can precede GI symptoms by months or years.  PSV presents as pustules that result in a “snail track” appearance, erosions, and vegetations involving the labial mucosa of the upper and lower lips, buccal mucosa, and gingival mucosa. While the tongue and floor of the mouth are generally spared, the filiform and fungiform lingual papillae may be atrophic. [2, 12, 16] PSV also affects mucosal membranes in the vagina, nasal passages, and periocular region.  Symptoms such as pain and burning may be severe or negligible.  Histologic examination reveals intraepithelial and subepithelial eosinophilic miliary abscesses. 
Although gastroesophageal reflux is physiologic and occurs in healthy individuals, gastroesophageal reflux disease (GERD) is defined as recurrent regurgitation of acidic gastric contents (pH 1-2) that causes damage to the esophageal mucosa and structures within the oral cavity. GERD has a prevalence of 18-28% in the United States.  The etiology of GERD varies among individuals, but it may be due to slackening of the lower esophageal sphincter, increased intra-abdominal pressure, or delayed gastric emptying. Obesity has been shown to significantly increase one’s risk of developing GERD. 
Patients with GERD commonly report heartburn, chronic cough, sore throat, globus (lump in the throat), dysphagia, and odynophagia.  If untreated, GERD may lead to erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma.  There are no cutaneous manifestations of GERD.
Regurgitation of gastric contents is not only caustic to the esophageal mucosa, but because the pH of the oral cavity may fall below 5.5, it has been associated with nonspecific burning oral sensation, mucosal erosions and ulcerations, halitosis, and both xerostomia and hypersalivation. [19, 20]
In terms of dentition, chronic exposure to acidic fluids in the oral cavity results in dissolution of the tooth surfaces (dental erosion). This is in contrast to labial enamel erosion seen with exposure to sucking on lemons or in patients with bulimia who are often in the habit of brushing their teeth after purging, which results in a labial or facial loss of enamel.
Enamel erosion due to gastric fluid exposure is most commonly seen on the palatal surfaces of the maxillary teeth.  Erosion of the enamel exposes the underlying dentin, which is softer and more opaque yellow. The extent of erosion depends on the frequency and quantity of exposure, along with the duration of disease. Newly exposed dentin is smooth and shiny, while previously exposed dentin may be stained. Exposed dentin is often sensitive to temperature changes, and, because of its lower mineral content, it may develop caries more quickly.  Enamel and dentin erosion results in hard, dished-out areas where enamel has dissolved and the underlying dentin is exposed. On the other hand, caries result from the bacterial breakdown of sugars into acid, which demineralizes the enamel surface of the teeth and thus exposes underlying dentin that then is also demineralized.  The prevalence of caries is not increased in persons with GERD, possibly because the acidic environment interferes with the formation of the dental bacterial biofilms.
Good dental care and control of acid helps decrease the prevalence of erosion. However, once the erosion occurs, it is irreversible and can only be treated with restorative procedures. Therefore, early recognition and patient education is the most effective treatment. The most effective medical therapy for GERD in adults is proton pump inhibitors (PPIs), although H2-receptor antagonists are also beneficial.  Patients may also benefit from decreased consumption of acidic foods and beverages.  Patients with xerostomia should consider discontinuing medications that may exacerbate hyposalivation or use a salivary supplement. 
Also see Gastroesophageal Reflux Disease.
Chronic liver disease
The liver has numerous synthetic, storage, and excretory functions. The liver synthesizes many of the coagulation factors necessary for hemostasis. In addition, adequate liver function is required for intestinal absorption of vitamin K, a fat-soluble vitamin critical to the formation of numerous clotting factors. The liver also is responsible for the metabolism of circulating estrogens and the secretion of bilirubin, a product of normal heme catabolism. The hepatic portal vasculature is also an important component of the circulatory system, which enables the immediate processing of nutrients absorbed in the small intestines.
Numerous infections, inflammatory diseases, environmental (or iatrogenic) exposures, addictive behaviors, and idiopathic conditions cause damage to the liver. Chronic liver disease (CLD) refers to liver disease lasting 6 months or longer and is generally the result of damage to, and fibrosis of, liver architecture, known as cirrhosis. In the United States, the prevalence of CLD is approximately 15% and has been steadily increasing since the 1980s.  Major causes include chronic hepatitis C, chronic hepatitis B, alcoholic liver disease, and nonalcoholic fatty liver disease, although countless other conditions can cause CLD.  CLD is a leading cause of mortality and morbidity both in the United States and around the world. 
The systemic manifestations of CLD are numerous and beyond the scope of this article. They can be classified as those due to synthetic dysfunction (eg, coagulopathies, hypoalbuminemia), portal hypertension (eg, ascites, esophageal varices, hemorrhoids), bilirubin secretion (eg, jaundice), increased circulating estrogen (eg, gynecomastia, testicular atrophy), as well as more complex syndromes including hepatorenal syndrome and hepatopulmonary syndrome. [26, 27]
Cutaneous manifestations due to CLD are well documented. Patients may present with spider nevi due to estrogen excess, easy bruising or petechiae secondary to coagulopathies, jaundice, or caput medusa, which is pathognomonic for portal hypertension. 
Oral manifestations are also common in patients with CLD. For example, due to coagulopathies, patients may have petechiae on the mucous membranes or excessive gingival bleeding with minor trauma, often in the absence of inflammation.  Therefore, special care must be taken during any type of surgery, oral or otherwise, as the patient is at high risk for severe hemorrhage.
Jaundice may also appear in the oral mucosa due to the yellow pigmentation that results from deposition of bilirubin into the submucosa.  Of note, because the sublingual and soft palate mucosae are very thin, they are often first to show a yellow hue.  Examination of these regions may provide useful diagnostic clues in patients with darker skin or physiologic conjunctival pigmentation.
Owing to its high rate of progression to chronic hepatitis and cirrhosis, hepatitis C is one of the leading causes of CLD worldwide. [31, 32, 33] Meta-analyses show that patients with hepatitis C virus (HCV) infection have a 2.5- to 4.5-fold increased risk of developing lichen planus (LP). [31, 32]
LP is a mucocutaneous disorder with a prevalence estimated between 0.4-4% in the general population. [34, 35] Notably, however, the association between HCV infection and LP is greater in Europe and Asia than it is in the United States. [31, 32]
Cutaneous lesions are classically pruritic, violaceous, polygonal papules and often present on the trunk or extremities, although nail, vulvar mucosal, and oral mucosal involvement can be significant. 
Oral manifestations of LP are more common in women aged 30-70 years. [37, 38] Oral LP may be classified based on clinical presentation. Reticular LP, the most common form, presents as white papules or plaques on a bed of erythema with Wickham striae. [38, 39] The buccal mucosa, tongue, and gingivae may be involved. It is generally asymptomatic.  Other less common forms of LP include erosive LP, erythematous (or atrophic) LP, and papular (or plaquelike) LP. [38, 39] Rarely, bullous LP may be observed.  Histology reveals a bandlike lymphocytic infiltrate with a saw-tooth appearance of the rete ridges, as well as parakeratosis, acanthosis, and orthokeratotic hyperkeratosis.  Colloid bodies and Max-Joseph spaces are also classic findings more specific to LP. 
While the diagnosis of LP should be considered in patients with HCV infection presenting with oral or cutaneous lesions, screening patients with LP for HCV or CLD remains controversial. Physicians should use their clinical judgment based on findings from a comprehensive medical history, including exposures to HCV risk factors, and a thorough physical examination.
Also see Hepatitis C.
Vitamins and minerals are essential to maintain the epithelial surfaces of the human body. As a result, nutritional deficiencies often result in impairments in the integrity of skin and mucous membranes.  Nutritional deficiencies can be indicators of latent disease, and every effort should be made to identify the cause of the deficiency. Some deficiencies result from a reduced intake due to poor diet, fatty diets, alcohol or drug addiction, or psychiatric disease, such as anorexia nervosa or bulimia nervosa. Other deficiencies may result from failure to absorb ingested vitamins and minerals due to pancreatic insufficiency, infectious agents, enzyme deficiencies, GI disease, systemic diseases, and intestinal resection or radiation. Finally, nutritional deficiencies can also result from increased host demand, such as in the case of gravid women.
Of course, each nutritional deficiency (or toxicity) has unique etiologies, epidemiologic characteristics, and systemic and cutaneous signs and symptoms, the details of which are beyond the scope of this article. Please consult the cited references for more information.
Water-soluble vitamins include vitamin B-2 (riboflavin), B-3 (niacin), B-5 (pantothenic acid), B-6 (pyridoxine), B-7 (biotin, vitamin H), B-9 (folic acid), B-12 (cobalamin), and C (L-ascorbic acid).  These vitamins are stored in the body in limited quantities and therefore require regular replenishment through dietary intake. Thus, hypervitaminosis of water-soluble vitamins is rare. Water-soluble vitamin deficiencies with oral manifestations are listed in Table 1. Currently, there are no known oral manifestation of vitamin B-5 (pantothenic acid) or B-7 (biotin, vitamin H) deficiencies.
Table 1.Oral Manifestation of Water-Soluble Vitamin Deficiencies (Open Table in a new window)
|Vitamin Deficiency||Oral Manifestations||References|
|Vitamin B-2 (riboflavin, lactoflavin) deficiency||
||Schlosser et al |
|Vitamin B-3 (niacin, nicotinic acid) deficiency (pellagra)||
||Schlosser et al,  Boyd and Palmer |
|Vitamin B-6 (pyridoxine, pyridoxal, pyridoxamine) deficiency||
||Schlosser et al |
|Vitamin B-9 (folic acid, folate) deficiency||
||Schlosser et al,  Kozlak et al |
|Vitamin B-12 (cobalamin, cyanocobalamin) deficiency||
||Schlosser et al,  Kozlak et al,  Field et al |
|Vitamin C (ascorbic acid, L-ascorbic acid, ascorbate) deficiency, also known as scurvy||
||Schlosser et al,  Leggott et al,  Yasui et al |
Vitamins A, D, E, and K are fat soluble and thus are readily stored in the body.  While these reservoirs successfully prevent against deficiencies, the resultant risk of hypervitaminosis is increased. There are no oral manifestations vitamins E, D, or K toxicity or vitamin E deficiency. Oral manifestations of fat-soluble vitamin deficiencies and toxicities are listed in Table 2.
