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Oral Manifestations of Systemic Diseases

  • Author: Heather C Rosengard, MPH; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Jul 27, 2016
 

Overview

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.

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Gastrointestinal Diseases

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.

Ulcerative colitis

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.[3] Rarely, patients can develop pyostomatitis vegetans (PSV), the oral counterpart of pyoderma vegetans.

Also see Ulcerative Colitis.

Crohn disease

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.[4] 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.[4] 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.[4] 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.[4] 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.[4]

Symptoms of Crohn disease include intermittent attacks of diarrhea, constipation, abdominal pain, and fever.[5] Patients may develop malabsorption and subsequent malnutrition.[5] Systemic features of Crohn disease include arthritis, clubbing of the fingers, and sacroiliitis.[5]

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.[5] 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.[5] Nonspecific, reactive skin findings in patients with Crohn disease include erythema nodosum, pyoderma gangrenosum, and Sweet syndrome.[6]

Intraoral involvement occurs in up to 50% of patients with Crohn disease and may precede intestinal involvement.[7] Oral manifestations can prove crucial in diagnosis and usually parallel the intestinal disease course.[8] 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.[9] 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.[13] 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.[12] 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.[2] Of note, patients may also develop dental caries.[14]

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.

Pyostomatitis vegetans

Although relatively rare, most PSV cases occur concurrently with either Crohn disease or UC.[15] As such, PSV is considered a specific finding of IBD, and its presence can precede GI symptoms by months or years.[6] 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.[12] Symptoms such as pain and burning may be severe or negligible.[2] Histologic examination reveals intraepithelial and subepithelial eosinophilic miliary abscesses.[2]

Gastroesophageal reflux

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.[17] 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.[18]

Patients with GERD commonly report heartburn, chronic cough, sore throat, globus (lump in the throat), dysphagia, and odynophagia.[19] If untreated, GERD may lead to erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma.[18] 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.[21] 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.[21] 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.[22] 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.[23] Patients may also benefit from decreased consumption of acidic foods and beverages.[21] Patients with xerostomia should consider discontinuing medications that may exacerbate hyposalivation or use a salivary supplement.[21]

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.[24] Major causes include chronic hepatitis C, chronic hepatitis B, alcoholic liver disease, and nonalcoholic fatty liver disease, although countless other conditions can cause CLD.[24] CLD is a leading cause of mortality and morbidity both in the United States and around the world.[25]

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.[28]

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.[29] 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.[30] Of note, because the sublingual and soft palate mucosae are very thin, they are often first to show a yellow hue.[30] Examination of these regions may provide useful diagnostic clues in patients with darker skin or physiologic conjunctival pigmentation.

Hepatitis C

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.[36]

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.[38] 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.[39] Histology reveals a bandlike lymphocytic infiltrate with a saw-tooth appearance of the rete ridges, as well as parakeratosis, acanthosis, and orthokeratotic hyperkeratosis.[40] Colloid bodies and Max-Joseph spaces are also classic findings more specific to LP.[40]

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.

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Nutritional Disease

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.[41] 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

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).[42] 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
  • Erythema of pharyngeal and oral mucous membranes
  • Atrophic glossitis, often with a magenta hue
  • Glossodynia
  • Cheilosis
  • Angular cheilitis
Schlosser et al[41]
Vitamin B-3 (niacin, nicotinic acid) deficiency (pellagra)
  • Mucosal edema
  • Cheilosis
  • Angular cheilitis
  • Bright red glossitis
  • Burning mouth
  • Gingival erythema
  • Dental caries
Schlosser et al,[41] Boyd and Palmer[43]
Vitamin B-6 (pyridoxine, pyridoxal, pyridoxamine) deficiency
  • Atrophic glossitis
  • Cheilosis
  • Angular stomatitis
  • Gingival erythema
Schlosser et al[41]
Vitamin B-9 (folic acid, folate) deficiency
  • Atrophic glossitis with erythema and swelling of the tongue
  • Angular cheilitis
  • Glossodynia
  • Dysphagia
  • Recurrent aphthous stomatitis
Schlosser et al,[41] Kozlak et al[44]
Vitamin B-12 (cobalamin, cyanocobalamin) deficiency
  • Generalized stomatitis
  • Taste disturbance
  • Red, atrophic, beefy, burning tongue with bald appearance due to loss of filiform papillae
  • Recurrent aphthous stomatitis
Schlosser et al,[41] Kozlak et al,[44] Field et al[45]
Vitamin C (ascorbic acid, L-ascorbic acid, ascorbate) deficiency, also known as scurvy
  • Mucosal petechiae
  • Hemorrhagic gingivitis
  • Gingival bleeding
  • Gingival hypertrophy
  • Interdental infarcts
  • Loosening or loss of teeth
Schlosser et al,[41] Leggott et al,[46] Yasui et al[47]

Fat-soluble vitamins

Vitamins A, D, E, and K are fat soluble and thus are readily stored in the body.[48] 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
  • Xerostomia
  • Periodontal disease
  • Increased intraoral infection
  • Impaired tooth development in children
Schlosser et al[41]
Vitamin A (retinol) toxicity
  • Cheilitis
  • Gingivitis
  • Impaired healing
Schlosser et al[41]
Vitamin D (calciferol, cholecalciferol, ergocalciferol) deficiency
  • Periodontal attachment
  • Recurrent aphthous stomatitis
Schlosser et al,[41] Khabbazi et al,[49] Holick and Chen[50]
Vitamin K (phylloquinone) deficiency
  • Submucosal hemorrhage
  • Gingival bleeding
Schlosser et al[41]

Minerals

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.[51] Additional oral manifestations of mineral deficiencies are listed in Table 3.

Table 3. Oral Manifestation of Mineral Deficiencies (Open Table in a new window)

Iron deficiency
  • Angular cheilitis
  • Atrophic glossitis
  • Glossodynia
  • Recurrent Aphthous Stomatitis
Schlosser et al,[41] Sun et al,[52] Zimmermann and Hurrell[53]
Zinc deficiency
  • Burning mouth syndrome
  • Recurrent aphthous stomatitis
  • Perioral or intraoral erosions
  • Dysgeusia (taste alteration)
Cho et al,[54] Orback et al,[55] Nakano et al,[56] Epstein and Barasch,[57] Hambidge and Krebs[58]
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Hematologic Disorders

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.[41]

White blood cell disorders

Leukemia

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.[59] 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.[59]

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.[64] Gingival hypertrophy and hyperplasia are most commonly associated with acute myelogenous leukemia and acute promyelocytic leukemia.[65] 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.[66]

Chemotherapeutic drugs may cause diffuse oral ulceration, also known as mucositis, which is often mistaken to herpes simplex virus (HSV) or cytomegalovirus (CMV) infection.[67] 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.[64]

Lymphoma

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).[68] 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.[71] 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.[41]

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.[72] Oral manifestations include ulcerated plaques or solid tumors on the gingiva, palate, or tongue.[72] Histologic examination reveals a dense inflammatory infiltrate with atypical lymphocytes and Darier-Pautrier microabscesses.[72] Oral lesions represent advanced disease and indicate a poor prognosis.[72]

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.[73] 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.[76] These AIDS-associated lymphomas may present with masses or ulcers that involve the gingiva, palate, tonsils, tongue, and lower jaw.[75]

Cyclic neutropenia

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.[78] 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.[41] Onset of symptoms occurs in childhood and may improve as the patient approaches adulthood.[80]

Cutaneous manifestations are generally due to poor immune function and include skin infections and abscesses.[82] Oral manifestations are present in over 90% of patients with cyclic neutropenia.[82] In one series, investigators found that 94% have recurrent ulcers similar to recurrent aphthous stomatitis.[82] 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.[83] 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.[82] This gingivitis may result in periodontitis, with alveolar bone loss and loosening of the teeth, as well as mucosal scarring.[41]

Although lifelong morbidity is a feature of cyclic neutropenia, mortality due to severe infections is relatively uncommon.[41] Granulocyte colony-stimulating factor (G-CSF) can be used to improve neutrophil counts and reduce morbidity.[84] 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.[86] Still, it is estimated that 1-2 million adults per year are diagnosed with LCH.[87]

The most common form of LCH is an eosinophilic granuloma, which presents as localized, lytic bone lesions and is generally benign.[85] Skin lesions are rare in this form.[85] In contrast, oral swellings or ulcerations resulting from mandibular or maxillary bone involvement are common.[88]

In multisystem disease, bone lesions are still the most common finding, although cutaneous involvement is seen in about one third of patients.[87] Skin lesions may include dry, scaling skin on the scalp, erythematous rashes in intertriginous regions, or diffuse, papular rashes on the trunk and extremities.[87] Oral ulcerations may develop on the gingiva or palate, along with a necrotizing gingivitis.[88] 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.[89]

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.[88] Radiologic findings demonstrate rapid, progressive alveolar bone loss with dental extrusion, producing the characteristic appearance of "floating teeth”.[85] These lesions result in fractures and displaced teeth.[85]

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.[85]

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.[85] 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.[85]

Also see Langerhans Cell Histiocytosis.

Multiple myeloma

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.[90]

Cutaneous manifestations in multiple myeloma are rare, although multiple myeloma has been associated with certain paraneoplastic conditions, including erythema gyratum repens and pityriasis rotunda.[91]

Patients often present with osteolytic lesions, and about 30% of patients have mandibular involvement, with associated swelling, pain, paresthesias, and tooth loss.[41] 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

Mastocytosis is a rare myeloproliferative neoplasm, estimated to affect about 10 in 100,000 people.[94] 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.[94]

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.[99]

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.

Platelet disorders

Thrombocytopenia

Thrombocytopenia is defined as a reduced number of circulating platelets, generally below 150,000/µL.[100] 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.[41] 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.[100] 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.[102]

In the oral cavity, petechiae and ecchymoses may be visible on the soft palate and buccal mucosa.[41] Gingival bleeding is common and often spontaneous.[41] Hemorrhagic bullae that appear as deep‒red-to-violaceous or black blisters may appear on mucosal surfaces in cases of severe thrombocytopenia.[103]

Red blood cell disorders

Anemias

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

Hemochromatosis, a syndrome of systemic iron overload, may be caused by hereditary hemochromatosis, transfusional iron overload, chronic hemolysis, or excess dietary iron.[104] 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.[106] Cutaneous manifestations of hemochromatosis include skin hyperpigmentation resulting in the classic “bronzed” appearance.[106]

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.[107] 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.[41]

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.[108] 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.[41]

The classic primary manifestation of congenital erythropoietic porphyria is pink-red discoloration of the urine in infancy or childhood.[41] 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.[108]

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.[108] 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.[41]

Also see Congenital Erythropoietic Porphyria.

Thalassemias

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%.[113] In the United States, 1 in 13 black or African American babies is born with SCT and 1 in 365 is born with SCD.[114] 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.[112] Cutaneous manifestations of SCD include ulcers (mostly commonly leg ulcers) and pseudoxanthoma elasticum‒like lesions.[115]

Pallor and jaundice of the oral mucosa secondary to anemia and hemolysis are the most common oral manifestations of SCD.[41] 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

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.[116] 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.[116] The mean age of onset is 60 years.[116]

The clinical signs of PV include elevated hematocrit, thrombocytosis, and leukocytosis.[116] 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]

Cutaneous manifestations include aquagenic pruritus and evidence of bleeding complications such as ecchymoses.[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.

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Connective-Tissue Disorders

Sjögren syndrome

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.[122]

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.[123] 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.[126]

In SS, saliva can be thick, ropey, and mucinous, or it may be altogether absent.[127] 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.[128] Tongue fissuring and angular cheilitis are also common.[128] Candidiasis is common in persons with SS.[129] 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.[136] This inflammation, and the resultant epithelial hyperplasia, block salivary ducts.[128] Atrophy of the acini, as well as fibrosis and hyalinization of the glands, follow.[128]

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

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.[137] 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.[138]

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.[139] Cardiac sequelae of the vasculitis include aneurysms and myocardial infarction.[138, 139] Myocarditis commonly occurs within a week following fever resolution.[139]

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.[140] Ulceration in the oral cavity is a common presenting sign.[141] The labia may appear cracked, cherry-red, swollen, or hemorrhagic.[127]

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.[142] The prevalence is estimated to be 40-50 cases per 100,000 population.[142]

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.”[143]

Table 4. 2012 SLICC Clinical and Immunologic Criteria for SLE Diagnosis (Open Table in a new window)

Clinical Criteria
Acute cutaneous lupus, including:
  • Lupus malar rash (do not count if malar discoid)

  • Bullous lupus

  • Toxic epidermal necrolysis variant of SLE

  • Maculopapular lupus rash

  • Photosensitive lupus rash in the absence of dermatomyositis
  • OR subacute cutaneous lupus (nonindurated psoriasiform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias)

Chronic cutaneous lupus, including:
  • Classic discoid rash
  • Localized (above the neck)
  • Generalized (above and below the neck)
  • Hypertrophic (verrucous) lupus
  • Lupus panniculitis (profundus)
  • Mucosal lupus
  • Lupus erythematosus tumidus
  • Chilblains lupus
  • Discoid lupus/lichen planus overlap
Oral ulcers
  • Palate
  • Buccal
  • Tongue
  • OR nasal ulcers, in the absence of other causes, such as vasculitis, Behçet disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic food exposure

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
Serositis
  • Typical pleurisy for more than 1 day OR pleural effusions OR pleural rub
  • Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day OR pericardial effusion OR pericardial rub OR pericarditis by electrocardiography in the absence of other causes, such as infection, uremia, and Dressler pericarditis
Urine protein–to-creatinine ratio (or 24-h urine protein) representing 500 mg protein/24 hours OR red blood cell casts

Neurologic
  • Seizures
  • Psychosis
  • Mononeuritis multiplex in the absence of other known causes such as primary vasculitis
  • Myelitis
  • Peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus
  • Acute confusional state in the absence of other causes, including toxic/metabolic, uremia, drugs
Hemolytic anemia
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

Immunologic Criteria
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:
  • Positive test result for lupus anticoagulant
  • False-positive test result for rapid plasma reagin
  • Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)
  • Positive test result for anti–β 2-glycoprotein I (IgA, IgG, or IgM)
Low complement
  • Low C3

  • Low C4

  • Low CH50

Direct Coombs test in the absence of hemolytic anemia

Oral manifestations are found in 5-25% of patients with SLE.[117] 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.[127] Lesions may be located on the palate, gingiva, or buccal mucosa.[127] Cheilitis involving the lower lip vermilion is also seen in patients with SLE and is referred to as lupus cheilitis.[127] Xerostomia can also occur, with resultant increased risk for candidiasis and periodontal disease.[127] Histologic analysis reveals a lichenoid mucositis with an inflammatory infiltrate, primarily composed of T cells.[144] The basement membrane zone has linear deposits of IgG and C3 visualized by direct immunofluorescence.[144]

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.[127] Lesions appear as well-demarcated ulcerations or erythematous plaques with atrophy encircled by white, radiating striae.[127] 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

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.[145]

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.[146]

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.[145] Cutaneous involvement is marked by significant skin fibrosis, which may limit movement.[147] Other dermatologic signs include pigmentary changes and shiny skin.[147]

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.[148] Other oral manifestations of diffuse scleroderma include telangiectasias and atrophy of the oral mucosa.[148] Histology generally reveals extensive fibrosis, as well as endothelial cell and capillary basal cell damage.[148]

Also see Scleroderma.

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Pulmonary Conditions

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.[151]

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.[152] Cutaneous manifestations include leukocytoclastic vasculitis, subcutaneous nodules, ulcers, and gangrenous necrosis.[152]

Oral involvement in GPA is very common; autopsy studies of patients with GPA show the oral cavity is affected in nearly all cases.[153] Oral lesions include ulcerations and gingival enlargement.[154] Nonspecific oral ulcerations, which occur on the buccal mucosa or palate, are the most common oral lesions in GPA.[153] 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.[153] Involvement may eventually include the lingual and palatal mucosa.[153] Early identification of these lesions may enable diagnosis prior to manifestation of other symptoms.[157] 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.[153]

Histologically, biopsy findings of the gingivae demonstrate necrotizing inflammation of vessels with accompanying granulomatous inflammation.[158] The pseudoepitheliomatous hyperplasia, microabscess formation, and multinucleate giant cells found in this condition are seen in few other gingival conditions.[158] 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

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.[159] 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).[159] In all studied populations, sarcoidosis is more common in females.[159]

Sarcoidosis can involve nearly any organ, including the liver, heart, spleen, kidneys, and lymph system.[160] Pulmonary manifestations are the most common and include dyspnea with exertion, nonproductive cough, chest pain, wheezing, nasal congestion, and hemoptysis.[160] Ocular and cutaneous manifestations are also common.[160]

Sarcoidosis may manifest cutaneous findings in 5-20% of patients and they are more common in African Americans.[161] Examples of skin manifestations include alopecia, erythroderma, subcutaneous nodules, erythema nodosum, macules, papules and plaques, and lupus pernio.[161] Papules are small with a waxy consistency, and they may appear on the trunk and around the nose and eyes.[162]

Oral manifestations may include papules and nodules or painless nonspecific ulcerations of the gingiva, buccal mucosa, labial mucosae, and palate.[160] These papules and nodules appear brown or purple and may have a granular and hyperkeratotic quality.[127] Between 19% and 59% of patients may also experience salivary gland involvement, leading to tumorlike swellings on the mucosa.[160] A rare manifestation of sarcoidosis, known as Heertfordt syndrome, is the constellation of fever, parotid gland swelling, uveitis, and facial nerve palsy.[160] 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.[163]

Histologic analysis reveals noncaseating granulomas surrounded by multinucleate giant cells along with lymphocytic infiltrate.[160] 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.[162]

Also see Sarcoidosis.

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Multisystem Conditions

Amyloidosis

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.[165] 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.[166]

The most common oral manifestation of primary systemic amyloidosis is macroglossia, which occurs in 12-40% of patients.[127] The enlarged tongue demonstrates lateral ridging secondary to teeth indentation.[169] 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.[171] Submandibular adenopathy occurs subsequent to tongue enlargement, and both can lead to respiratory obstruction.[172] 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.[171] 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.

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HIV Disease

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.[173]

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.[174] Similarly, the cutaneous manifestations of HIV disease are also numerous and diverse, but generally present as bacterial, viral, or fungal skin infections.[175]

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.[176] 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.

Candidiasis

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.[176] 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. [176] 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). [176]
  • Angular cheilitis: Angular cheilitis presents as cracked, red, and sometimes ulcerated fissures in the corners of the mouth, with or without intraoral symptoms. [184]
  • Hyperplastic candidiasis: This form is uncommon and manifests as adherent white plaques that cannot be easily removed. It is often mistaken for premalignant leukoplakia. [184]

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.[176] 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.[185] 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.[187]

Also see Candidiasis.

Herpes simplex

Herpes simplex virus (HSV) is a double-stranded DNA virus that has two subtypes: HSV-1 and HSV-2.[188] Stress, fever, sunlight, or decreased immunosurveillance may precipitate reactivation of HSV, enabling the virus to travel down peripheral nerves and produce lesions.[188] 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%.[189]

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.[188] 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.[191] 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.[193] Herpetic lesions may extend to other areas, including the tonsillar pillars and the esophagus.[194]

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.[195] These include acyclovir, valacyclovir, and famciclovir. However, acyclovir-resistant strains are more common among HIV-infected individuals.[195] In these instances, infections are treated aggressively with intravenous foscarnet.[195]

Also see Herpes Simplex.

Hairy leukoplakia

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.[199] 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.[200] 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.[197]

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.[203]

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.[204] 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

Kaposi sarcoma (KS) is the second most common malignancy in patients who are HIV positive and is considered an AIDS-defining illness.[205] 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%.[206] 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.[205] 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.[209] 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.[212] Treatment is accomplished through a variety of methods, including surgical excision, cryotherapy, sclerotherapy, radiotherapy, laser therapy, and topical or intralesional chemotherapy.[212]

Also see Kaposi Sarcoma.

Cytomegalovirus

Cytomegalovirus (CMV) is a double-stranded DNA virus. In the United States, data indicate that 30-70% of people are seropositive.[213]

In immunocompetent hosts, primary CMV infection often presents as mononucleosis, which can be accompanied by a morbilliform rash.[214] 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.[215]

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.[219] CMV infection is treated with intravenous agents such as ganciclovir or cidofovir.[218]

Also see Cytomegalovirus.

Human papillomavirus

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.[223] Of note, the prevalence of HPV has been decreasing since the advent of the quadrivalent vaccine.[224]

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.[228]

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.[220] These papillomas or condylomas are soft, pink masses with a characteristic papillary texture that appear on the gingiva, lips, and labial mucosa.[220] 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.[230] Such malignancies may derive from asymptomatic, precancerous lesions on the oral mucosa that appear as white patches (leukoplakia) or red patches (erythroplakia).[230]

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.[231] Therapeutic options for HPV-associated oral warts include excision, laser ablation, cryotherapy, or topical 5-fluorouracil or imiquimod.[220, 233]

Also see Human Papillomavirus.

Aphthouslike ulcerations

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.[234] The ulcerations are surrounded with a halo of erythema and are usually very painful.[234] Major aphthae are generally larger than 1 cm and form deep crateriform erosions that may take 14-21 days to heal.[235] 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.[238]

In immunocompetent individuals, aphthous ulcerations (colloquially termed canker sores) affect only nonkeratinized surfaces within the oral cavity.[234] However, in immunocompromised hosts, these ulcerations can appear anywhere.[235] Additionally, although relatively uncommon in immunocompetent individuals, the major form of aphthous ulcers is most common in HIV-positive patients.[235] The recurrent appearance of these lesions in an HIV-infected patient is a reliable indicator of severe immunodeficiency and disease progression.[235]

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.[234] 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.

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Cutaneous Diseases

Psoriasis 

Psoriasis is a chronic papulosquamous inflammatory condition of the skin that affects approximately 2% of the US population.[244] 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.[244] Psoriasis affects both men and women at equal rates and is slightly more common in whites than in African Americans or Latinos.[245]

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.[252] 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.[246] Dilated and tortuous blood vessels high in the submucosa may also be present.[246] 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

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.[254] 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.[255]

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%).[256] 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.[256]

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).[263] 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.[264] 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.[266] While the buccal mucosa may have similar papillae, it is more common to see velvety white plaques and an uneven appearance.[259] 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.[259]

Also see Acanthosis Nigricans.

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Neurologic Diseases

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.[268] NF is one of the most common genetic disorders, with an incidence at birth of 1 in 3000.[268] Although highly penetrant, expression is highly variable, resulting in a broad spectrum of associated phenotypes.[268] It is classically characterized by cutaneous neurofibromas, plexiform neurofibromas, café-au-lait macules, axillary or inguinal freckling, iris hamartomas (Lisch nodules), and optic gliomas.[268]

Neurofibromatosis type 2 (NF2; OMIM 101000) is caused by a mutation in a different gene, NF2, which is located on a separate chromosome.[269] It can also be inherited in an autosomal dominant fashion or by de novo mutation.[269] It is far less common than NF1, with an incidence of 1 in 33,000-40,000.[269] NF2 is characterized by vestibular schwannomas and other benign tumors of neural tissue such as meningiomas and gliomas.[269] 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.[269]

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.[270] Many of these reviews documented intraoral neurofibromas on the lips, palate, buccal mucosa, gingiva, and tongue.[270] 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.[271] 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.