Table 2. Oral Manifestation of Fat Soluble Vitamin Deficiencies and Toxicities (Open Table in a new window)
|Vitamin Deficiency/Toxicity||Oral Manifestations||References|
|Vitamin A (retinol) deficiency||
||Schlosser et al |
|Vitamin A (retinol) toxicity||
||Schlosser et al |
|Vitamin D (calciferol, cholecalciferol, ergocalciferol) deficiency||
||Schlosser et al,  Khabbazi et al,  Holick and Chen |
|Vitamin K (phylloquinone) deficiency||
||Schlosser et al |
Minerals are crucial to numerous cellular functions and deficiencies have been associated with many systemic diseases. Minerals such as calcium and magnesium have been associated with periodontal disease.  Additional oral manifestations of mineral deficiencies are listed in Table 3.
Table 3. Oral Manifestation of Mineral Deficiencies (Open Table in a new window)
||Schlosser et al,  Sun et al,  Zimmermann and Hurrell |
||Cho et al,  Orback et al,  Nakano et al,  Epstein and Barasch,  Hambidge and Krebs |
Hematologic malignancies and blood cell dyscrasias are a remarkably diverse collection of diseases with numerous systemic sequelae. The etiology, diagnostic criteria, prognosis, and treatment of each condition is unique and complex. As such, a complete analysis is not within the scope of this review. The oral manifestations of numerous hematologic disorders are summarized. Please refer to the references for more detailed information. 
White blood cell disorders
Leukemia is a white blood cell malignancy that manifests as an increased number of circulating immature leukocytes. Leukemias represent 3.6% of all new cancer diagnoses. In 2016, it is estimated that there will be over 60,000 new diagnoses of leukemia and nearly 25,000 deaths from leukemia.  The incidence of leukemia is higher in men than in women of all racial backgrounds and is higher in whites than in African Americans or Latinos. 
Leukemias are classified by their clinical course (acute or chronic) and the progenitor cell lineage primarily effected (lymphoid or myeloid). [60, 61] Systemically, dysregulated leukocyte proliferation results in a suppression of normal hematopoiesis, often leading to anemia and thrombocytopenia. Of course, as leukocytes are a critical component of the immune system, patients with leukemias are also at increased risk of infection. Cutaneous manifestations include leukemic skin infiltrations (leukemia cutis), as well as nonspecific lesions (eg, cutaneous infections, vasculitis, purpura, paraneoplastic pemphigus, Sweet syndrome) or therapy-induced lesions (eg, drug reactions, graft vs host disease). [62, 63]
Oral manifestations are more common in acute leukemias than in chronic leukemias.  Gingival hypertrophy and hyperplasia are most commonly associated with acute myelogenous leukemia and acute promyelocytic leukemia.  The gingiva are friable, edematous, and erythematous. [65, 66] Thrombocytopenia commonly manifests as petechiae and ecchymoses on the mucosal surfaces of the mouth, as well as spontaneous gingival bleeding. 
Chemotherapeutic drugs may cause diffuse oral ulceration, also known as mucositis, which is often mistaken to herpes simplex virus (HSV) or cytomegalovirus (CMV) infection.  It is important to distinguish between ulcer etiologies so appropriate treatment can be initiated. Chemotherapeutics used to treat leukemias are often immunosuppressive agents and, thus, increase the risk for secondary viral, fungal, and bacterial infections in the oral cavity. 
Neoplasms of lymphoid tissue and lymphoid precursors are a diverse group of malignancies, known collectively as lymphomas. In 2008, the World Health Organization (WHO) classified these lymphomas as Hodgkin lymphoma, mature B-cell neoplasms, mature T-cell and natural killer cell neoplasms, histiocytic and dendritic cell neoplasms, and posttransplantation lymphoproliferative disorders (PTLDs).  Hodgkin lymphoma accounts for 0.5% of new cancer diagnoses, while the non-Hodgkin lymphomas accounts for 4.3% of new cancer diagnoses, making them the seventh most common cancer in the United States. [69, 70]
Systemic manifestations, aside from local tumor invasion and metastatic spread, include nonspecific signs such as anemia, fever, and weight loss.
Cutaneous manifestations of Hodgkin lymphoma include cutaneous Hodgkin disease, eczema, pruritus, and erythema nodosum.  Oral manifestations of Hodgkin disease are uncommon, although they may develop secondary to chemotherapeutics.
Certain subtypes of non-Hodgkin lymphomas, such as cutaneous T-cell lymphoma, Burkett lymphoma, and AIDS-associated lymphoma, are commonly associated with both cutaneous and oral manifestations and are discussed individually. When oral involvement is noted with non-Hodgkin lymphomas, the lymphoid tissues of the Waldeyer ring are preferentially affected, although palatal and buccal mucosal involvement is possible. Lymphomas in the oral cavity are generally described as painless, soft masses, with or without traumatic ulceration. 
Cutaneous T-cell lymphoma is a malignant proliferation of T cells, which frequently involves the skin. Although cutaneous and lymph node involvement is most common, oral lesions have been observed in a minority of patients.  Oral manifestations include ulcerated plaques or solid tumors on the gingiva, palate, or tongue.  Histologic examination reveals a dense inflammatory infiltrate with atypical lymphocytes and Darier-Pautrier microabscesses.  Oral lesions represent advanced disease and indicate a poor prognosis. 
An aggressive B-cell lymphoma, Burkitt lymphoma is associated with Epstein-Barr virus (EBV). Burkett lymphoma can be classified as one of three subtypes: endemic, sporadic, or immunodeficiency-related. Burkett lymphoma generally presents as a rapidly enlarging mass, frequently involving the head and neck.  The oropharynx, maxilla, and mandible are common sites of soft tissue and bone destruction, which may lead to painful loosening of the teeth and paresthesias of the face. [73, 74]
Lymphoma in HIV-positive individuals is considered an AIDS-defining illness. [75, 76] Oral involvement in AIDS-associated lymphoma is estimated at approximately 3%. [75, 76] While Burkitt lymphoma is an AIDS-associated lymphoma, falling under the immunodeficiency-related classification, oral manifestations have been noted in large B-cell lymphomas as well as plasmablastic lymphomas.  These AIDS-associated lymphomas may present with masses or ulcers that involve the gingiva, palate, tonsils, tongue, and lower jaw. 
Cyclic neutropenia is a rare disorder due to an inherited or sporadic mutation in the neutrophil elastase gene (ELANE), which is located on band 19p13.3. [77, 78] Cyclic neutropenia is associated with the 162800 phenotype of the OMIM database.  The disease is characterized by periodic (21-d cycles) failures of hematopoiesis, leading to neutropenia, as well as decreased monocyte, eosinophil, lymphocyte, platelet, and reticulocyte counts. [79, 80, 81] These failures lead to transient recurrent fevers, malaise, and recurrent infections that may be life threatening.  Onset of symptoms occurs in childhood and may improve as the patient approaches adulthood. 
Cutaneous manifestations are generally due to poor immune function and include skin infections and abscesses.  Oral manifestations are present in over 90% of patients with cyclic neutropenia.  In one series, investigators found that 94% have recurrent ulcers similar to recurrent aphthous stomatitis.  These ulcers vary in size and may be found on the buccal mucosa, lips, tongue, and pharynx. [82, 83] They generally present during periods of neutropenia and resolve within 1-2 days once neutrophil counts rebound.  Patients with cyclic neutropenia also have recurrent gingivitis, which is generally worse during periods of neutropenia but can persist even if the neutrophil count is within normal limits.  This gingivitis may result in periodontitis, with alveolar bone loss and loosening of the teeth, as well as mucosal scarring. 
Although lifelong morbidity is a feature of cyclic neutropenia, mortality due to severe infections is relatively uncommon.  Granulocyte colony-stimulating factor (G-CSF) can be used to improve neutrophil counts and reduce morbidity.  Patients should also be diligent about oral hygiene to reduce the risk of intraoral infection.
Langerhans cell histiocytosis
Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is a condition of unknown etiology characterized by an abnormal proliferation of histiocytes and eosinophils. [85, 86] LCH may manifest as solid, localized tumors or as multiorgan disease. LCH is most common in pediatric populations, with a peak incidence in children aged 1-3 years.  Still, it is estimated that 1-2 million adults per year are diagnosed with LCH. 
The most common form of LCH is an eosinophilic granuloma, which presents as localized, lytic bone lesions and is generally benign.  Skin lesions are rare in this form.  In contrast, oral swellings or ulcerations resulting from mandibular or maxillary bone involvement are common. 
In multisystem disease, bone lesions are still the most common finding, although cutaneous involvement is seen in about one third of patients.  Skin lesions may include dry, scaling skin on the scalp, erythematous rashes in intertriginous regions, or diffuse, papular rashes on the trunk and extremities.  Oral ulcerations may develop on the gingiva or palate, along with a necrotizing gingivitis.  Rarely, oral involvement may occur without underlying bone destruction, such as in the floor of the mouth. Solitary oral lesions may be part of a multisystem disease or may be an early sign of disease reactivation. 
A biopsy specimen reveals the pale Langerhans cells with bilobed nuclei, which resemble coffee beans. Clusters of eosinophils also may be present. Electron microscopic findings reveal the classic Birbeck granule. Biopsy is essential for accurate diagnosis as oral ulcerations are nonspecific and have a broad differential.  Radiologic findings demonstrate rapid, progressive alveolar bone loss with dental extrusion, producing the characteristic appearance of "floating teeth”.  These lesions result in fractures and displaced teeth. 
Two other forms of LCH may also be associated with oral manifestations: Letterer-Siwe disease and Hand-Schüller-Christian disease.
Letterer-Siwe disease is most common in infants and is highly aggressive. Histiocytes can infiltrate the liver, spleen, or bone marrow, creating significant systemic complications. Mucocutaneous nodules and ulcerations are common. Oral symptoms include large ulcerations, ecchymoses, gingivitis, periodontitis, and subsequent tooth loss. 