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Endocrine Diseases

Diabetes

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.[276] This corresponds to 9.3% of the total population.[276] African American and Latino populations have a higher prevalence of diabetes than white and Asian populations.[276] Numerous genes have been implicated in susceptibility to DM type 2.[277]

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.[276] Similarly, there are numerous skin diseases and infections associated with DM.[278] 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.[278]

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.[280] 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.[279]

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.[286] MEN type 2b (OMIM #162300) is also associated with thyroid and adrenal medulla tumors, but is found in patients with marfanoid features.[286] The prevalence of MEN type 2 (both a and b) is approximately 1 in 35,000 persons.[288]

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.[290] Nodules on the tongue and neuromas of the cheek, gingiva, and palatal mucosa have also been described.[289] These patients may also exhibit a prognathic or retrognathic mandible.[289] 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.[289]

Also see Multiple Endocrine Neoplasia Type 1 and Type 2 Multiple Endocrine Neoplasia.

Thyroid disorders

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%.[291] Hyperthyroidism has a prevalence of 0.5-2% in women; however, it is 10 times less common in men.[291]

Common systemic manifestations of hypothyroid include cold intolerance, constipation, weight gain, and lethargy, while cutaneous manifestations include dry skin and hair.[292] 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.[292]

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.[127] 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 disorders

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.[294] In a related condition known as pseudohypoparathyroidism, the body’s tissues become resistant to PTH.[294] Large population studies are lacking, but it has been estimated that 115,000 patients in the United States have hypoparathyroidism of any cause.[294]

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).[294] Cutaneous manifestations include xerotic skin, skin pigmentation, and changes in the hair and nails.[295]

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.[127]

Also see Hypoparathyroidism and Hyperparathyroidism.

Adrenal disorders

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.

Hypocorticalism

States of hypocorticalism, also known as adrenal insufficiency (AI), can be classified as primary, secondary, or tertiary.[298] 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.[298] The prevalence estimates of primary and secondary AI are 93-144 cases per million population and 150-280 cases per million population, respectively.[298] 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.[300] Systemic symptoms of chronic AI include malaise, anorexia, weight loss, joint pain, and salt cravings.[300] 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

Hypercortisolism (also known as Cushing syndrome) can be iatrogenic induced or due to pituitary pathology, ectopic ACTH production, or adrenal pathology.[302] 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.[303] 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.[127]

Also see Iatrogenic Cushing Syndrome.

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Drug-Induced Conditions

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.

Aphthous stomatitis

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).[304] Patients may have outbreaks of multiple ulcerations at one time.[304] 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.[304]

Offending drugs may include nonsteroidal anti-inflammatory drugs (NSAIDs), nicorandil, ACE inhibitors, or bisphosphonates, but any drug can potentially produce an aphthouslike reaction.[305]

Also see Aphthous Stomatitis.

Dry mouth

An adverse effect of many medications is dry mouth (hyposalivation or xerostomia). Table 5 classifies numerous medications that cause xerostomia by their pathophysiologic mechanism.[306]

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.[307] Patients with severely impaired salivary flow also have difficulty with eating, swallowing, and speech.[306] The former can result in decreased food intake and poor nutrition.[306]

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.[306]

Table 5. Causes of Drug-Associated Xerostomia (Open Table in a new window)

Dehydrating Agents
  • Diuretics
Anticholinergic Agents
  • Tricyclic antidepressants
  • Muscarinic agonists
  • Alpha-receptor antagonists
  • Antipsychotics
  • Antihistamines
Sympathetic Effectors
  • Antihypertensives
  • Selective serotonin reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants
  • Appetite suppressants
  • Decongestants
  • Bronchodilators
  • Muscle relaxers
  • Antimigraine medications
Drugs of Abuse
  • Opioids
  • Benzodiazepines
  • Cannabis
  • 3,4-Methylenedioxymethamphetamine (MDMA) (ecstasy)
Other
  • Anti-HIV drugs
  • Retinoids
  • Cytotoxic drugs
  • Proton-pump inhibitors and H2 receptor antagonists
  • Caffeinated and alcoholic beverages/products

Lichen planus

As discussed above, lichen planus (LP) is a mucocutaneous disorder with a prevalence estimated at 0.4-4% in the general population.[40] The prevalence of oral lichen planus (OLP) is unknown, but both forms may be triggered by pharmacologic agents.[40]

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.[308] 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.[308] A small subset of OLP cases, specifically the erosive types, have been linked to the development of squamous cell carcinoma.[309]

Currently, over 200 agents have been implicated in OLDRs.[310] Well-documented drugs known to trigger OLDRs include ACE inhibitors, beta-blockers, NSAIDs, diuretics, hydroxychloroquine, and zidovudine.[311] 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.[40] 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.[315] 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.[318] Numerous studies have reported a link between poor oral hygiene and gingival overgrowth.[318] 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.[318]

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.[319] Gingival overgrowth develops in approximately half the patients taking phenytoin.[320] When compared with drugs such as ACE inhibitors, calcium-channel blockers carry twice the risk of gingival enlargement.[321] 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.[317]

Gingival enlargement typically begins 1-3 months following initiation of therapy.[324] 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.[324] As growth continues, oral hygiene becomes difficult to maintain and the risk of oral infections increases.[324]

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.[320] . Histologic analysis of cyclosporine-induced overgrowth reveals increased connective tissue and parakeratinized epithelium of varying thickness.[320] Lymphocytes and plasma cells may be present because of increased plaque around the gingiva.[324]

Discontinuing the medication or changing to an alternative medication within the same drug class may reduce overgrowth.[320] Spontaneous remission or regression of the condition is rare.[320] Therapy usually involves conservative surgical excision of the excess tissue using a scalpel, electrosurgery, or a laser.[324] 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.[318] Antiseptic mouthwashes have shown some efficacy in reducing recurrence of gingival overgrowth following surgery.[325] 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.[325]

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.[327]

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.[326]

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.[329]

Also see Candidiasis.

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Summary

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.

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Contributor Information and Disclosures
Author

Heather C Rosengard, MPH Johns Hopkins University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Ginat W Mirowski, MD, DMD Adjunct Associate Professor, Departments of Oral Pathology, Medicine, and Radiology, Indiana University School Medicine

Ginat W Mirowski, MD, DMD is a member of the following medical societies: American Academy of Dermatology, American Medical Womens Association

Disclosure: Nothing to disclose.

Diana V Messadi, DDS, MMSc, DMSc Professor of Dentistry, Associate Dean for Education and Faculty Development, Chair, Section of Oral Medicine and Orofacial Pain, University of California, Los Angeles, School of Dentistry

Diana V Messadi, DDS, MMSc, DMSc is a member of the following medical societies: American Academy of Oral and Maxillofacial Pathology, American Academy of Oral Medicine, American Association for Cancer Research, American Association for Cancer Research, Women in Cancer Research, American Association for Dental Research, American Association of University Women, American Dental Association, American Dental Education Association, Arab American Dental Society, Association of Egyptian-American Scholars, California Dental Association, Egyptian Dental Association, International Association for Dental Research, Southern California Academy of Oral Pathology, West Los Angeles Dental Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Drore Eisen, MD, DDS Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati

Drore Eisen, MD, DDS is a member of the following medical societies: American Academy of Dermatology, American Academy of Oral Medicine, American Dental Association

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Franklin Flowers, MD Department of Dermatology, Professor Emeritus Affiliate Associate Professor of Pathology, University of Florida College of Medicine

Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Surgery

Disclosure: Nothing to disclose.

Jeffrey M Casiglia, DMD, DMSc Lecturer, Harvard School of Dental Medicine; Private Practice, Salem, Massachusetts

Jeffrey M Casiglia, DMD, DMSc is a member of the following medical societies: American Academy of Oral Medicine, American Dental Association

Disclosure: Nothing to disclose.

References
  1. Bianchi L, Carrozzo AM, Orlandi A, Campione E, Hagman JH, Chimenti S. Pyoderma vegetans and ulcerative colitis. Br J Dermatol. 2001 Jun. 144 (6):1224-7. [Medline].

  2. Mirowski GW, LeBlanc J, Mark LA. Oral Disease and Oral-Cutaneous Manifestations of Gastrointestinal and Liver Disease. Friedman LS and Brandt LJ, eds. Feldman, Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 10th ed. Philadelphia, Pa: Elsevier; 2016. 377-96.

  3. Boirivant M, Cossu A. Inflammatory bowel disease. Oral Dis. 2012 Jan. 18 (1):1-15. [Medline].

  4. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015 Apr. 12 (4):205-17. [Medline].

  5. Mazza M, Giovanna Cilluffo M, Cappello M. Clinical Presentation of Crohn’s Disease. Crohn’s Disease. Switzerland: Springer International Publishing; 2015. 7-14.

  6. Marzano AV, Borghi A, Stadnicki A, Crosti C, Cugno M. Cutaneous manifestations in patients with inflammatory bowel diseases: pathophysiology, clinical features, and therapy. Inflamm Bowel Dis. 2014 Jan. 20 (1):213-27. [Medline].

  7. Katsanos KH, Torres J, Roda G, Brygo A, Delaporte E, Colombel JF. Review article: non-malignant oral manifestations in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015 Jul. 42 (1):40-60. [Medline].

  8. Lourenço SV, Hussein TP, Bologna SB, Sipahi AM, Nico MM. Oral manifestations of inflammatory bowel disease: a review based on the observation of six cases. J Eur Acad Dermatol Venereol. 2010 Feb. 24(2):204-7. [Medline].

  9. Halme L, Meurman JH, Laine P, et al. Oral findings in patients with active or inactive Crohn's disease. Oral Surg Oral Med Oral Pathol. 1993 Aug. 76(2):175-81. [Medline].

  10. Hussey S, Fleming P, Rowland M, Harty S, Chan L, Broderick A. Disease outcome for children who present with oral manifestations of Crohn's disease. Eur Arch Paediatr Dent. 2011 Jun. 12(3):167-9. [Medline].

  11. Plauth M, Jenss H, Meyle J. Oral manifestations of Crohn's disease. An analysis of 79 cases. J Clin Gastroenterol. 1991 Feb. 13(1):29-37. [Medline].

  12. Lankarani KB, Sivandzadeh GR, Hassanpour S. Oral manifestation in inflammatory bowel disease: a review. World J Gastroenterol. 2013 Dec 14. 19 (46):8571-9. [Medline].

  13. Sciubba JJ, Said-Al-Naief N. Orofacial granulomatosis: presentation, pathology and management of 13 cases. J Oral Pathol Med. 2003 Nov. 32 (10):576-85. [Medline].

  14. Pittock S, Drumm B, Fleming P, McDermott M, Imrie C, Flint S, et al. The oral cavity in Crohn's disease. J Pediatr. 2001 May. 138 (5):767-71. [Medline].

  15. Femiano F, Lanza A, Buonaiuto C, Perillo L, Dell'Ermo A, Cirillo N. Pyostomatitis vegetans: a review of the literature. Med Oral Patol Oral Cir Bucal. 2009 Mar 1. 14 (3):E114-7. [Medline].

  16. Hegarty AM, Barrett AW, Scully C. Pyostomatitis vegetans. Clin Exp Dermatol. 2004 Jan. 29 (1):1-7. [Medline].

  17. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014 Jun. 63 (6):871-80. [Medline].

  18. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005 Aug 2. 143 (3):199-211. [Medline].

  19. Di Fede O, Di Liberto C, Occhipinti G, Vigneri S, Lo Russo L, Fedele S, et al. Oral manifestations in patients with gastro-oesophageal reflux disease: a single-center case-control study. J Oral Pathol Med. 2008 Jul. 37 (6):336-40. [Medline].