Hand-Schüller-Christian disease is a more localized variant, with skin and oral lesions similar to those in Letterer-Siwe disease. The classic triad of osteolytic defects, diabetes insipidus, and exophthalmos is pathognomonic, although the majority of patients do not present with all three features of this triad.  Oral manifestations may be the primary manifestation of Hand-Schüller-Christian disease and include irregular ulcerations of the hard palate, gingival inflammation, difficulty in chewing, and halitosis. 
Also see Langerhans Cell Histiocytosis.
Multiple Myeloma is a malignancy of plasma cells, which leads to suppression of normal hematopoiesis and the production of abnormal antibodies, called paraproteins. Multiple myeloma accounts for 1.3% of new cancer diagnoses and 1.9% of all cancer deaths. 
Cutaneous manifestations in multiple myeloma are rare, although multiple myeloma has been associated with certain paraneoplastic conditions, including erythema gyratum repens and pityriasis rotunda. 
Patients often present with osteolytic lesions, and about 30% of patients have mandibular involvement, with associated swelling, pain, paresthesias, and tooth loss.  Approximately 14% of patients have oral manifestations, which include gingivitis, periodontitis, and dome-shaped masses with a tendency to ulcerate. [41, 92, 93] Thrombocytopenia secondary to hematopoietic suppression can result in ecchymoses and gingival bleeding.
Also see Multiple Myeloma.
Mastocytosis is a rare myeloproliferative neoplasm, estimated to affect about 10 in 100,000 people.  Mast cells are granulocytes that play a critical role in immune responses, especially allergy and anaphylaxis, so their pathologic proliferation can result in a wide array of clinical presentations. [95, 96, 97, 98]
There are numerous subclassifications of mastocytosis, including mastocytosis in the skin, indolent systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic non‒mast cell disorder, and mast cell leukemia and sarcoma. 
Systemic mastocytosis is an abnormal proliferation of mast cells that subsequently invades various organs and releases cellular mediators, such as interleukins and histamine, which results in systemic symptoms including headache, urticaria, diarrhea, flushing, and anaphylaxis. 
Infiltration of the salivary glands can result in a Sjögren-like sicca syndrome, characterized by xerostomia and associated complications. [97, 98] While oral manifestations are rare relative to involvement of long bones or ribs, painful osteolytic lesions of the mandible or maxilla have been reported. [95, 96]
Also see Mastocytosis.
Thrombocytopenia is defined as a reduced number of circulating platelets, generally below 150,000/µL.  Since platelets play an integral role in the maintenance of hemostasis, thrombocytopenia leads to an increased risk of bleeding. There are numerous causes of thrombocytopenia, including autoimmune destruction, splenic sequestration, bone marrow infiltration by tumor cells, infection, and drug reactions.  As a result, it is difficult to estimate the incidence and prevalence of thrombocytopenia in the general population.
Systemic manifestations of thrombocytopenia largely depend on the underlying etiology. In general, mild thrombocytopenia (100,000-150,000/µL) or moderate thrombocytopenia (50,000-99,999/µL) results in increased bleeding following what would generally be considered mild trauma.  Severe thrombocytopenia (<50,000/µL) may result in an increased risk for spontaneous bleeding, although no direct correlation exists between platelet number and bleeding risk. [100, 101] Cutaneous manifestations of thrombocytopenia include easy bruising, petechiae, and—in the case of heparin-induced thrombocytopenia—skin necrosis. 
In the oral cavity, petechiae and ecchymoses may be visible on the soft palate and buccal mucosa.  Gingival bleeding is common and often spontaneous.  Hemorrhagic bullae that appear as deep‒red-to-violaceous or black blisters may appear on mucosal surfaces in cases of severe thrombocytopenia. 
Red blood cell disorders
Common anemias associated with oral manifestations include iron-deficiency anemia and macrocytic anemia secondary to B-12 deficiency. Please refer to Tables 1 and 3 to see the specific oral manifestations of iron and B-12 deficiency. Of note, all forms of anemia can result in mucosal pallor.
Hemochromatosis, a syndrome of systemic iron overload, may be caused by hereditary hemochromatosis, transfusional iron overload, chronic hemolysis, or excess dietary iron.  Hereditary hemochromatosis, of which there are five subtypes, is the most common genetic disease among individuals of northern European descent. Of these five subtypes, hemochromatosis type 1 (OMIM #235200) is the most common, with population studies in the United States indicating a frequency of homozygosity at about 0.3%. [104, 105]
As iron is deposited in the tissues of the body, organ function may be disrupted. Common systemic sequelae include liver cirrhosis, cardiomyopathy, arthritis, and various endocrinopathies.  Cutaneous manifestations of hemochromatosis include skin hyperpigmentation resulting in the classic “bronzed” appearance. 
Oral manifestations are observed in approximately 15-25% of patients. In the majority of these patients, there is a blue-gray hyperpigmentation of the oral mucosa.  The most commonly affected sites are the buccal mucosa and gingiva, although a minority of patients have diffuse, homogenous pigmentation of the oral cavity. [41, 106, 107] Histologic examination with Prussian blue stain reveals iron mineral deposits. 
Also see Hemochromatosis.
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria (OMIM #263700) is a rare, autosomal recessive disease caused by a mutation in the UROS gene, which encodes uroporphyrinogen III synthase.  This enzyme defect disrupts heme biosynthesis and leads to an accumulation of uroporphyrin in erythrocytes, which, in turn, increases their osmotic fragility and results in hemolysis. 
The classic primary manifestation of congenital erythropoietic porphyria is pink-red discoloration of the urine in infancy or childhood.  However, the clinical phenotype and severity of symptoms vary greatly and include nonimmune hydrops fetalis in utero, scarring and deformities, hemolytic anemia, corneal scarring, and blindness. Cutaneous manifestations include severe photosensitivity with blistering hypertrichosis. 
In the oral cavity, erythrodontia, a red-brown discoloration of the teeth, is pathognomonic for congenital erythropoietic porphyria. [41, 109] Teeth appear bright red with exposure to UV fluorescence.  It has been proposed that erythrodontia is due the binding of excess porphyrin to calcium phosphate in dentin and enamel, although this condition is not present in other porphyrias. 
Also see Congenital Erythropoietic Porphyria.
Sickle cell disease
Sickle cell disease (SCD; OMIM 603903) is an autosomal recessive hemoglobinopathy that causes erythrocyte malformation. [41, 110, 111, 112] It occurs almost exclusively in individuals of African, Asian, or Middle Eastern descent. [41, 110, 112] The prevalence of SCD and sickle cell trait (SCT) varies greatly with location. For example, although the global carrier frequency is estimated at approximately 5%, in certain regions in Africa the carrier frequency is as high as 25%.  In the United States, 1 in 13 black or African American babies is born with SCT and 1 in 365 is born with SCD.  Although homozygous individuals die in early childhood without medical intervention, heterozygous individuals actually have reduced morbidity and mortality from malaria, which is likely why the mutation is common in equatorial regions where malaria is endemic. [41, 110, 112]
The clinical manifestations of SCD are diverse, but often relate to the vaso-occlusive events, microvascular infarctions, hemolysis, and increased infectious susceptibility. Pain crises, acute chest syndrome, priapism, dactylitis, osteomyelitis, and strokes represent some of the most common and best-known sequelae of SCD, although there are many more.  Cutaneous manifestations of SCD include ulcers (mostly commonly leg ulcers) and pseudoxanthoma elasticum‒like lesions. 
Pallor and jaundice of the oral mucosa secondary to anemia and hemolysis are the most common oral manifestations of SCD.  Osteomyelitis of the jaw is uncommon, but has been reported in the mandible and maxilla. [41, 110] Patients with SCD may also experience mental nerve neuropathy secondary to infarction of nerve branches, which may cause numbness of the chin, lips, gingiva, mucosa, and even teeth. [41, 110] Dental caries are also more common in patients with SCD, possibly because of increased susceptibility to infections with pathogens such as Streptococcus mutans, but possibly because dental healthcare is a secondary concern for many patients struggling to manage SCD. [41, 110]
Also see Sickle Cell Anemia.
Polycythemia vera (PV) is a chronic, trilineage myeloproliferative disorder. While no specific genetic mutation has been identified, PV is thought to be a clonal stem cell disease.  PV has an incidence of 2.3 cases per 100,000 population and has been reported in nearly all patient populations, although it is slightly more common among Jewish and male patients.  The mean age of onset is 60 years. 
The clinical signs of PV include elevated hematocrit, thrombocytosis, and leukocytosis.  Patients are at significantly increased risk of thrombosis. [116, 117] Common systemic manifestations include microvascular abnormalities, erythromegaly, and splenomegaly. [117, 118] Patients often experience constitutional symptoms, such as fatigue and headache. [117, 118]
Rarely, PV can manifest orally with petechial hemorrhages, easy bruising, and gingival bleeding with minor trauma. [119, 120] A deep-red, violaceous hue may be present on the tongue, gingiva, and other mucosal surfaces. [119, 120, 121]
Also see Polycythemia Vera.
Sjögren syndrome (SS) is an autoimmune disease in which the exocrine glands, such as the salivary and lacrimal glands, are targeted. SS is classified as either primary or secondary. Secondary SS is associated with rheumatoid arthritis and other autoimmune diseases such as lupus erythematosus. SS is the second most common autoimmune disease, affecting as many as 3% of women aged 50 years or older. The sex predilection is profound: over 85% of patients are female. 
Systemically, any organ depending on exocrine glands may be affected, and patients often experience constitutional symptoms such as fatigue and joint pain. SS is characterized by sicca syndrome, including keratoconjunctivitis sicca and xerostomia.  The most common serological finding in SS is hypergammaglobulinemia, which includes an elevation of several autoantibodies. The most characteristic serum circulating autoantibodies of SS are anti-SS-A/Ro and anti-SS-B/La, which are found in up to 60% of patients with primary SS. [124, 125] The presence of anti-SSA/Ro and SSB/La autoantibodies correlates with earlier onset and longer duration of the disease. [124, 125] Cutaneous manifestations include xerosis, angular cheilitis, eyelid dermatitis, annular erythema, and vascular lesions, such as palpable purpura and urticarial vasculitis. 
In SS, saliva can be thick, ropey, and mucinous, or it may be altogether absent.  Oral mucosal changes are those typical of xerostomia. They include dry, red, and wrinkled mucosa and a cobblestonelike appearance of the tongue, owing to atrophy of the papillae.  Tongue fissuring and angular cheilitis are also common.  Candidiasis is common in persons with SS.  An increased incidence of dental caries is also seen in SS because the amount of saliva is insufficient to rinse away or dilute dietary sugar and the buffering capacity is greatly reduced. [130, 131] Common symptoms include odynophagia, dysphagia, disturbances in taste, and difficulty speaking secondary to decreased salivary production. [128, 132, 133, 134]
Labial minor salivary gland biopsy is a commonly used diagnostic tool for SS because it is a less invasive than obtaining a biopsy sample from one of the major salivary glands or the lacrimal glands. Histologic examination of minor salivary or lacrimal glands reveals a lymphocytic infiltrate surrounding the gland ducts. [128, 135] The presence of several lymphocytic foci adjacent to normal-appearing mucous acini, containing more than 50 lymphocytes per 4 mm2 of glandular tissue, is considered a diagnostic criterion for SS.  This inflammation, and the resultant epithelial hyperplasia, block salivary ducts.  Atrophy of the acini, as well as fibrosis and hyalinization of the glands, follow. 
While these changes are irreversible, certain medications can maximize saliva production from the remaining functional glands. Good oral hygiene and frequent dental visits are essential to minimize the deleterious effects of compromised salivary flow.
Also see Sjogren Syndrome.
Kawasaki disease, or mucocutaneous lymph node syndrome, is a vasculitis that primarily affects medium and large vessels. Kawasaki disease generally affects children younger than 5 years and has replaced rheumatic fever as the primary cause of childhood heart disease in the United States.  Kawasaki disease is common in East Asia and in children of East Asian descent. For example, in Japan, there is an incidence of 239 cases per 100,000 children, which is nearly 20-fold higher than the disease incidence in white populations. 
Diagnostic criteria include a fever lasting 5 days or more, as well as at least four of the five following findings: (1) acute cervical adenopathy; (2) peripheral extremity edema, erythema, or desquamation; (3) bilateral painless conjunctival injection; (4) polymorphous exanthem; and (5) oral mucosae erythema or strawberry tongue.  Cardiac sequelae of the vasculitis include aneurysms and myocardial infarction. [138, 139] Myocarditis commonly occurs within a week following fever resolution. 
Oral findings, one of the five diagnostic criteria, include swelling of papillae on the surface of the tongue (strawberry tongue) and intense erythema of the mucosal surfaces.  Ulceration in the oral cavity is a common presenting sign.  The labia may appear cracked, cherry-red, swollen, or hemorrhagic. 
Also see Kawasaki Disease.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune connective-tissue disorder that affects numerous organ systems, including the musculoskeletal system, lungs, heart, and kidneys. Lupus is more common in women, particularly women of African American descent.  The prevalence is estimated to be 40-50 cases per 100,000 population. 
There are numerous systemic and cutaneous manifestations of SLE. Of note, SLE is often called “the great imitator” because its presentation mimics many other conditions and varies greatly from one patient to another. Systemic Lupus International Collaborating Clinics (SLICC) revised and validated the diagnostic criteria for SLE in 2012. To be diagnosed with SLE, the patient must “satisfy 4 of the clinical and immunologic criteria used in the SLICC classification criteria, including at least one clinical criterion and one immunologic criterion, OR…[the patient must have] biopsy-proven nephritis compatible with SLE in the presence of ANAs or anti-dsDNA antibodies.” 
Table 4. 2012 SLICC Clinical and Immunologic Criteria for SLE Diagnosis (Open Table in a new window)
Acute cutaneous lupus, including:
Chronic cutaneous lupus, including:
|Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs) in the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia|
|Synovitis involving two or more joints, characterized by swelling or effusion OR tenderness in two or more joints and at least 30 minutes of morning stiffness|
|Urine protein–to-creatinine ratio (or 24-h urine protein) representing 500 mg protein/24 hours OR red blood cell casts|
|Leukopenia (<4,000/µL at least once) in the absence of other known causes such as Felty syndrome, drugs, and portal hypertension OR lymphopenia (<1,000/µL at least once) in the absence of other known causes such as corticosteroids, drugs, and infection|
|Thrombocytopenia (<100,000/µL) at least once in the absence of other known causes such as drugs, portal hypertension, and thrombotic thrombocytopenic purpura|
|Antinuclear antibody (ANA) level above laboratory reference range|
|Anti-dsDNA antibody level above laboratory reference range (or >2-fold the reference range if tested by enzyme-linked immunosorbent assay [ELISA])|
|Anti-Sm: Presence of antibody to Sm nuclear antigen|
Antiphospholipid antibody positivity as determined by any of the following:
|Direct Coombs test in the absence of hemolytic anemia|
Oral manifestations are found in 5-25% of patients with SLE.  In fact, oral ulceration is one of the major diagnostic criteria (See Table 4). Lichenoid lesions are common, although lesions with a granulomatous appearance have been reported.  Lesions may be located on the palate, gingiva, or buccal mucosa.  Cheilitis involving the lower lip vermilion is also seen in patients with SLE and is referred to as lupus cheilitis.  Xerostomia can also occur, with resultant increased risk for candidiasis and periodontal disease.  Histologic analysis reveals a lichenoid mucositis with an inflammatory infiltrate, primarily composed of T cells.  The basement membrane zone has linear deposits of IgG and C3 visualized by direct immunofluorescence. 
A form of lupus known as discoid lupus erythematous is limited to the skin and mucous membranes. Oral manifestations appear with cutaneous lesions and are clinically and histologically similar to oral lichen planus.  Lesions appear as well-demarcated ulcerations or erythematous plaques with atrophy encircled by white, radiating striae.  The sunburst pattern is typically unilateral as compared with the reticulated red and white plaques of lichen planus.
Also see Systemic Lupus Erythematosus (SLE).
Scleroderma is a rare autoimmune disease characterized by progressive fibrosis in numerous organ systems. The prevalence is estimated at 50-300 cases per 1 million persons, and women are at a 3- to 14-fold increased risk. 
Limited scleroderma, commonly known as CREST (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasias) syndrome, has minimal oral involvement, although intraoral and perioral telangiectasias may be present. 
Diffuse scleroderma has is a rapidly progressing disease with significant systemic involvement. Nearly any internal organ may be affected by the pathologic fibrosis, so the systemic signs and symptoms of diffuse scleroderma are, consequently, diverse.  Cutaneous involvement is marked by significant skin fibrosis, which may limit movement.  Other dermatologic signs include pigmentary changes and shiny skin. 
Oral manifestations can be profound in diffuse scleroderma. From 70-80% of patients experience microstomia, a phenomenon in which the opening to the oral cavity reduces in size secondary to perioral collagen deposition. [127, 146] Xerostomia occurs as a result of progressive fibrosis of the salivary glands, and it often mirrors the progression of microstomia.  Other oral manifestations of diffuse scleroderma include telangiectasias and atrophy of the oral mucosa.  Histology generally reveals extensive fibrosis, as well as endothelial cell and capillary basal cell damage. 
Also see Scleroderma.
Granulomatosis with polyangiitis
Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a necrotizing vasculitis of small- to medium-sized vessels associated with necrotizing granulomas of the upper and lower airways and necrotizing glomerulonephritis. [149, 150] The prevalence of GPA is between 20 and 160 cases per million persons, and evidence suggests it is more common in Northern European countries. 
Although classically associated with pulmonary and renal pathology, GPA can also affect the eyes, ears, heart, central nervous system, peripheral nervous system, pharynx, and sinuses.  Cutaneous manifestations include leukocytoclastic vasculitis, subcutaneous nodules, ulcers, and gangrenous necrosis. 
Oral involvement in GPA is very common; autopsy studies of patients with GPA show the oral cavity is affected in nearly all cases.  Oral lesions include ulcerations and gingival enlargement.  Nonspecific oral ulcerations, which occur on the buccal mucosa or palate, are the most common oral lesions in GPA.  The characteristic gingival appearance in GPA is a pathognomonic finding known as strawberry gingivitis. [155, 156] The gingivae take on a characteristic boggy, erythematous-to-violaceous appearance, are exquisitely friable, and may also develop granular papules on the labial interdental papillae.  Involvement may eventually include the lingual and palatal mucosa.  Early identification of these lesions may enable diagnosis prior to manifestation of other symptoms.  Oral and skin manifestations may correlate with disease progression and thereby provide prognostic value. Increased tooth mobility and loss of teeth, as well as resorption of alveolar bone, are common in advanced disease. 
Histologically, biopsy findings of the gingivae demonstrate necrotizing inflammation of vessels with accompanying granulomatous inflammation.  The pseudoepitheliomatous hyperplasia, microabscess formation, and multinucleate giant cells found in this condition are seen in few other gingival conditions.  Pathological findings consistent with GPA combined with a positive result from antineutrophil cytoplasmic antibody (ANCA) testing are diagnostic.
Also see Granulomatosis with Polyangiitis (Wegener Granulomatosis).
Sarcoidosis is an idiopathic systemic disease characterized by bilateral hilar lymphadenopathy and noncaseating granulomas in the lungs. The epidemiology of sarcoidosis is complicated by the diagnostic ambiguity resulting from a lack of sensitive and specific tests.  It is known that the incidence of sarcoidosis is much higher in African Americans (35-80 cases per 100,000 population) than in European Americans (3-10 cases per 100,000 population).  In all studied populations, sarcoidosis is more common in females. 
Sarcoidosis can involve nearly any organ, including the liver, heart, spleen, kidneys, and lymph system.  Pulmonary manifestations are the most common and include dyspnea with exertion, nonproductive cough, chest pain, wheezing, nasal congestion, and hemoptysis.  Ocular and cutaneous manifestations are also common. 
Sarcoidosis may manifest cutaneous findings in 5-20% of patients and they are more common in African Americans.  Examples of skin manifestations include alopecia, erythroderma, subcutaneous nodules, erythema nodosum, macules, papules and plaques, and lupus pernio.  Papules are small with a waxy consistency, and they may appear on the trunk and around the nose and eyes. 