  20. Aframian DJ, Ofir M, Benoliel R. Comparison of oral mucosal pH values in bulimia nervosa, GERD, BMS patients and healthy population. Oral Dis. 2010 Nov. 16(8):807-11. [Medline].

  21. Ranjitkar S, Smales RJ, Kaidonis JA. Oral manifestations of gastroesophageal reflux disease. J Gastroenterol Hepatol. 2012 Jan. 27 (1):21-7. [Medline].

  22. Schroeder PL, Filler SJ, Ramirez B, Lazarchik DA, Vaezi MF, Richter JE. Dental erosion and acid reflux disease. Ann Intern Med. 1995 Jun 1. 122(11):809-15. [Medline].

  23. van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev. 2010 Nov 10. CD002095. [Medline].

  24. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011 Jun. 9 (6):524-530.e1; quiz e60. [Medline].

  25. Byass P. The global burden of liver disease: a challenge for methods and for public health. BMC Med. 2014 Sep 18. 12:159. [Medline].

  26. Karnath B. Stigmata of chronic liver disease. Turner-White Communications. Available at http://www.turner-white.com/pdf/hp_jul03_stigmata.pdf. 2003; Accessed: July 18, 2016.

  27. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008 Mar 8. 371 (9615):838-51. [Medline].

  28. Ghosn SH, Kibbi AG. Cutaneous manifestations of liver diseases. Clin Dermatol. 2008 May-Jun. 26 (3):274-82. [Medline].

  29. Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagulation disorders in liver disease. Semin Liver Dis. 2002 Feb. 22 (1):83-96. [Medline].

  30. Daley TD, Armstrong JE. Oral manifestations of gastrointestinal diseases. Can J Gastroenterol. 2007 Apr. 21 (4):241-4. [Medline].

  31. Lodi G, Pellicano R, Carrozzo M. Hepatitis C virus infection and lichen planus: a systematic review with meta-analysis. Oral Dis. 2010 Oct. 16 (7):601-12. [Medline].

  32. Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Binyou W. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009 Sep. 145 (9):1040-7. [Medline].

  33. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013 Apr. 57 (4):1333-42. [Medline].

  34. Bhattacharya M, Kaur I, Kumar B. Lichen planus: a clinical and epidemiological study. J Dermatol. 2000 Sep. 27 (9):576-82. [Medline].

  35. McCartan BE, Healy CM. The reported prevalence of oral lichen planus: a review and critique. J Oral Pathol Med. 2008 Sep. 37 (8):447-53. [Medline].

  36. Le Cleach L, Chosidow O. Clinical practice. Lichen planus. N Engl J Med. 2012 Feb 23. 366 (8):723-32. [Medline].

  37. Al-Hashimi I, Schifter M, Lockhart PB, Wray D, Brennan M, Migliorati CA, et al. Oral lichen planus and oral lichenoid lesions: diagnostic and therapeutic considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Mar. 103 Suppl:S25.e1-12. [Medline].

  38. Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol. 2002 Feb. 46 (2):207-14. [Medline].

  39. Wagner G, Rose C, Sachse MM. Clinical variants of lichen planus. J Dtsch Dermatol Ges. 2013 Apr. 11 (4):309-19. [Medline].

  40. Schlosser BJ. Lichen planus and lichenoid reactions of the oral mucosa. Dermatol Ther. 2010 May-Jun. 23 (3):251-67. [Medline].

  41. Schlosser BJ, Pirigyi M, Mirowski GW. Oral manifestations of hematologic and nutritional diseases. Otolaryngol Clin North Am. 2011 Feb. 44 (1):183-203, vii. [Medline].

  42. Said HM. Water-soluble vitamins. Bier DM, Mann J, Alpers DH, Vorster HHE, Gibney MJ, eds. Nutrition for the Primary Care Provider. Karger Publishers; 2014. 111: 30-7.

  43. Boyd L, Palmer C. Complete review of dental hygiene. Brian NJ, Cooper MD, eds. Nutrition and Oral Health. Upper Saddle River, NJ: Prentice-Hall; 2001.

  44. Kozlak ST, Walsh SJ, Lalla RV. Reduced dietary intake of vitamin B12 and folate in patients with recurrent aphthous stomatitis. J Oral Pathol Med. 2010 May. 39 (5):420-3. [Medline].

  45. Field EA, Speechley JA, Rugman FR, Varga E, Tyldesley WR. Oral signs and symptoms in patients with undiagnosed vitamin B12 deficiency. J Oral Pathol Med. 1995 Nov. 24 (10):468-70. [Medline].

  46. Leggott PJ, Robertson PB, Jacob RA, Zambon JJ, Walsh M, Armitage GC. Effects of ascorbic acid depletion and supplementation on periodontal health and subgingival microflora in humans. J Dent Res. 1991 Dec. 70 (12):1531-6. [Medline].

  47. Yasui K, Kurata T, Yashiro M, Tsuge M, Ohtsuki S, Morishima T. The effect of ascorbate on minor recurrent aphthous stomatitis. Acta Paediatr. 2010 Mar. 99 (3):442-5. [Medline].

  48. Albahrani AA, Greaves RF. Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement. Clin Biochem Rev. 2016 Feb. 37 (1):27-47. [Medline].

  49. Khabbazi A, Ghorbanihaghjo A, Fanood F, Kolahi S, Hajialiloo M, Rashtchizadeh N. A comparative study of vitamin D serum levels in patients with recurrent aphthous stomatitis. Egyptian Rheumatol. 2015. 37(3):133-37.

  50. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr. 87 (4):1080S-6S. [Medline].

  51. Meisel P, Schwahn C, Luedemann J, John U, Kroemer HK, Kocher T. Magnesium deficiency is associated with periodontal disease. J Dent Res. 2005 Oct. 84 (10):937-41. [Medline].

  52. Sun A, Chen HM, Cheng SJ, Wang YP, Chang JY, Wu YC, et al. Significant association of deficiencies of hemoglobin, iron, vitamin B12, and folic acid and high homocysteine level with recurrent aphthous stomatitis. J Oral Pathol Med. 2015 Apr. 44 (4):300-5. [Medline].

  53. Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet. 2007 Aug 11. 370 (9586):511-20. [Medline].

  54. Cho GS, Han MW, Lee B, Roh JL, Choi SH, Cho KJ, et al. Zinc deficiency may be a cause of burning mouth syndrome as zinc replacement therapy has therapeutic effects. J Oral Pathol Med. 2010 Oct. 39 (9):722-7. [Medline].

  55. Orbak R, Cicek Y, Tezel A, Dogru Y. Effects of zinc treatment in patients with recurrent aphthous stomatitis. Dent Mater J. 2003 Mar. 22 (1):21-9. [Medline].

  56. Nakano A, Nakano H, Nomura K, Toyomaki Y, Hanada K. Novel SLC39A4 mutations in acrodermatitis enteropathica. J Invest Dermatol. 2003 Jun. 120 (6):963-6. [Medline].

  57. Epstein JB, Barasch A. Taste disorders in cancer patients: pathogenesis, and approach to assessment and management. Oral Oncol. 2010 Feb. 46 (2):77-81. [Medline].

  58. Hambidge KM, Krebs NF. Zinc deficiency: a special challenge. J Nutr. 2007 Apr. 137 (4):1101-5. [Medline].

  59. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Leukemia. Surveillance Research Program, National Cancer Institute. Available at http://seer.cancer.gov/statfacts/html/leuks.html. Accessed: June 29, 2016.

  60. Vogel VG, Fisher RE. Epidemiology and etiology of leukemia. Curr Opin Oncol. 1993 Jan. 5 (1):26-34. [Medline].

  61. Swerdlow SH, International Agency for Research on Cancer. WHO classification of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours. 4th ed. Lyon, France: World Health Organization; 2008.

  62. Yamaguchi T, Ohshima K, Karube K, Tutiya T, Kawano R, Suefuji H, et al. Clinicopathological features of cutaneous lesions of adult T-cell leukaemia/ lymphoma. Br J Dermatol. 2005 Jan. 152 (1):76-81. [Medline].

  63. Desch JK, Smoller BR. The spectrum of cutaneous disease in leukemias. J Cutan Pathol. 1993 Oct. 20 (5):407-10. [Medline].

  64. Hou GL, Huang JS, Tsai CC. Analysis of oral manifestations of leukemia: a retrospective study. Oral Dis. 1997 Mar. 3 (1):31-8. [Medline].

  65. Cooper CL, Loewen R, Shore T. Gingival hyperplasia complicating acute myelomonocytic leukemia. J Can Dent Assoc. 2000 Feb. 66 (2):78-9. [Medline].

  66. Chavan M, Subramaniam A, Jhaveri H, Khedkar S, Durkar S, Agrwal A. Acute myeloid leukemia: a case report with palatal and lingual gingival alterations. Braz J Oral Sci. 2010. 9(1):67-9.

  67. Ponce-Torres E, Ruíz-Rodríguez Mdel S, Alejo-González F, Hernández-Sierra JF, Pozos-Guillén Ade J. Oral manifestations in pediatric patients receiving chemotherapy for acute lymphoblastic leukemia. J Clin Pediatr Dent. 2010 Spring. 34 (3):275-9. [Medline].

  68. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011 May 12. 117 (19):5019-32. [Medline].

  69. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Hodgkin Lymphoma. Surveillance Research Program, National Cancer Institute. Available at http://seer.cancer.gov/statfacts/html/hodg.html. Accessed: June 29, 2016.

  70. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Non-Hodgkin Lymphoma. Surveillance Research Program, National Cancer Institute. Available at http://seer.cancer.gov/statfacts/html/nhl.html. Accessed: June 29, 2016.

  71. Rubenstein M, Duvic M. Cutaneous manifestations of Hodgkin's disease. Int J Dermatol. 2006 Mar. 45 (3):251-6. [Medline].

  72. Sirois DA, Miller AS, Harwick RD, Vonderheid EC. Oral manifestations of cutaneous T-cell lymphoma. A report of eight cases. Oral Surg Oral Med Oral Pathol. 1993 Jun. 75 (6):700-5. [Medline].

  73. Molyneux EM, Rochford R, Griffin B, Newton R, Jackson G, Menon G, et al. Burkitt's lymphoma. Lancet. 2012 Mar 31. 379 (9822):1234-44. [Medline].

  74. Liu RS, Liu HC, Bu JQ, Dong SN. Burkitt's lymphoma presenting with jaw lesions. J Periodontol. 2000 Apr. 71 (4):646-9. [Medline].

  75. Corti M, Villafañe MF, Solari R, De Carolis L, Cangelosi D, Santoro J, et al. Non-Hodgkin lymphomas of the oral cavity in AIDS patients in a reference hospital of infectious diseases in Argentina: report of eleven cases and review of the literature. J Gastrointest Cancer. 2011 Sep. 42 (3):143-8. [Medline].

  76. Bower M. Acquired immunodeficiency syndrome-related systemic non-Hodgkin's lymphoma. Br J Haematol. 2001 Mar. 112 (4):863-73. [Medline].

  77. Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999 Dec. 23 (4):433-6. [Medline].

  78. Online Mendelian Inheritance in Man, OMIM®. MIM Number: Cyclic Neutropenia. Available at http://omim.org/. Accessed: June 2, 2016.

  79. Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology Am Soc Hematol Educ Program. 2004. 63-79. [Medline].

  80. Dale DC, Bolyard AA, Aprikyan A. Cyclic neutropenia. Semin Hematol. 2002 Apr. 39 (2):89-94. [Medline].

  81. Bellanné-Chantelot C, Clauin S, Leblanc T, Cassinat B, Rodrigues-Lima F, Beaufils S, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood. 2004 Jun 1. 103 (11):4119-25. [Medline].