Oral manifestations may include papules and nodules or painless nonspecific ulcerations of the gingiva, buccal mucosa, labial mucosae, and palate.  These papules and nodules appear brown or purple and may have a granular and hyperkeratotic quality.  Between 19% and 59% of patients may also experience salivary gland involvement, leading to tumorlike swellings on the mucosa.  A rare manifestation of sarcoidosis, known as Heertfordt syndrome, is the constellation of fever, parotid gland swelling, uveitis, and facial nerve palsy.  Xerostomia, secondary to either salivary gland involvement or Heertfordt syndrome, is common. Rarely, sarcoidosis may involve the tongue, including swelling, enlargement, and ulcerations. Involvement of the tongue is an uncommon oral manifestation of sarcoidosis, but in rare cases may be the presenting sign of the disease. 
Histologic analysis reveals noncaseating granulomas surrounded by multinucleate giant cells along with lymphocytic infiltrate.  Still, sarcoidosis is considered a diagnosis of exclusion, and other granulomatous diseases, such as GPA, Crohn disease, syphilis, and tuberculosis, must be ruled out. [162, 164] Treatment with systemic corticosteroids may be useful, but symptoms may resolve spontaneously or progress despite treatment. 
Also see Sarcoidosis.
Amyloidosis is the deposition of amyloid protein in the body’s tissues leading to tissue damage. Amyloidosis is classified based on the type of amyloid fibril protein. Amyloid light chain (AL) amyloidosis results from monoclonal plasma cell dyscrasias, such as multiple myeloma. It is the most common type of amyloid in developed countries, with an estimated incidence of 9 cases per million patient years. [165, 166]
Amyloid A (AA) amyloidosis is often a sequela of a chronic inflammatory or infectious disease process since the fibrilla protein is produced in response to inflammation. [167, 168] AA amyloidosis is more common in developing countries, but it only has an incidence of 1-2 cases per million patient years in Europe.  Other causes of amyloidosis, including the acquired transthyretin (TTR) amyloidosis and numerous hereditary amyloidoses, are far less common.
Amyloidosis commonly affects the heart, kidneys, and GI tract. Of note, AA amyloidosis has no cutaneous or oral manifestations. In other forms of amyloidosis, cutaneous manifestations include periorbital purpura and nail dystrophy. 
The most common oral manifestation of primary systemic amyloidosis is macroglossia, which occurs in 12-40% of patients.  The enlarged tongue demonstrates lateral ridging secondary to teeth indentation.  Grossly, the tongue may be firm and appear relatively normal, or it may have nodules, fissures, or ulcerations, often on the lateral surface. [170, 171] Hyposalivation may result from amyloid deposition in the salivary glands.  Submandibular adenopathy occurs subsequent to tongue enlargement, and both can lead to respiratory obstruction.  Although pain is not usually present, loss of mobility is common. Interference with taste has also been reported in some patients.
The amorphous, fissured appearance of deposited amyloid can be seen with microscopic examination of a biopsy sample from an enlarged tongue.  A characteristic green negative birefringence is seen when polarized light is shone on tissue stained with Congo red. [168, 171]
Also see Amyloidosis and AA (Inflammatory) Amyloidosis.
HIV targets critical components of the human immune system, leading to AIDS. In 2014, the World Health Organization estimated that there were 36.9 million people living with HIV worldwide, noting that approximately 54% of individuals are unaware of their HIV-positive status. 
HIV/AIDS manifests systemically in numerous ways as the host immune system collapses. Patients are highly susceptible to infections—many of which are rare in immunocompetent hosts—as well as malignancies.  Similarly, the cutaneous manifestations of HIV disease are also numerous and diverse, but generally present as bacterial, viral, or fungal skin infections. 
HIV infection has been associated with numerous oral lesions and diseases. While no condition described is unique to HIV disease, clinical presentations are often severe or atypical in these patients.  In general, these conditions only occur when CD4 lymphocyte counts drop below 400 cells/µL, and many have a positive predictive value for immune decline. The most common of these entities are discussed below. [177, 178, 179, 180, 181, 182]
Also see HIV Disease.
Candida albicans is a fungal organism ubiquitous in the environment. While immunocompetent hosts can experience candidal infections in the mouth or genitals, immunocompromised patients are at increased risk for recurrent and severe candidiasis.  In fact, oral candidiasis is often the first presenting sign of HIV infection, and it may occur in as many as 50-90% of patients infected with HIV. [176, 183] HIV infection should be considered in patients presenting with repeated oral candidiasis in the absence of other associated risk factors, such as steroid or antibiotic use. The frequency of candidal infection increases as HIV disease progresses (ie, as viral loads increase and CD4 lymphocyte counts decline).
The four common classifications of candidal infections are as follows:
Pseudomembranous candidiasis: The most common presentation in HIV-infected individuals, this form is characterized by white or cream-colored papules that can be wiped from the oral mucosa to reveal erythematous or eroded mucosa.  It commonly affects the buccal mucosa, palate, and vestibule, although any oral surface may be involved.
Erythematous candidiasis: This form manifests as nonspecific areas of erythema and atrophy, commonly on the palate or dorsum of the tongue (or both as a result of autoinoculation). 
Angular cheilitis: Angular cheilitis presents as cracked, red, and sometimes ulcerated fissures in the corners of the mouth, with or without intraoral symptoms. 
Hyperplastic candidiasis: This form is uncommon and manifests as adherent white plaques that cannot be easily removed. It is often mistaken for premalignant leukoplakia. 
Although the history and physical examination findings help establish the diagnosis, confirmation can be made using a potassium hydroxide (KOH) preparation, which shows hyphae, pseudohyphae, or spores. The KOH preparation is often negative in persons with erythematous candidiasis or angular cheilitis. If confirmation is required, cytology or tissue biopsy can also be used, with the latter test being definitive.
HIV-positive patients adhering to the highly active antiretroviral therapy (HAART) regimen have a significantly reduced incidence of oral candidiasis.  Treatment with antifungals is recommended; however, oral candidiasis can be difficult to eradicate in immunocompromised patients as clinical recovery does not always coincide with mycologic recovery. Thus, the patient may appear well, but may still be harboring fungal organisms. Additionally, fungal resistance to azole drugs (eg, fluconazole) is increased among HIV-infected patients.  If patients do not respond to azole antifungal drugs, cultures and sensitivity studies should be considered to ensure targeted treatment. [183, 186] Patients must also remember to treat any removable dental prostheses, such as dentures, which can act as fomites and reinoculate the patient. 
Also see Candidiasis.
Herpes simplex virus (HSV) is a double-stranded DNA virus that has two subtypes: HSV-1 and HSV-2.  Stress, fever, sunlight, or decreased immunosurveillance may precipitate reactivation of HSV, enabling the virus to travel down peripheral nerves and produce lesions.  Since the HSV infections generally lie dormant in the basal ganglia, prevalence is usually estimated using testing populations for antibodies against HSV. From 2005-2010, seroprevalence of antibodies against HSV-1 was 53.9% and seroprevalence of antibodies against HSV-2 was 15.7%. 
In rare cases, HSV can cause a systemic infection, although in healthy hosts its presentation is generally limited to a mucocutaneous vesicular eruption. The frequency and the severity of these recurrences vary, but the lesions most commonly occur on the vermilion of the lips and are sometimes preceded by a burning or tingling sensation. [190, 191] Numerous small (<1 mm) vesicles appear, which sometimes coalesce into larger vesicles. [190, 191] These rupture and leave behind painful, weeping ulcerations. [190, 191] HSV ulcerations are highly infectious for about 3-5 days, until they form an overlying crust. In immunocompetent individuals, the normal duration of lesions is 7-10 days. [190, 191]
Immunodeficiency, as seen with HIV infection, permits reactivation of latent herpes infections. [188, 192] As such, HSV must be ruled out in all HIV-positive patients presenting for perineal or orolabial ulcerations.  HSV infection in an HIV-positive patient is often more aggressive, prolonged, and diffuse than in an immunocompetent individual. [188, 190] For example, intraoral HSV lesions generally occur on keratinized mucosa, such as the dorsal aspect of the tongue, gingiva, and hard palate.  However, in immunocompromised hosts, HSV lesions can manifest on nonkeratinized surfaces, including the labial mucosa, ventral tongue, floor of the mouth, buccal mucosa, and the soft palate.  Herpetic lesions may extend to other areas, including the tonsillar pillars and the esophagus. 
Diagnosis is made by physical examination and a history of prodrome at the site of the vesicles. A Tzanck smear demonstrating multinucleate giant cells is highly suggestive of HSV infection, but culture and antibody staining results are diagnostic. Tissue biopsy may also be used to obtain a definitive diagnosis.
Thymidine kinase inhibitors are the most commonly used antivirals to treat HSV infections.  These include acyclovir, valacyclovir, and famciclovir. However, acyclovir-resistant strains are more common among HIV-infected individuals.  In these instances, infections are treated aggressively with intravenous foscarnet. 
Also see Herpes Simplex.
Hairy leukoplakia (HL) is caused by activity of the Epstein-Barr virus (EBV) within the epithelial cells. [196, 197] In the early 1980s, HL was identified and characterized in HIV-positive patients, but it has also been described in other immunocompromised patients. [197, 198] HL remains the most specific manifestation of HIV disease to occur in the mouth, and its presence has prognostic implications for the progression to AIDS because patients rarely manifest the condition with CD4 counts greater than 200 cells/µL.  An analysis of 198 patients with HL in the pre-HAART era demonstrated that the median time to the onset of AIDS was 24 months and to death was 41 months.  In the pre-HAART era, the prevalence of HL in HIV-infected patients was 25.8%; this has since decreased to 11.4% following the advent of HAART. [197, 201]
HL most commonly manifests as corrugated white verrucous plaques on the lateral portions of the tongue. These plaques range in size and appearance from thin and homogenous to thickened and rough, mimicking hyperplastic candidiasis. [196, 197] In fact, since these lesions can be clinically mistaken for candidiasis, a biopsy should be performed for definitive diagnosis. 
Histologic examination reveals hairlike projections, which demonstrate hyperparakeratosis, acanthosis, groups of ballooning cells, and a limited inflammatory infiltrate. [202, 203] Definitive diagnosis may be made with in situ hybridization of the DNA from EBV in surface epithelial cells. 
Because HL is usually asymptomatic, treatment is elective. Common treatment regimens include 25% podophyllin resin, a 25% podophyllin resin with a 1% penciclovir cream, and a 25% podophyllin resin with a 5% acyclovir cream.  If a patient reports symptoms associated with HL, the lesions are most likely superinfected with Candida species. Antifungal treatment usually ameliorates these symptoms.
Also see Hairy Leukoplakia.
Kaposi sarcoma (KS) is the second most common malignancy in patients who are HIV positive and is considered an AIDS-defining illness.  KS herpesvirus/human herpesvirus-8 (KSHV/HHV8) infection is necessary for the development of KS. In the early years of the AIDS epidemic, AIDS-associated KS incidence peaked at nearly 80%.  Fortunately, HAART has significantly reduced the incidence and clinical course of KS. [205, 207]
KS presents as angioproliferative tumors on visceral organs or the skin.  Oral involvement is seen in approximately 50% of AIDS-KS cases and may be present at the time of HIV diagnosis in up to 20% of patients. [176, 208] Intraorally, KS appears as brown, blue, purple, or red patches and papules on the hard palate, mucosa, and gingiva. [176, 209] While early lesions appear as flat macules or patches on the mucosal surface, over time they become nodular, with a predilection to ulcerate and bleed.  KS can also affect the salivary glands and may cause head and neck lymphadenopathy. [210, 211]
A biopsy should be performed to definitively diagnose KS. Histologically, KS is characterized by increased vascularity, spindle-shaped cells with minimal mitotic activity, and hemosiderin deposition.  Treatment is accomplished through a variety of methods, including surgical excision, cryotherapy, sclerotherapy, radiotherapy, laser therapy, and topical or intralesional chemotherapy. 
Also see Kaposi Sarcoma.
Cytomegalovirus (CMV) is a double-stranded DNA virus. In the United States, data indicate that 30-70% of people are seropositive. 
In immunocompetent hosts, primary CMV infection often presents as mononucleosis, which can be accompanied by a morbilliform rash.  In HIV-positive patients, as in other immunocompromised patients, CMV is known to cause retinitis, pneumonia, and encephalitis and is associated with significant morbidity and mortality. 
Even in patients who are immunocompromised, CMV infection rarely manifests intraorally. However, in these rare cases, CMV infection produces deep, penetrating oral ulcerations on the lips, tongue, pharynx, or any mucosal site [216, 217, 218] The aphthouslike ulcerations have a punched-out look with rolled, erythematous borders. [216, 217] Diagnosis can be confirmed histologically, with identification of the characteristic "owl's-eye" appearance of cellular inclusions.  CMV infection is treated with intravenous agents such as ganciclovir or cidofovir. 
Also see Cytomegalovirus.
Human papillomavirus (HPV) is a DNA virus that affects both immunocompetent and immunocompromised individuals. [220, 221] Prevalence estimates vary depending on patient demographics, HPV serotype, and location of testing (oral cavity vs genitalia). As of 2010, the prevalence of oral HPV in adolescents and adults (aged 15-69 y) in the United States was 6.9%, while the prevalence of oral HPV 16 (the leading cause of HPV-related oropharyngeal cancers) was 1%. [220, 222] Estimates of the genital HPV prevalence is much higher, nearly 43% in females aged 18-59.  Of note, the prevalence of HPV has been decreasing since the advent of the quadrivalent vaccine. 
HIV-positive patients have a higher prevalence of oral and genital HPV infections and a higher risk of developing HPV-associated malignancies. [221, 225] Some studies suggest that this association is caused by reduced HPV clearance rates in the setting of immunosuppression. [226, 227] Conversely, other studies have found no significant difference in clearance rates, but rather suggest that an increased risk of incident infections in HIV-positive individuals is responsible for the higher HPV prevalence and higher risk of HPV-associated malignancies in this population. 
HPV has numerous serotypes, many of which are linked to specific systemic or cutaneous sequelae. For example, HPV 6 and 11 are associated with anogenital warts, while HPV 16, 18, 31, and 45 are known to be oncogenic and are implicated in the majority of cervical and anal cancers, as well as many oropharyngeal, vaginal, penile, and vulvar cancers. [220, 221, 229]
The most common oral manifestation of HPV is oral warts, generally caused by HPV 13 or 32.  These papillomas or condylomas are soft, pink masses with a characteristic papillary texture that appear on the gingiva, lips, and labial mucosa.  HPV-associated oral squamous cell carcinomas may present as a nonhealing ulcer with signs of bleeding, loosening of teeth, neck masses, and symptoms including dysphagia, dysarthria, and odynophagia.  Such malignancies may derive from asymptomatic, precancerous lesions on the oral mucosa that appear as white patches (leukoplakia) or red patches (erythroplakia). 
Although HAART has been effective in reducing the incidence of many HIV-associated oral lesions, the incidence of HPV-associated oral warts has actually increased with HAART. [231, 232] This phenomena is poorly understood, although theories of immune reconstitution and improved local inflammatory responses have been proposed.  Therapeutic options for HPV-associated oral warts include excision, laser ablation, cryotherapy, or topical 5-fluorouracil or imiquimod. [220, 233]
Also see Human Papillomavirus.
Aphthous ulcerations are ulcerations of the oral cavity that are not caused by an infectious agent. Three forms of recurrent aphthous ulcerations are recognized: minor, major, and herpetiform. Similar ulcerations can occur in the GI tract or on genital mucosal surfaces.
Aphthous lesions manifest as yellow-gray areas of ulceration ranging in size from a few millimeters to larger than a centimeter.  The ulcerations are surrounded with a halo of erythema and are usually very painful.  Major aphthae are generally larger than 1 cm and form deep crateriform erosions that may take 14-21 days to heal.  Major aphthae differ from other forms of aphthae in that they often heal with scarring. [236, 237] Herpetiform aphthae, which are often mistaken for HSV lesions, tend to occur in clusters consisting of 10-100 ulcers and may be localized or distributed throughout the soft mucosa of the oral cavity. 
In immunocompetent individuals, aphthous ulcerations (colloquially termed canker sores) affect only nonkeratinized surfaces within the oral cavity.  However, in immunocompromised hosts, these ulcerations can appear anywhere.  Additionally, although relatively uncommon in immunocompetent individuals, the major form of aphthous ulcers is most common in HIV-positive patients.  The recurrent appearance of these lesions in an HIV-infected patient is a reliable indicator of severe immunodeficiency and disease progression. 
Biopsy is indicated for definitive diagnosis of all HIV-related ulcerations because bacterial, viral, and fungal pathogens, as well as HIV-medications, may cause atypical oral ulcerations.
Numerous treatment modalities are available for recurrent aphthous ulcerations, including topical, intralesional, and systemic therapies.  In the HIV-positive population, immunosuppressants should be prescribed with particular care, owing to the associated risk of other intraoral infections, such as with Candida species. Thalidomide and amlexanox are currently the only US Food and Drug Administration‒approved treatments for aphthae, with thalidomide specifically designated for HIV-associated aphthous ulceration. [239, 240, 241, 242, 243]
Also see Aphthous Ulcers.
Psoriasis is a chronic papulosquamous inflammatory condition of the skin that affects approximately 2% of the US population.  Although psoriasis can present at any age, population-based studies have revealed a bimodal distribution for age of onset: the first peak occurs in the second or third decade of life, while the second peak occurs in the sixth and seventh decades.  Psoriasis affects both men and women at equal rates and is slightly more common in whites than in African Americans or Latinos. 
The precise etiology of psoriasis remains unknown. Clinically, its extent and severity can vary greatly. Characteristic scaly, white, well-demarcated plaques typically affect the scalp, elbows, and knees. [244, 246] When the silvery scale is elevated or scratched, bleeding points are evident (ie, Auspitz sign). In moist intertriginous areas, such as the axillae and groin, well-demarcated erythematous patches and plaques, without the presence of slivery scale, predominate. [244, 246]
Although controversial, psoriasis can manifest in the oral cavity. [247, 248, 249, 250, 251] On the lips, psoriasis may present as nonspecific scale. Intraorally, sites affected include the palate, buccal mucosa, gingiva, and tongue with nonspecific inflammatory plaques. Pindborg and van der Waal identified three findings suggestive of oral psoriasis: (1) small, white papules that yield bleeding points upon scraping; (2) red and white plaques that follow skin lesions; and (3) bright-red patches.  Since oral psoriasis rarely manifests without cutaneous involvement, definitive oral diagnosis is made with the finding of corresponding cutaneous lesions and is confirmed with biopsy results. Of note, geographic tongue and fissured tongue have an increased incidence in patients with psoriasis. [251, 253]
Histologic findings demonstrate parakeratosis and hyperplasia of the epidermis, elongation of rete ridges, a thinned stratum granulosum, Munro microabscesses of neutrophils superficially, and chronic inflammation of the epidermis and the dermis with polymorphonuclear leukocytes, lymphocytes, and histiocytes.  Dilated and tortuous blood vessels high in the submucosa may also be present.  Although these are the characteristic psoriatic histologic findings, they are identical to geographic tongue, so a careful clinical history and physical examination are important to make a diagnosis.
Also see Psoriasis.
Acanthosis nigricans (AN; OMIM #100600) is a cutaneous disorder of hyperpigmentation and papillomatosis. AN is generally associated with fibroblast growth factor receptor mutations and genetic or acquired insulin resistance.  In fact, evidence suggests that AN is a heritable condition, strongly influenced by genetics that may have pleiotropic effects on genes related to diabetes and metabolic syndrome. 
In one study, nearly 20% of patients in primary care clinics were found to have AN, although it was more common in African American patients (26.8%) and Latino patients (26.1%) and less common in white patients (6%).  It was also found that the prevalence of AN positively correlated with the number of diabetes risk factors (ie, dyslipidemia, hypertension, weight, family history) possessed by the patient. 