  82. Dale DC, Hammond WP 4th. Cyclic neutropenia: a clinical review. Blood Rev. 1988 Sep. 2 (3):178-85. [Medline].

  83. Cohen DW, Morris AL. Periodontal manifestations of cyclic neutropenia. J Periodontol. 1961. 32(2):159-68.

  84. Dale DC, Bolyard AA, Kelley ML, Makaryan V, Bonilla MA, Boxer LA, et al. Long Term Outcomes for Patients with Cyclic Neutropenia Treated with Granulocyte Colony-Stimulating Factor (G-CSF). Blood. 2015. 126(23):996.

  85. Caldemeyer KS, Parks ET, Mirowski GW. Langerhans cell histiocytosis. J Am Acad Dermatol. 2001 Mar. 44 (3):509-11. [Medline].

  86. Nicholson HS, Egeler RM, Nesbit ME. The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998 Apr. 12 (2):379-84. [Medline].

  87. Zinn DJ, Chakraborty R, Allen CE. Langerhans Cell Histiocytosis: Emerging Insights and Clinical Implications. Oncology (Williston Park). 2016 Feb. 30 (2):122-32, 139. [Medline].

  88. Milian MA, Bagan JV, Jimenez Y, Perez A, Scully C, Antoniades D. Langerhans' cell histiocytosis restricted to the oral mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Jan. 91(1):76-9. [Medline].

  89. Annibali S, Cristalli MP, Solidani M, Ciavarella D, La Monaca G, Suriano MM. Langerhans cell histiocytosis: oral/periodontal involvement in adult patients. Oral Dis. 2009 Nov. 15(8):596-601. [Medline].

  90. Baris D, et al. Epidemiology of multiple myeloma. Wiernik P, Goldman JM, Dutcher J, Kyle RA, eds. Neoplastic Diseases of the Blood. New York, NY: Springer; 2013. 547-63.

  91. Silva JA, Mesquita Kde C, Igreja AC, Lucas IC, Freitas AF, Oliveira SM, et al. Paraneoplastic cutaneous manifestations: concepts and updates. An Bras Dermatol. 2013 Jan-Feb. 88 (1):9-22. [Medline].

  92. Epstein JB, Voss NJ, Stevenson-Moore P. Maxillofacial manifestations of multiple myeloma. An unusual case and review of the literature. Oral Surg Oral Med Oral Pathol. 1984 Mar. 57 (3):267-71. [Medline].

  93. Cardoso RC, Gerngross PJ, Hofstede TM, Weber DM, Chambers MS. The multiple oral presentations of multiple myeloma. Support Care Cancer. 2014 Jan. 22 (1):259-67. [Medline].

  94. Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am. 2014 May. 34 (2):283-95. [Medline].

  95. Castling B, Smith AT, Myers B. Involvement of the jaw bones in systemic mastocytosis. Br J Oral Maxillofac Surg. 2006 Apr. 44 (2):87-8. [Medline].

  96. Medina R, Faecher RS, Stafford DS, Zander DS, Baughman RA. Systemic mastocytosis involving the mandible. Oral Surg Oral Med Oral Pathol. 1994 Jul. 78 (1):28-35. [Medline].

  97. Bac DJ, van Marwijk Kooy M. Mastocytosis and Sjögren's syndrome. Ann Rheum Dis. 1992 Feb. 51 (2):277-8. [Medline].

  98. Pal B. Systemic mastocytosis and Sjögren's syndrome. Ann Rheum Dis. 1992 Oct. 51 (10):1183. [Medline].

  99. Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol. 2014 Jun. 38 (6):832-43. [Medline].

  100. George JN, Arnold DM. Approach to the adult with unexplained thrombocytopenia. UpToDate. Available at http://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-thrombocytopenia. Accessed: July 10, 2016.

  101. [Guideline] Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011 Apr 21. 117 (16):4190-207. [Medline].

  102. Dabiri G, Damstetter E, Chang Y, Baiyee Ebot E, Powers JG, Phillips T. Coagulation disorders and their cutaneous presentations: Diagnostic work-up and treatment. J Am Acad Dermatol. 2016 May. 74 (5):795-804. [Medline].

  103. James WD, Guiry CC, Grote WR. Acute idiopathic thrombocytopenic purpura. Oral Surg Oral Med Oral Pathol. 1984 Feb. 57 (2):149-51. [Medline].

  104. Adams PC. Epidemiology and diagnostic testing for hemochromatosis and iron overload. Int J Lab Hematol. 2015 May. 37 Suppl 1:25-30. [Medline].

  105. Online Mendelian Inheritance in Man, OMIM®. MIM Number: #235200. Available at http://omim.org/. Accessed: July 9, 2016.

  106. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010 Aug. 139 (2):393-408, 408.e1-2. [Medline].

  107. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005 Apr 28. 352 (17):1769-78. [Medline].

  108. Erwin A, Balwani M, Desnick RJ. Congenital Erythropoietic Porphyria. GeneReviews. Available at http://www.ncbi.nlm.nih.gov/books/NBK154652/. 2013; Accessed: July 10, 2016.

  109. Fayle SA, Pollard MA. Congenital erythropoietic porphyria--oral manifestations and dental treatment in childhood: a case report. Quintessence Int. 1994 Aug. 25 (8):551-4. [Medline].

  110. Javed F, Correa FO, Nooh N, Almas K, Romanos GE, Al-Hezaimi K. Orofacial manifestations in patients with sickle cell disease. Am J Med Sci. 2013 Mar. 345 (3):234-7. [Medline].

  111. Online Mendelian Inheritance in Man, OMIM®. OMIM 603903. Available at http://omim.org/. Accessed: May 16, 2016.

  112. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11. 376 (9757):2018-31. [Medline].

  113. World Health Organization. Sickle-cell Disease and Other Haemoglobin Disorders. Available at http://www.who.int/mediacentre/factsheets/fs308/en/. Jan 2011; Accessed: July 10, 2016.

  114. Centers for Disease Control and Prevention. Sickle Cell Disease - Data & Statistics. Available at http://www.cdc.gov/ncbddd/sicklecell/data.html. February 29, 2016; Accessed: July 10, 2016.

  115. Jones H, Blinder M, Anadkat M. Cutaneous manifestations of sickle cell disease. Open J Blood Dis. 2013.

  116. Tefferi A. Polycythemia vera: a comprehensive review and clinical recommendations. Mayo Clin Proc. 2003 Feb. 78 (2):174-94. [Medline].

  117. Anía BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ 3rd. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. Am J Hematol. 1994 Oct. 47 (2):89-93. [Medline].

  118. Najean Y, Rain JD, Billotey C. Epidemiological data in polycythaemia vera: a study of 842 cases. Hematol Cell Ther. 1998 Aug. 40 (4):159-65. [Medline].

  119. Lele MV. Oral manifestations of polycythaemia rubra vera. J All India Dent Assoc. 1965 Nov. 37 (11):345-8. [Medline].

  120. Ruparella PB, Ruparella KP, Shirolkar R, Tipathy A. Chronic myeloproliferative disorders: A rarest case with oral manifestations and dental management. J Indian Aca Oral Med Radio. 2012. 24(2):155-57.

  121. Carlson ER, Chewning LC. Polycythemia vera in an oral surgical patient. A case report. Oral Surg Oral Med Oral Pathol. 1989 Jun. 67 (6):673-5. [Medline].

  122. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003 May. 2 (3):119-25. [Medline].

  123. Baldini C, Talarico R, Tzioufas AG, Bombardieri S. Classification criteria for Sjogren's syndrome: a critical review. J Autoimmun. 2012 Aug. 39 (1-2):9-14. [Medline].

  124. Moutsopoulos HM. Sjögren's syndrome: a forty-year scientific journey. J Autoimmun. 2014 Jun. 51:1-9. [Medline].

  125. Goules AV, Tzioufas AG, Moutsopoulos HM. Classification criteria of Sjögren's syndrome. J Autoimmun. 2014 Feb-Mar. 48-49:42-5. [Medline].

  126. Baldini C, Bernacchi E, Talarico R. Skin Manifestations and Sjögren’s Syndrome. Matucci-Cerinic M, Furst D, Fiorentino D, eds. Skin Manifestations in Rheumatic Disease. New York, NY: Springer; 2014. 207-15.

  127. Islam NM, Bhattacharyya I, Cohen DM. Common oral manifestations of systemic disease. Otolaryngol Clin North Am. 2011 Feb. 44 (1):161-82, vi. [Medline].

  128. Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med. 2004 Jun 28. 164 (12):1275-84. [Medline].

  129. Rhodus NL, Bloomquist C, Liljemark W, Bereuter J. Prevalence, density, and manifestations of oral Candida albicans in patients with Sjögren's syndrome. J Otolaryngol. 1997 Oct. 26 (5):300-5. [Medline].

  130. Rhodus NL, Bloomquist C, Liljemark W, Bereuter J. Prevalence, density, and manifestations of oral Candida albicans in patients with Sjögren's syndrome. J Otolaryngol. 1997 Oct. 26(5):300-5. [Medline].

  131. Soto-Rojas AE, Villa AR, Sifuentes-Osornio J, Alarcon-Segovia D, Kraus A. Oral candidiasis and Sjogren's syndrome. J Rheumatol. 1998 May. 25(5):911-5. [Medline].

  132. Ravald N, List T. Caries and periodontal conditions in patients with primary Sjögren's syndrome. Swed Dent J. 1998. 22 (3):97-103. [Medline].

  133. Williams RC, Gibbons RJ. Inhibition of streptococcal attachment to receptors on human buccal epithelial cells by antigenically similar salivary glycoproteins. Infect Immun. 1975 Apr. 11 (4):711-8. [Medline].

  134. Epstein JB, Truelove EL, Izutzu KT. Oral candidiasis: pathogenesis and host defense. Rev Infect Dis. 1984 Jan-Feb. 6 (1):96-106. [Medline].

  135. Daniels TE, Cox D, Shiboski CH, Schiødt M, Wu A, Lanfranchi H, et al. Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants. Arthritis Rheum. 2011 Jul. 63(7):2021-30. [Medline]. [Full Text].

  136. Sankar V, Noll JL, Brennan MT. Diagnosis of Sjögren's syndrome: American-European and the American College of Rheumatology classification criteria. Oral Maxillofac Surg Clin North Am. 2014 Feb. 26 (1):13-22. [Medline].

  137. Taubert KA. Epidemiology of Kawasaki disease in the United States and worldwide. Prog Pediatr Cardio. 1997. 6(3):181-5.

  138. Yim D, Curtis N, Cheung M, Burgner D. Update on Kawasaki disease: epidemiology, aetiology and pathogenesis. J Paediatr Child Health. 2013 Sep. 49 (9):704-8. [Medline].

  139. Council on Cardiovascular Disease in the Young, Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, American Heart Association. Diagnostic guidelines for Kawasaki disease. Circulation. 2001 Jan 16. 103 (2):335-6. [Medline].

  140. Ogden GR, Kerr M. Mucocutaneous lymph node syndrome (Kawasaki disease). Oral Surg Oral Med Oral Pathol. 1989 May. 67 (5):569-72. [Medline].

  141. Ozdemir H, Ciftçi E, Tapisiz A, Ince E, Tutar E, Atalay S, et al. Clinical and epidemiological characteristics of children with Kawasaki disease in Turkey. J Trop Pediatr. 2010 Aug. 56(4):260-2. [Medline].

  142. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998 May. 41 (5):778-99. [Medline].

  143. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug. 64 (8):2677-86. [Medline].

  144. Lourenço SV, de Carvalho FR, Boggio P, Sotto MN, Vilela MA, Rivitti EA, et al. Lupus erythematosus: clinical and histopathological study of oral manifestations and immunohistochemical profile of the inflammatory infiltrate. J Cutan Pathol. 2007 Jul. 34 (7):558-64. [Medline].

  145. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009 May 7. 360 (19):1989-2003. [Medline].

  146. Fischer DJ, Patton LL. Scleroderma: oral manifestations and treatment challenges. Spec Care Dentist. 2000 Nov-Dec. 20 (6):240-4. [Medline].

  147. Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem disease. Am Fam Physician. 2008 Oct 15. 78 (8):961-8. [Medline].

  148. Nagy G, Kovács J, Zeher M, Czirják L. Analysis of the oral manifestations of systemic sclerosis. Oral Surg Oral Med Oral Pathol. 1994 Feb. 77 (2):141-6. [Medline].

  149. Eufinger H, Machtens E, Akuamoa-Boateng E. Oral manifestations of Wegener's granulomatosis. Review of the literature and report of a case. Int J Oral Maxillofac Surg. 1992 Feb. 21(1):50-3. [Medline].

  150. Patten SF, Tomecki KJ. Wegener's granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol. 1993 May. 28(5 Pt 1):710-8. [Medline].

  151. Mahr AD, Neogi T, Merkel PA. Epidemiology of Wegener's granulomatosis: Lessons from descriptive studies and analyses of genetic and environmental risk determinants. Clin Exp Rheumatol. 2006 Mar-Apr. 24 (2 Suppl 41):S82-91. [Medline].

  152. Tarabishy AB, Schulte M, Papaliodis GN, Hoffman GS. Wegener's granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthalmol. 2010 Sep-Oct. 55 (5):429-44. [Medline].

  153. Almouhawis HA, Leao JC, Fedele S, Porter SR. Wegener's granulomatosis: a review of clinical features and an update in diagnosis and treatment. J Oral Pathol Med. 2013 Aug. 42 (7):507-16. [Medline].

  154. Eufinger H, Machtens E, Akuamoa-Boateng E. Oral manifestations of Wegener's granulomatosis. Review of the literature and report of a case. Int J Oral Maxillofac Surg. 1992 Feb. 21 (1):50-3. [Medline].

  155. Knight JM, Hayduk MJ, Summerlin DJ, Mirowski GW. "Strawberry" gingival hyperplasia: a pathognomonic mucocutaneous finding in Wegener granulomatosis. Arch Dermatol. 2000 Feb. 136(2):171-3. [Medline].

  156. Napier SS, Allen JA, Irwin CR, McCluskey DR. Strawberry gums: a clinicopathological manifestation diagnostic of Wegener's granulomatosis?. J Clin Pathol. 1993 Aug. 46(8):709-12. [Medline].

  157. Ruokonen H, Helve T, Arola J, Hietanen J, Lindqvist C, Hagstrom J. "Strawberry like" gingivitis being the first sign of Wegener's granulomatosis. Eur J Intern Med. 2009 Oct. 20(6):651-3. [Medline].

  158. Patten SF, Tomecki KJ. Wegener's granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol. 1993 May. 28 (5 Pt 1):710-8. [Medline].

  159. Rybicki BA, Iannuzzi MC. Epidemiology of sarcoidosis: recent advances and future prospects. Semin Respir Crit Care Med. 2007 Feb. 28 (1):22-35. [Medline].

  160. Suresh L, Radfar L. Oral sarcoidosis: a review of literature. Oral Dis. 2005 May. 11 (3):138-45. [Medline].

  161. Yanardağ H, Pamuk ON, Karayel T. Cutaneous involvement in sarcoidosis: analysis of the features in 170 patients. Respir Med. 2003 Aug. 97 (8):978-82. [Medline].

  162. Lisowe JA, Fleck JD, Mirowski GW. Pearls in neurodermatology. Semin Neurol. 1998. 18(2):243-55. [Medline].

  163. Marcoval J, Mañá J. Specific (granulomatous) oral lesions of sarcoidosis: report of two cases. Med Oral Patol Oral Cir Bucal. 2010 May 1. 15(3):e456-8. [Medline].

  164. Nagata Y, Kanekura T, Kawabata H, et al. A case of sarcoidosis involving the tongue. J Dermatol. 1999 Oct. 26(10):666-70. [Medline].

  165. Real de Asúa D, Costa R, Galván JM, Filigheddu MT, Trujillo D, Cadiñanos J. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Clin Epidemiol. 2014. 6:369-77. [Medline].

  166. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016 Jun 25. 387 (10038):2641-54. [Medline].

  167. Salisbury PL 3rd, Jacoway JR. Oral amyloidosis: a late complication of multiple myeloma. Oral Surg Oral Med Oral Pathol. 1983 Jul. 56(1):48-50. [Medline].

  168. Georgiades CS, Neyman EG, Barish MA, Fishman EK. Amyloidosis: review and CT manifestations. Radiographics. 2004 Mar-Apr. 24 (2):405-16. [Medline].

  169. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997 Sep 25. 337(13):898-909. [Medline].

  170. Viggor SF, Frezzini C, Farthing PM, Freeman CO, Yeoman CM, Thornhill MH. Amyloidosis: an unusual case of persistent oral ulceration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Nov. 108(5):e46-50. [Medline].

  171. Elad S, Czerninski R, Fischman S, Keshet N, Drucker S, Davidovich T, et al. Exceptional oral manifestations of amyloid light chain protein (AL) systemic amyloidosis. Amyloid. 2010 Mar. 17 (1):27-31. [Medline].

  172. Carbone JE, Barker D, Stauffer JL. Sleep apnea in amyloidosis. Chest. 1985 Mar. 87 (3):401-3. [Medline].

  173. World Health Organization. HIV/AIDS Fact Sheet. Available at http://www.who.int/mediacentre/factsheets/fs360/en/. Nov 2015; Accessed: July 11, 2016.

  174. Meyer U, Kleinheinz J, Handschel J, Kruse-Lösler B, Weingart D, Joos U. Oral findings in three different groups of immunocompromised patients. J Oral Pathol Med. 2000 Apr. 29 (4):153-8. [Medline].

  175. Zancanaro PC, McGirt LY, Mamelak AJ, Nguyen RH, Martins CR. Cutaneous manifestations of HIV in the era of highly active antiretroviral therapy: an institutional urban clinic experience. J Am Acad Dermatol. 2006 Apr. 54 (4):581-8. [Medline].

  176. Nokta M. Oral manifestations associated with HIV infection. Curr HIV/AIDS Rep. 2008 Feb. 5 (1):5-12. [Medline].

  177. Casiglia JW, Woo S. Oral manifestations of HIV infection. Clin Dermatol. 2000 Sep-Oct. 18(5):541-51. [Medline].

  178. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992 Dec 18. 41:1-19. [Medline].

  179. Greenspan JS, Barr CE, Sciubba JJ, Winkler JR. Oral manifestations of HIV infection. Definitions, diagnostic criteria, and principles of therapy. The U.S.A. Oral AIDS Collaborative Group. Oral Surg Oral Med Oral Pathol. 1992 Feb. 73(2):142-4. [Medline].

  180. Kademani D, Glick M. Oral ulcerations in individuals infected with human immunodeficiency virus: clinical presentations, diagnosis, management, and relevance to disease progression. Quintessence Int. 1998 Aug. 29(8):523-34. [Medline].

  181. Mirowski GW, Hilton JF, Greenspan D, et al. Association of cutaneous and oral diseases in HIV-infected men. Oral Dis. 1998 Mar. 4(1):16-21. [Medline].

  182. Scully C, Laskaris G, Pindborg J, Porter SR, Reichart P. Oral manifestations of HIV infection and their management. I. More common lesions. Oral Surg Oral Med Oral Pathol. 1991 Feb. 71(2):158-66. [Medline].

  183. Nweze EI, Ogbonnaya UL. Oral Candida isolates among HIV-infected subjects in Nigeria. J Microbiol Immunol Infect. 2011 Jun. 44(3):172-7. [Medline].

  184. Dodd CL, Greenspan D, Katz MH, Westenhouse JL, Feigal DW, Greenspan JS. Oral candidiasis in HIV infection: pseudomembranous and erythematous candidiasis show similar rates of progression to AIDS. AIDS. 1991 Nov. 5 (11):1339-43. [Medline].

  185. Armstrong-James D, Meintjes G, Brown GD. A neglected epidemic: fungal infections in HIV/AIDS. Trends Microbiol. 2014 Mar. 22 (3):120-7. [Medline].

  186. Gaitán-Cepeda LA, Sánchez-Vargas O, Castillo N. Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis. Int J STD AIDS. 2015 Aug. 26 (9):625-32. [Medline].

  187. Perezous LF, Flaitz CM, Goldschmidt ME, Engelmeier RL. Colonization of Candida species in denture wearers with emphasis on HIV infection: a literature review. J Prosthet Dent. 2005 Mar. 93 (3):288-93. [Medline].

  188. Langenberg AG, Corey L, Ashley RL, Leong WP, Straus SE. A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group. N Engl J Med. 1999 Nov 4. 341(19):1432-8. [Medline].

  189. Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex virus types 1 and 2--United States, 1999-2010. J Infect Dis. 2014 Feb 1. 209 (3):325-33. [Medline].

  190. Birek C, Ficarra G. The diagnosis and management of oral herpes simplex infection. Curr Infect Dis Rep. 2006 May. 8 (3):181-8. [Medline].

  191. Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998 Oct. 86 (4):432-7. [Medline].

  192. Patton LL, Phelan JA, Ramos-Gomez FJ, Nittayananta W, Shiboski CH, Mbuguye TL. Prevalence and classification of HIV-associated oral lesions. Oral Dis. 2002. 8 Suppl 2:98-109. [Medline].

  193. Ficarra G. Oral ulcers in HIV-infected patients: an update on epidemiology and diagnosis. Oral Dis. 1997 May. 3 Suppl 1:S183-9. [Medline].

  194. Généreau T, Lortholary O, Bouchaud O, Lacassin F, Vinceneux P, De Truchis P, et al. Herpes simplex esophagitis in patients with AIDS: report of 34 cases. The Cooperative Study Group on Herpetic Esophagitis in HIV Infection. Clin Infect Dis. 1996 Jun. 22 (6):926-31. [Medline].

  195. Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis. 2004 Nov 1. 39 Suppl 5:S248-57. [Medline].

  196. Greenspan D, Greenspan JS. Significance of oral hairy leukoplakia. Oral Surg Oral Med Oral Pathol. 1992 Feb. 73(2):151-4. [Medline].

  197. Greenspan JS, Greenspan D, Webster-Cyriaque J. Hairy leukoplakia; lessons learned: 30-plus years. Oral Dis. 2016 Apr. 22 Suppl 1:120-7. [Medline].

  198. Itin P, Rufli T, Rüdlinger R, Cathomas G, Huser B, Podvinec M, et al. Oral hairy leukoplakia in a HIV-negative renal transplant patient: a marker for immunosuppression?. Dermatologica. 1988. 177 (2):126-8. [Medline].

  199. Chattopadhyay A, Caplan DJ, Slade GD, Shugars DC, Tien HC, Patton LL. Risk indicators for oral candidiasis and oral hairy leukoplakia in HIV-infected adults. Community Dent Oral Epidemiol. 2005 Feb. 33 (1):35-44. [Medline].

  200. Greenspan D, Greenspan JS, Overby G, et al. Risk factors for rapid progression from hairy leukoplakia to AIDS: a nested case-control study. J Acquir Immune Defic Syndr. 1991. 4(7):652-8. [Medline].

  201. Patton LL, McKaig R, Strauss R, Rogers D, Eron JJ Jr. Changing prevalence of oral manifestations of human immuno-deficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Mar. 89 (3):299-304. [Medline].

  202. Schiødt M, Greenspan D, Daniels TE, Greenspan JS. Clinical and histologic spectrum of oral hairy leukoplakia. Oral Surg Oral Med Oral Pathol. 1987 Dec. 64 (6):716-20. [Medline].