Patients generally present in childhood or adolescence with hyperpigmented, velvety, papillated plaques in flexural areas, such as the neck, axilla, groin, and fingers. [254, 257] Rarely, benign AN manifests in an exuberant fashion, with involvement of the umbilicus, areolae, and oral cavity. [257, 258]
Malignancy-associated AN (MAN) is a mucocutaneous paraneoplastic disorder of hyperpigmentation and exuberant papillomatosis. It is hypothesized to be due to overproduction of an epidermal growth factor promoter secreted by the associated neoplasm. MAN is most commonly associated with gastric adenocarcinoma, but it has been reported in cancers of the lung, ovary, and endometrium. [259, 260, 261, 262] MAN may present in conjunction with tripe palms (hyperkeratosis of the palms and soles) and the Leser-Trélat sign (a sudden eruption of seborrheic keratosis).  Recognition of these lesions could facilitate the early diagnosis of a potentially fatal malignancy.
Oral manifestations have been noted in 25-50% of patients with MAN, in contrast to the benign form in which oral involvement is rare.  In oral MAN, the tongue, lips, palate, and gingiva may be involved. Nonpigmented hypertrophy of the papillae along the tongue’s dorsal surface and lateral edge yield a characteristic shaggy, fissured texture. [259, 265] The lips are also subject to these papillomatous growths and often exhibit profound swelling.  While the buccal mucosa may have similar papillae, it is more common to see velvety white plaques and an uneven appearance.  Gingival hyperplasia may be prominent, with interdental gingiva so hyperplastic as to cover teeth and interfere with eating. [259, 267]
Histologically, oral MAN shows acanthosis and epithelial papillary hyperplasia with minimal inflammatory infiltrate. [259, 265] While cutaneous AN shows increased melanin deposition in the basal cell layer, oral lesions do not share this characteristic feature. 
Also see Acanthosis Nigricans.
Neurofibromatosis types 1 and 2
Neurofibromatosis type 1 (NF1; von Recklinghausen disease; OMIM 162200) is a neurocutaneous syndrome caused by an inherited or de novo mutation in the NF1 gene.  NF is one of the most common genetic disorders, with an incidence at birth of 1 in 3000.  Although highly penetrant, expression is highly variable, resulting in a broad spectrum of associated phenotypes.  It is classically characterized by cutaneous neurofibromas, plexiform neurofibromas, café-au-lait macules, axillary or inguinal freckling, iris hamartomas (Lisch nodules), and optic gliomas. 
Neurofibromatosis type 2 (NF2; OMIM 101000) is caused by a mutation in a different gene, NF2, which is located on a separate chromosome.  It can also be inherited in an autosomal dominant fashion or by de novo mutation.  It is far less common than NF1, with an incidence of 1 in 33,000-40,000.  NF2 is characterized by vestibular schwannomas and other benign tumors of neural tissue such as meningiomas and gliomas.  Patients with NF2 generally do not exhibit the same degree of cutaneous involvement as patients with NF1, although cutaneous neurofibromas are typical and café-au-lait macules occur at rates higher than the general population. 
Many historical case reports detailing the oral manifestations of NF do not differentiate between NF1 and NF2. Geist et al completed a thorough review of many reports and concluded that most patients in these studies had NF1, which is expected given that NF1 is more common than NF2.  Many of these reviews documented intraoral neurofibromas on the lips, palate, buccal mucosa, gingiva, and tongue.  More recent studies looking at NF1 specifically have corroborated these findings and confirmed previous observations that the tongue is the most common site of intraoral involvement. [271, 272] Although most lesions of the tongue are nodular, diffuse macroglossia and enlargement of the fungiform papillae have also been noted. [270, 272] Hyperpigmentation and enlargement of the gingiva may also be seen in NF1.  Osseous manifestations include lesions of the cranial and jawbones, while dental abnormalities such as impacted teeth, supernumerary teeth, overgrowth of the alveolar process, and a possible increase risk of caries have been described. [271, 273, 274, 275]
Also see Neurofibromatosis Type 1 and Neurofibromatosis Type 2.
Diabetes mellitus (DM) refers to a group of metabolic diseases characterized by elevations in blood glucose. Blood glucose levels are generally regulated by the hormone insulin, which is produced by the islet beta cells of the pancreas. DM type 1 is due to the immune-mediated destruction of these cells, resulting in a failure to produce and release a sufficient amount of insulin. DM type 2 occurs when the tissues of the body become insulin-resistant and fail to respond to the insulin released by the pancreas. Other causes of DM include gestational diabetes; pancreatic pathologies; and genetic defects in beta cell function, insulin processing, or insulin action. Approximately 21 million people in the United States have been diagnosed with diabetes, and the US Centers for Disease Control and Prevention (CDC) estimates that an additional 8.1 million cases are undiagnosed.  This corresponds to 9.3% of the total population.  African American and Latino populations have a higher prevalence of diabetes than white and Asian populations.  Numerous genes have been implicated in susceptibility to DM type 2. 
The consequences of DM are diverse and cause significant morbidity and mortality. Common complications from DM include hyperglycemic crises, kidney disease, heart disease, stroke, eye problems (including blindness), and amputations.  Similarly, there are numerous skin diseases and infections associated with DM.  Specific cutaneous markers of DM type 1 include necrobiosis lipoidica diabeticorum and diabetic bullae, while specific cutaneous markers of DM type 2 include generalized granuloma annulare, scleredema diabeticorum, diabetic dermopathy, and acanthosis nigricans. 
Diabetes has also been associated with numerous diseases and lesions of the oral cavity. Mucosal manifestations include fissured tongue, benign migratory glossitis, coated tongue, irritation fibroma, traumatic ulcers, and recurrent aphthous ulcers. [279, 280] Some studies also indicate an increased prevalence lichen planus, although this remains highly controversial.  Premalignant conditions such as leukoplakia, erythroplakia, and actinic cheilitis may also be more prevalent in patients with diabetes. [280, 281] Salivary dysfunction, with or without signs of salivary gland enlargement, burning mouth syndrome, and taste disturbances are also common in diabetes, likely owing to secondary neuropathy. [282, 283] Diabetic individuals are also at an increased risk for oral fungal infections, specifically candidiasis. [283, 284] Similarly, dental caries, periodontitis, and gingivitis are also more common in persons with diabetes. [283, 284]
Of note, while tight glycemic control may reduce morbidity, patients are still increased risk for multiple conditions. [282, 285] As such, all lesions and infections should be managed individually, apart from general diabetes therapies. Oral hygiene is critical to reduce the risk of infection, dental caries, periodontitis, and gingivitis. 
Also see Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus.
Multiple endocrine neoplasia
The multiple endocrine neoplasia (MEN) syndromes refer to distinct constellations of benign and malignant endocrine tumors with autosomal dominant inheritance.
MEN type 1 (OMIM #131100), which occurs in 1 in 30,000 people, is characterized by pituitary, parathyroid, and pancreatic tumors. [286, 287] MEN type 2a (OMIM 171400) is associated with tumors of the thyroid, parathyroid, and adrenal medulla.  MEN type 2b (OMIM #162300) is also associated with thyroid and adrenal medulla tumors, but is found in patients with marfanoid features.  The prevalence of MEN type 2 (both a and b) is approximately 1 in 35,000 persons. 
Only MEN type 2b has been associated with specific oral manifestations. Nodules on the lips, resulting in a “bumpy” lip appearance, are a common finding caused by mucosal and submucosal ganglioneuromatosis. [289, 290] In fact, some believe that all patients with MEN type 2b develop this feature at some point.  Nodules on the tongue and neuromas of the cheek, gingiva, and palatal mucosa have also been described.  These patients may also exhibit a prognathic or retrognathic mandible.  Oral radiographic studies are limited, but in one case report, a patient with MEN type 2b had enlarged inferior alveolar nerves resulting in the enlarged and bifurcated appearance of the inferior alveolar canal. 
Also see Multiple Endocrine Neoplasia Type 1 and Type 2 Multiple Endocrine Neoplasia.
The thyroid produces hormones that act as critical regulators of metabolism. Dysregulation of thyroid hormones may be a result of autoimmune disease, benign tumors, malignancy, genetic influences, and pregnancy. In general, these conditions cause a state of either hypothyroidism or hyperthyroidism. Hypothyroidism has a prevalence of approximately 1-2%.  Hyperthyroidism has a prevalence of 0.5-2% in women; however, it is 10 times less common in men. 
Common systemic manifestations of hypothyroid include cold intolerance, constipation, weight gain, and lethargy, while cutaneous manifestations include dry skin and hair.  On the other hand, common manifestations of hyperthyroid include heat intolerance, abdominal pain, weight loss, and tachycardia, while cutaneous manifestations include fine hair and warm, smooth skin. 
Oral manifestations are more common in hypothyroidism and generally relate to its severe form, called myxedema. In these cases, deposition of glycosaminoglycans results in diffuse swelling of the lips and tongue.  Patients with hyperthyroidism have an increased susceptibility to caries, periodontal disease, and burning mouth syndrome. [292, 293] Sjögren syndrome is also more common in these patients. [292, 293] Of note, congenital hypothyroidism is characterized by thick lips, macroglossia, delayed tooth eruption, and dysgeusia, as well as severe intellectual delay. [292, 293]
Also see Hyperthyroidism and Hypothyroidism.
Parathyroid hormone (PTH) is critical to the maintenance of calcium and phosphate homeostasis in the body. There are numerous etiologies for PTH dysregulation, including benign tumors, malignancy, renal disease, surgical excision, and rare genetic syndromes.  In a related condition known as pseudohypoparathyroidism, the body’s tissues become resistant to PTH.  Large population studies are lacking, but it has been estimated that 115,000 patients in the United States have hypoparathyroidism of any cause. 
Hypoparathyroidism is characterized by low levels of calcium, and systemic manifestations include paresthesias, increased neuromuscular irritability, laryngospasm and bronchospasm, cataracts, central nervous system effects (ie, personality alterations, seizures), and cardiac involvement (ie, prolonged QT and arrhythmias).  Cutaneous manifestations include xerotic skin, skin pigmentation, and changes in the hair and nails. 
Oral manifestations of hyperparathyroidism include loss of the lamina dura of roots of the teeth; an abnormal trabecular pattern in the bones; and the well-demarcated, unilocular, radiolucent “brown” tumors that can effect jawbones. [296, 297] If hypoparathyroidism develops early in life, oral manifestations include failure of tooth eruption or a pitting enamel hypoplasia. 
Also see Hypoparathyroidism and Hyperparathyroidism.
The adrenal glands are responsible for the production of numerous steroid hormones, including the glucocorticoid cortisol that plays a critical role in the regulation of metabolism and the immune system.
States of hypocorticalism, also known as adrenal insufficiency (AI), can be classified as primary, secondary, or tertiary.  Primary AI refers to direct impairment of the adrenal gland (Addison disease), including dysgenesis or defective hormone synthesis. [298, 299] Secondary and tertiary AI, together referred to as central AI, are due to impaired production or action of corticotropin (ACTH) and may be caused by pituitary or hypothalamic pathology or longer-term administration of glucocorticoids.  The prevalence estimates of primary and secondary AI are 93-144 cases per million population and 150-280 cases per million population, respectively.  Epidemiologic data on tertiary AI are lacking and no reliable prevalence estimates are available.
While acute adrenal crises are characterized by hypotension, fever, hypoglycemia, and even circulatory collapse, chronic AI is an insidious disease with mucocutaneous manifestations.  Systemic symptoms of chronic AI include malaise, anorexia, weight loss, joint pain, and salt cravings.  The classic cutaneous hyperpigmentation is due to an elevation of ACTH in response to low cortisol levels. [300, 301] ACTH not only directly promotes melanogenesis, but is cleaved into alpha-melanocyte‒stimulating hormone, which further stimulates melanocytes. [300, 301]
In the oral mucosa, hyperpigmentation may been seen on the tongue and on the periodontal and buccal mucosa. [300, 301] There may also be hyperpigmentation of the vermillion border, in additional to common cutaneous sites of hyperpigmentation, such as the flexural creases and recent scars. [300, 301]
Also see Addison Disease.
Hypercortisolism (also known as Cushing syndrome) can be iatrogenic induced or due to pituitary pathology, ectopic ACTH production, or adrenal pathology.  Cushing syndrome has an estimated incidence of 10-15 cases per million population and is characterized by weight gain, fatigue, moon facies, buffalo hump, mood instability, glucose intolerance, bone fragility, and increased susceptibility to infections.  Cutaneous manifestations include striae, acne, hirsutism, and increased skin fragility. Oral manifestations generally relate to jawbone fractures, secondary to skeletal fragility, and slow healing lesions, secondary to impaired wound healing. 
Also see Iatrogenic Cushing Syndrome.
Having reviewed the oral manifestations of systemic diseases, it is also worthwhile to note that many lesions and disorders of the oral cavity are caused by medical therapies. As such, a thorough medication reconciliation is essential for any patient presenting with oral pathology. Below, common oral pathologies and the major pharmacologic agents that either cause or are associated with these conditions are reviewed.
Pharmacologic agents are among the most common causes of recurrent aphthous ulcers, commonly known as canker sores. These ulcerations are round, crateriform, white-yellow depressions surrounded by a rim of erythema. The size of an aphthous ulcer may vary from 1-3 mm (aphthous minor, approximately 80% of cases) to larger than 1 cm (aphthous major, approximately 15% of cases).  Patients may have outbreaks of multiple ulcerations at one time.  These are usually quite painful but typically are self-limiting and resolve in 7-10 days for aphthous minor and 14-21 days for aphthous major lesions. 
Offending drugs may include nonsteroidal anti-inflammatory drugs (NSAIDs), nicorandil, ACE inhibitors, or bisphosphonates, but any drug can potentially produce an aphthouslike reaction. 
Also see Aphthous Stomatitis.
An adverse effect of many medications is dry mouth (hyposalivation or xerostomia). Table 5 classifies numerous medications that cause xerostomia by their pathophysiologic mechanism. 
Dry mouth has a number of consequences, including altered taste, increased risk of fungal infection, increased risk of caries, and increased prevalence of traumatic ulceration due to lack of lubrication.  Patients with severely impaired salivary flow also have difficulty with eating, swallowing, and speech.  The former can result in decreased food intake and poor nutrition. 
Numerous management options are available for decreased salivation, which are beyond the scope of this article. These range from simple solutions, such as increased hydration, to systemic procholinergic agents to increase salivation. 
Table 5. Causes of Drug-Associated Xerostomia (Open Table in a new window)
|Drugs of Abuse||
As discussed above, lichen planus (LP) is a mucocutaneous disorder with a prevalence estimated at 0.4-4% in the general population.  The prevalence of oral lichen planus (OLP) is unknown, but both forms may be triggered by pharmacologic agents. 
Drug-associated OLP, or oral lichenoid drug reactions (OLDRs), generally present in the oral cavity as the classic reticular form; however, ulcerated or eroded forms have also been described.  In addition to a clinical evaluation, a biopsy is warranted to verify diagnosis. Histopathology reveals a dense lichenoid infiltrate along the dermoepidermal junction and a saw-toothed rete-ridge pattern with Max-Joseph spaces.  A small subset of OLP cases, specifically the erosive types, have been linked to the development of squamous cell carcinoma. 
Currently, over 200 agents have been implicated in OLDRs.  Well-documented drugs known to trigger OLDRs include ACE inhibitors, beta-blockers, NSAIDs, diuretics, hydroxychloroquine, and zidovudine.  Many vaccines, most notably the hepatitis B vaccine, have also been known to cause LP. [312, 313, 314] A thorough medication history may be required to identify the causative agent; although the average time span between drug intake and an OLDR is 2-3 months, delayed onset of the OLDR after 12 months has been described.  In rare circumstances, the OLDR can become extensive or painful enough to warrant changing the culprit medication.
Also see Lichen Planus and Oral Lichen Planus.
Gingival overgrowth (hyperplasia)
Gingival overgrowth may occur because of congenital abnormalities, hormone abnormalities, or certain medications.  Historically, this condition was termed gingival hyperplasia, but this is a misnomer as histologic examination does not show true hyperplasia.
The pathogenesis of gingival overgrowth is multifactorial and likely results from disruption of collagen homeostasis—either a promotion of collagen synthesis or a reduction of collagenase activity. [316, 317, 318] Many believe a genetic predisposition underlies the individual variation in susceptibility to gingival overgrowth.  Numerous studies have reported a link between poor oral hygiene and gingival overgrowth.  Consequently, it has been hypothesized that inflammation (either secondary to plaque accumulation or other factors) may sensitize gingival fibroblasts to the drug metabolites and thereby stimulate proliferation. 
Phenytoin, calcium channel blockers, and cyclosporine are the drugs most commonly associated gingival overgrowth, although amlodipine has also been implicated as a cause in select cases.  Gingival overgrowth develops in approximately half the patients taking phenytoin.  When compared with drugs such as ACE inhibitors, calcium-channel blockers carry twice the risk of gingival enlargement.  Gingival enlargement due to nifedipine has an approximate prevalence of 38%, and the prevalence of cyclosporine-associated gingival hyperplasia varies from 13-85%. [320, 322, 323] Currently, it is estimated that one million patients in North America have drug-induced gingival overgrowth. 
Gingival enlargement typically begins 1-3 months following initiation of therapy.  The overgrowth may be localized or diffuse, often presenting as nodular enlargement of the interdental papillae and occasionally progressing until gingival tissue covers the facial surface of the crowns. [315, 324] The anterior gingiva is the most common site of enlargement.  As growth continues, oral hygiene becomes difficult to maintain and the risk of oral infections increases. 
The histologic features of phenytoin hyperplasia and calcium channel blocker‒related gingival overgrowth are very similar. [320, 324] Findings include an increased number of fibroblasts and increased extracellular ground substance.  . Histologic analysis of cyclosporine-induced overgrowth reveals increased connective tissue and parakeratinized epithelium of varying thickness.  Lymphocytes and plasma cells may be present because of increased plaque around the gingiva. 
Discontinuing the medication or changing to an alternative medication within the same drug class may reduce overgrowth.  Spontaneous remission or regression of the condition is rare.  Therapy usually involves conservative surgical excision of the excess tissue using a scalpel, electrosurgery, or a laser.  This helps to improve the cosmetic appearance for the patient and facilitates plaque control. The gingival tissue continues to regrow, however, and patients typically need repeated surgeries for as long as they are on the offending medication. Diligent oral hygiene is essential to reduce the severity of gingival hyperplasia, especially in light of the proposed pathophysiologic link between inflammation and increased gingival fibroblast proliferation.  Antiseptic mouthwashes have shown some efficacy in reducing recurrence of gingival overgrowth following surgery.  The literature on the use of systemic antibiotics is inconclusive. While some small studies have reported reductions of gingival overgrowth following short courses of azithromycin or metronidazole, no large randomized controlled trials have been conducted to confirm this effect. 
Also see Drug-Induced Gingival Hyperplasia.
Candidiasis (secondary to inhaled steroids)
Patients using inhaled corticosteroids (ICS) experience a 2- to 4-fold increased risk of contracting oral candidiasis (also known as thrush). [320, 326] Rates of oral candidiasis subsequent to ICS vary, but they may be over 15%. [326, 327] Some studies suggest that the use of Rotacaps inhalers confers a higher risk than use of metered-dose inhalers with a spacer. 
Patients experience overgrowth of Calbicans in correlation with the dose and the frequency of the steroid use. [320, 328] This overgrowth is likely due to an inhibition of the patient's normal immune function, altering the oral equilibrium in favor of the yeast. 
Oral candidiasis is characterized by small, curdy-appearing white papules and plaques that are easily wiped from the mucosa. [320, 329] The tissue beneath these plaques is often inflamed and may bleed. [320, 329] The infection is usually self-limiting, so steroid use can continue. To prevent further exacerbations, adding a spacer to the inhaler, decreasing the frequency of steroid use, and using anticandidal mouthwashes after taking the steroids are recommended. [327, 329] Any oral hardware (eg, dentures) must be cleaned regularly so it does not become a microbial reservoir. 
Also see Candidiasis.
Oral manifestations of systemic diseases are common and diverse. They may be the direct result of disease pathology, secondary infiltrative processes, or treatment-related adverse effects. As discussed here, oral manifestations can be the presenting symptom for many systemic diseases, and thus a careful medical and social history is critical to ensure that diagnosis and treatment are not delayed. Furthermore, many of the oral pathologies reviewed here cause pain and discomfort, which not only negatively impact patients’ quality of life, but may also lead to inadequate food and water intake. Thus, oral manifestations must be promptly recognized and appropriately treated.