  203. Triantos D, Porter SR, Scully C, Teo CG. Oral hairy leukoplakia: clinicopathologic features, pathogenesis, diagnosis, and clinical significance. Clin Infect Dis. 1997 Dec. 25 (6):1392-6. [Medline].

  204. Moura MD, Haddad JP, Senna MI, Ferreira e Ferreira E, Mesquita RA. A new topical treatment protocol for oral hairy leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Nov. 110 (5):611-7. [Medline].

  205. Martellotta F, Berretta M, Vaccher E, Schioppa O, Zanet E, Tirelli U. AIDS-related Kaposi's sarcoma: state of the art and therapeutic strategies. Curr HIV Res. 2009 Nov. 7 (6):634-8. [Medline].

  206. Bhutani M, Polizzotto MN, Uldrick TS, Yarchoan R. Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Semin Oncol. 2015 Apr. 42 (2):223-46. [Medline].

  207. Ives NJ, Gazzard BG, Easterbrook PJ. The changing pattern of AIDS-defining illnesses with the introduction of highly active antiretroviral therapy (HAART)in a London clinic. J Infect. 2001 Feb. 42 (2):134-9. [Medline].

  208. Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi's sarcoma. Eur J Cancer. 2001 Jul. 37 (10):1288-95. [Medline].

  209. Ficarra G, Berson AM, Silverman S Jr, Quivey JM, Lozada-Nur F, Sooy DD, et al. Kaposi's sarcoma of the oral cavity: a study of 134 patients with a review of the pathogenesis, epidemiology, clinical aspects, and treatment. Oral Surg Oral Med Oral Pathol. 1988 Nov. 66 (5):543-50. [Medline].

  210. Yeh CK, Fox PC, Fox CH, Travis WD, Lane HC, Baum BJ. Kaposi's sarcoma of the parotid gland in acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol. 1989 Mar. 67 (3):308-12. [Medline].

  211. Castle JT, Thompson LD. Kaposi sarcoma of major salivary gland origin: A clinicopathologic series of six cases. Cancer. 2000 Jan 1. 88 (1):15-23. [Medline].

  212. Fatahzadeh M. Kaposi sarcoma: review and medical management update. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Jan. 113 (1):2-16. [Medline].

  213. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010 Jul. 20 (4):202-13. [Medline].

  214. Kano Y, Shiohara T. Current understanding of cytomegalovirus infection in immunocompetent individuals. J Dermatol Sci. 2000 Apr. 22 (3):196-204. [Medline].

  215. Chakraborty A, Siddhanta S, De C, Bhattacharyya S, Guha Sk, et al. Cytomegalovirus Retinitis with Multiple Co Infections in a HIV/AIDS Patient having Extreme Low CD4 Count: A Case Report and Review of Literature. J AIDS Clin Res. 2014. 5:394.

  216. Greenspan D, Greenspan JS. Oral manifestations of human immunodeficiency virus infection. Dent Clin North Am. 1993 Jan. 37(1):21-32. [Medline].

  217. Itin PH, Lautenschlager S, Flückiger R, Rufli T. Oral manifestations in HIV-infected patients: diagnosis and management. J Am Acad Dermatol. 1993 Nov. 29(5 Pt 1):749-60. [Medline].

  218. Mathur S, Jani M, Thakkar P, Shah A. Oral Manifestations of HIV Infection. Int J Dent Med Res. 2014. 1(4):139.

  219. Mattes FM, McLaughlin JE, Emery VC, Clark DA, Griffiths PD. Histopathological detection of owl's eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7. J Clin Pathol. 2000 Aug. 53 (8):612-4. [Medline].

  220. Kreimer AR, Alberg AJ, Daniel R, Gravitt PE, Viscidi R, Garrett ES, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis. 2004 Feb 15. 189 (4):686-98. [Medline].

  221. Brickman C, Palefsky JM. Human papillomavirus in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era. Curr HIV/AIDS Rep. 2015 Mar. 12 (1):6-15. [Medline].

  222. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012 Feb 15. 307 (7):693-703. [Medline].

  223. Devarakonda S, Neppalli A, Liu L, Shi R. Abstract 278: Risk factors and prevalence of genital HPV infection among adult females in US between 2003-2010: Data from NHANES study. Cancer Res. 2014 Sept. 74(19 Supplement):278-278.

  224. Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. 2013 Aug 1. 208 (3):385-93. [Medline].

  225. Palefsky JM, Holly EA, Ralston ML, Jay N. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis. 1998 Feb. 177 (2):361-7. [Medline].

  226. Ahdieh L, Klein RS, Burk R, Cu-Uvin S, Schuman P, Duerr A, et al. Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J Infect Dis. 2001 Sep 15. 184 (6):682-90. [Medline].

  227. Blitz S, Baxter J, Raboud J, Walmsley S, Rachlis A, Smaill F, et al. Evaluation of HIV and highly active antiretroviral therapy on the natural history of human papillomavirus infection and cervical cytopathologic findings in HIV-positive and high-risk HIV-negative women. J Infect Dis. 2013 Aug 1. 208 (3):454-62. [Medline].

  228. Beachler DC, Sugar EA, Margolick JB, Weber KM, Strickler HD, Wiley DJ, et al. Risk factors for acquisition and clearance of oral human papillomavirus infection among HIV-infected and HIV-uninfected adults. Am J Epidemiol. 2015 Jan 1. 181 (1):40-53. [Medline].

  229. Centers for Disease Control and Prevention. Anogenital Warts. Available at https://www.cdc.gov/std/tg2015/warts.htm. June 4, 2015; Accessed: July 11, 2016.

  230. Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin. 2002 Jul-Aug. 52 (4):195-215. [Medline].

  231. King MD, Reznik DA, O'Daniels CM, Larsen NM, Osterholt D, Blumberg HM. Human papillomavirus-associated oral warts among human immunodeficiency virus-seropositive patients in the era of highly active antiretroviral therapy: an emerging infection. Clin Infect Dis. 2002 Mar 1. 34 (5):641-8. [Medline].

  232. Greenspan D, Canchola AJ, MacPhail LA, Cheikh B, Greenspan JS. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet. 2001 May 5. 357 (9266):1411-2. [Medline].

  233. Syrjanen S, Termine N, Capra G, Paderni C, Panzarella V, Campisi G. Oral HPV infection: current strategies for prevention and therapy. Curr Pharm Des. 2012. 18 (34):5452-69. [Medline].

  234. Chavan M, Jain H, Diwan N, Khedkar S, Shete A, Durkar S. Recurrent aphthous stomatitis: a review. J Oral Pathol Med. 2012 Sep. 41 (8):577-83. [Medline].

  235. Muzyka BC, Glick M. Major aphthous ulcers in patients with HIV disease. Oral Surg Oral Med Oral Pathol. 1994 Feb. 77 (2):116-20. [Medline].

  236. MacPhail LA, Greenspan D, Feigal DW, Lennette ET, Greenspan JS. Recurrent aphthous ulcers in association with HIV infection. Description of ulcer types and analysis of T-lymphocyte subsets. Oral Surg Oral Med Oral Pathol. 1991 Jun. 71 (6):678-83. [Medline].

  237. Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, Anaya-Saavedra G, González-Ramírez I, Ponce-de-León S. The Changing Clinical Spectrum of Human Immunodeficiency Virus (HIV)-Related Oral Lesions in 1,000 Consecutive Patients: A 12-Year Study in a Referral Center in Mexico. Medicine (Baltimore). 2003 Jan. 82 (1):39-50. [Medline].

  238. Messadi DV, Younai F. Aphthous ulcers. Dermatol Ther. 2010 May-Jun. 23 (3):281-90. [Medline].

  239. Randall P. Thalidomide effective treatment for AIDS-related mouth ulcers. NIAID AIDS Agenda. 1995 Dec. 2. [Medline].

  240. Khandwala A, Van Inwegen RG, Alfano MC. 5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: I. Clinical demonstration of acceleration of healing and resolution of pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Feb. 83 (2):222-30. [Medline].

  241. Meng W, Dong Y, Liu J, Wang Z, Zhong X, Chen R, et al. A clinical evaluation of amlexanox oral adhesive pellicles in the treatment of recurrent aphthous stomatitis and comparison with amlexanox oral tablets: a randomized, placebo controlled, blinded, multicenter clinical trial. Trials. 2009 May 6. 10:30. [Medline].

  242. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997 May 22. 336 (21):1487-93. [Medline].

  243. Challacombe SJ, Alsahaf S, Tappuni A. Recurrent Aphthous Stomatitis: Towards Evidence-Based Treatment?. Curr Oral Health Rep. 2015. 2:158-67.

  244. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005 Mar. 64 Suppl 2:ii18-23; discussion ii24-5. [Medline].

  245. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014 Mar. 70 (3):512-6. [Medline].

  246. Johnson MA, Armstrong AW. Clinical and histologic diagnostic guidelines for psoriasis: a critical review. Clin Rev Allergy Immunol. 2013 Apr. 44 (2):166-72. [Medline].

  247. Eastman JR, Goldblatt LI. Psoriasis. Palatal manifestations and physiologic considerations. J Periodontol. 1983 Dec. 54(12):736-9. [Medline].

  248. Morris LF, Phillips CM, Binnie WH, Sander HM, Silverman AK, Menter MA. Oral lesions in patients with psoriasis: a controlled study. Cutis. 1992 May. 49(5):339-44. [Medline].

  249. Richardson LJ, Kratochvil FJ, Zieper MB. Unusual palatal presentation of oral psoriasis. J Can Dent Assoc. 2000 Feb. 66(2):80-2. [Medline].

  250. Zhu JF, Kaminski MJ, Pulitzer DR, Hu J, Thomas HF. Psoriasis: pathophysiology and oral manifestations. Oral Dis. 1996 Jun. 2(2):135-44. [Medline].

  251. Mattsson U, Warfvinge G, Jontell M. Oral psoriasis-a diagnostic dilemma: a report of two cases and a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Oct. 120 (4):e183-9. [Medline].

  252. van der Waal I, Pindborg JJ. Diseases of the Tongue. Chicago, Ill: Quintessence Publishing; 1986. 103-4.

  253. Germi L, De Giorgi V, Bergamo F, Niccoli MC, Kokelj F, Simonacci M, et al. Psoriasis and oral lesions: multicentric study of Oral Mucosa Diseases Italian Group (GIPMO). Dermatol Online J. 2012 Jan 15. 18 (1):11. [Medline].

  254. Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: a practical approach to evaluation and management. Dermatol Online J. 2008 Sep 15. 14 (9):2. [Medline].

  255. Burke JP, Duggirala R, Hale DE, Blangero J, Stern MP. Genetic basis of acanthosis nigricans in Mexican Americans and its association with phenotypes related to type 2 diabetes. Hum Genet. 2000 May. 106 (5):467-72. [Medline].

  256. Kong AS, Williams RL, Rhyne R, Urias-Sandoval V, Cardinali G, Weller NF, et al. Acanthosis Nigricans: high prevalence and association with diabetes in a practice-based research network consortium--a PRImary care Multi-Ethnic network (PRIME Net) study. J Am Board Fam Med. 2010 Jul-Aug. 23 (4):476-85. [Medline].

  257. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol. 1994 Jul. 31(1):1-19; quiz 20-2. [Medline].

  258. Sedano HO, Gorlin RJ. Acanthosis nigricans. Oral Surg Oral Med Oral Pathol. 1987 Apr. 63(4):462-7. [Medline].

  259. Tyler MT, Ficarra G, Silverman S Jr, Odom RB, Regezi JA. Malignant acanthosis nigricans with florid papillary oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Apr. 81(4):445-9. [Medline].

  260. Bottoni U, Dianzani C, Pranteda G, Innocenzi D, De Giacomo P, Balzani A, et al. Florid cutaneous and mucosal papillomatosis with acanthosis nigricans revealing a primary lung cancer. J Eur Acad Dermatol Venereol. 2000 May. 14 (3):205-8. [Medline].

  261. Kebria MM, Belinson J, Kim R, Mekhail TM. Malignant acanthosis nigricans, tripe palms and the sign of Leser-Tre'lat, a hint to the diagnosis of early stage ovarian cancer: a case report and review of the literature. Gynecol Oncol. 2006 May. 101 (2):353-5. [Medline].

  262. Mekhail TM, Markman M. Acanthosis nigricans with endometrial carcinoma: case report and review of the literature. Gynecol Oncol. 2002 Feb. 84 (2):332-4. [Medline].

  263. Pentenero M, Carrozzo M, Pagano M, Gandolfo S. Oral acanthosis nigricans, tripe palms and sign of leser-trélat in a patient with gastric adenocarcinoma. Int J Dermatol. 2004 Jul. 43 (7):530-2. [Medline].

  264. Nomachi K, Mori M, Matsuda N. Improvement of oral lesions associated with malignant acanthosis nigricans after treatment of lung cancer. Oral Surg Oral Med Oral Pathol. 1989 Jul. 68 (1):74-9. [Medline].

  265. Ramirez-Amador V, Esquivel-Pedraza L, Caballero-Mendoza E, Berumen-Campos J, Orozco-Topete R, Angeles-Angeles A. Oral manifestations as a hallmark of malignant acanthosis nigricans. J Oral Pathol Med. 1999 Jul. 28 (6):278-81. [Medline].

  266. Mostofi RS, Hayden NP, Soltani K. Oral malignant acanthosis nigricans. Oral Surg Oral Med Oral Pathol. 1983 Oct. 56 (4):372-4. [Medline].

  267. Cairo F, Rubino I, Rotundo R, Prato GP, Ficarra G. Oral Acanthosis nigricans as a marker of internal malignancy. A case report. J Periodontol. 2001 Sep. 72 (9):1271-5. [Medline].

  268. Friedman JM. Neurofibromatosis 1. GeneReviews. Available at http://www.ncbi.nlm.nih.gov/books/NBK1109/. 2014; Accessed: July 10, 2016.

  269. Evans DG. Neurofibromatosis 2. GeneReviews. Available at http://www.ncbi.nlm.nih.gov/books/NBK1201/. 2011; Accessed: July 10, 2016.

  270. Geist JR, Gander DL, Stefanac SJ. Oral manifestations of neurofibromatosis types I and II. Oral Surg Oral Med Oral Pathol. 1992 Mar. 73 (3):376-82. [Medline].

  271. Javed F, Ramalingam S, Ahmed HB, Gupta B, Sundar C, Qadri T, et al. Oral manifestations in patients with neurofibromatosis type-1: a comprehensive literature review. Crit Rev Oncol Hematol. 2014 Aug. 91 (2):123-9. [Medline].

  272. Bongiorno MR, Pistone G, Aricò M. Manifestations of the tongue in Neurofibromatosis type 1. Oral Dis. 2006 Mar. 12 (2):125-9. [Medline].

  273. Tsang ES, Birch P, Friedman JM, Johnston D, Tucker T, Armstrong L. Prevalence of dental caries in children with neurofibromatosis 1. Clin Oral Investig. 2010 Aug. 14 (4):479-80; author reply 480. [Medline].

  274. D'Ambrosio JA, Langlais RP, Young RS. Jaw and skull changes in neurofibromatosis. Oral Surg Oral Med Oral Pathol. 1988 Sep. 66 (3):391-6. [Medline].

  275. Cunha KS, Barboza EP, Dias EP, Oliveira FM. Neurofibromatosis type I with periodontal manifestation. A case report and literature review. Br Dent J. 2004 Apr 24. 196 (8):457-60. [Medline].

  276. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Available at http://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html. May 15, 2015; Accessed: July 10, 2016.

  277. Online Mendelian Inheritance in Man, OMIM. MIM Number: {#125853}. Available at http://omim.org/. Accessed: February 10, 2016.

  278. Murphy-Chutorian B, Han G, Cohen SR. Dermatologic manifestations of diabetes mellitus: a review. Endocrinol Metab Clin North Am. 2013 Dec. 42 (4):869-98. [Medline].

  279. Leite RS, Marlow NM, Fernandes JK. Oral health and type 2 diabetes. Am J Med Sci. 2013 Apr. 345 (4):271-3. [Medline].

  280. Bastos AS, Leite AR, Spin-Neto R, Nassar PO, Massucato EM, Orrico SR. Diabetes mellitus and oral mucosa alterations: prevalence and risk factors. Diabetes Res Clin Pract. 2011 Apr. 92 (1):100-5. [Medline].

  281. Dikshit RP, Ramadas K, Hashibe M, Thomas G, Somanathan T, Sankaranarayanan R. Association between diabetes mellitus and pre-malignant oral diseases: a cross sectional study in Kerala, India. Int J Cancer. 2006 Jan 15. 118 (2):453-7. [Medline].

  282. Quirino MR, Birman EG, Paula CR. Oral manifestations of diabetes mellitus in controlled and uncontrolled patients. Braz Dent J. 1995. 6 (2):131-6. [Medline].

  283. Lamster IB, Lalla E, Borgnakke WS, Taylor GW. The relationship between oral health and diabetes mellitus. J Am Dent Assoc. 2008 Oct. 139 Suppl:19S-24S. [Medline].

  284. Murrah VA. Diabetes mellitus and associated oral manifestations: a review. J Oral Pathol. 1985 Apr. 14 (4):271-81. [Medline].

  285. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EA, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol. 2009 Jan 20. 53 (3):298-304. [Medline].

  286. Hoff AO, Cote GJ, Gagel RF. Multiple endocrine neoplasias. Annu Rev Physiol. 2000. 62:377-411. [Medline].

  287. Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E, et al. Multiple endocrine neoplasia type 1. Orphanet J Rare Dis. 2006 Oct 2. 1:38. [Medline].

  288. Znaczko A, Donnelly DE, Morrison PJ. Epidemiology, clinical features, and genetics of multiple endocrine neoplasia type 2B in a complete population. Oncologist. 2014 Dec. 19 (12):1284-6. [Medline].

  289. Schenberg ME, Zajac JD, Lim-Tio S, Collier NA, Brooks AM, Reade PC. Multiple endocrine neoplasia syndrome--type 2b. Case report and review. Int J Oral Maxillofac Surg. 1992 Apr. 21 (2):110-4. [Medline].

  290. Brauckhoff M, Gimm O, Weiss CL, Ukkat J, Sekulla C, Brauckhoff K, et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg. 2004 Dec. 28 (12):1305-11. [Medline].

  291. Vanderpump MPJ, Tunbridge WMG. The epidemiology of thyroid diseases. Werner SC, Ingbar SH, Braverman LE, Utiger RD, eds. Werner & Ingbar's the Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005. 398-406.

  292. Pinto A, Glick M. Management of patients with thyroid disease: oral health considerations. J Am Dent Assoc. 2002 Jul. 133 (7):849-58. [Medline].

  293. Chandna S, Bathla M. Oral manifestations of thyroid disorders and its management. Indian J Endocrinol Metab. 2011 Jul. 15 (Suppl 2):S113-6. [Medline].

  294. Wheeler AL, Shoback DM. Clinical presentation of hypoparathyroidism. Brandi ML, Brown EM, eds. Hypoparathyroidism. Milan: Springer; 2015. 155-165.

  295. Sarkar S, Mondal M, Das K, Shrimal A. Mucocutaneous manifestations of acquired hypoparathyroidism: An observational study. Indian J Endocrinol Metab. 2012 Sep. 16 (5):819-20. [Medline].

  296. Fletcher PD, Scopp IW, Hersh RA. Oral manifestations of secondary hyperparathyroidism related to long-term hemodialysis therapy. Oral Surg Oral Med Oral Pathol. 1977 Feb. 43 (2):218-26. [Medline].

  297. Triantafillidou K, Zouloumis L, Karakinaris G, Kalimeras E, Iordanidis F. Brown tumors of the jaws associated with primary or secondary hyperparathyroidism. A clinical study and review of the literature. Am J Otolaryngol. 2006 Jul-Aug. 27 (4):281-6. [Medline].

  298. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 Jun 21. 383 (9935):2152-67. [Medline].

  299. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996 Oct 17. 335 (16):1206-12. [Medline].

  300. Nieman LK, Chanco Turner ML. Addison's disease. Clin Dermatol. 2006 Jul-Aug. 24 (4):276-80. [Medline].

  301. Eisen D. Disorders of pigmentation in the oral cavity. Clin Dermatol. 2000 Sep-Oct. 18 (5):579-87. [Medline].

  302. Boscaro M, Barzon L, Fallo F, Sonino N. Cushing's syndrome. Lancet. 2001 Mar 10. 357 (9258):783-91. [Medline].

  303. Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012 Mar-Apr. 25 (2):199-208. [Medline].

  304. Scully C, Felix DH. Oral medicine--update for the dental practitioner. Aphthous and other common ulcers. Br Dent J. 2005 Sep 10. 199 (5):259-64. [Medline].

  305. Casiglia JM. Recurrent aphthous stomatitis: etiology, diagnosis, and treatment. Gen Dent. 2002 Mar-Apr. 50(2):157-66. [Medline].

  306. Scully C. Drug effects on salivary glands: dry mouth. Oral Dis. 2003 Jul. 9 (4):165-76. [Medline].

  307. Kharazmi M, Sjöqvist K, Rizk M, Warfvinge G. Oral ulcer associated with alendronate: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Dec. 110(6):e11-3. [Medline].

  308. Lehman JS, Tollefson MM, Gibson LE. Lichen planus. Int J Dermatol. 2009 Jul. 48 (7):682-94. [Medline].

  309. Fitzpatrick SG, Hirsch SA, Gordon SC. The malignant transformation of oral lichen planus and oral lichenoid lesions: a systematic review. J Am Dent Assoc. 2014 Jan. 145 (1):45-56. [Medline].

  310. Litt JZ. Litt's Drug Eruption and Reaction Manual. 21st ed. Boca Raton, Fla: CRC Press; 2015.

  311. Arirachakaran P, Hanvanich M, Kuysakorn P, Thongprasom K. Antiretroviral Drug-Associated Oral Lichenoid Reaction in HIV Patient: A Case Report. Int J Dent. 2010. 2010:291072. [Medline]. [Full Text].

  312. Calista D, Morri M. Lichen planus induced by hepatitis B vaccination: a new case and review of the literature. Int J Dermatol. 2004 Aug. 43 (8):562-4. [Medline].

  313. Agrawal A, Shenoi SD. Lichen planus secondary to hepatitis B vaccination. Indian J Dermatol Venereol Leprol. 2004 Jul-Aug. 70 (4):234-5. [Medline].

  314. Akay BN, Arslan A, Cekirge S, Erkin G, Anadolu-Brasie R. The first reported case of lichen planus following inactivated influenza vaccination. J Drugs Dermatol. 2007 May. 6 (5):536-8. [Medline].

  315. Meraw SJ, Sheridan PJ. Medically induced gingival hyperplasia. Mayo Clin Proc. 1998 Dec. 73(12):1196-9. [Medline].

  316. Kataoka M, Kido J, Shinohara Y, Nagata T. Drug-induced gingival overgrowth--a review. Biol Pharm Bull. 2005 Oct. 28 (10):1817-21. [Medline].

  317. Trackman PC, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res. 2015 Apr. 94 (4):540-6. [Medline].

  318. Seymour RA, Thomason JM, Ellis JS. The pathogenesis of drug-induced gingival overgrowth. J Clin Periodontol. 1996 Mar. 23 (3 Pt 1):165-75. [Medline].

  319. Brown RS, Arany PR. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis. Oral Dis. 2015 Jan. 21 (1):e51-61. [Medline].

  320. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Med. 1995 Feb. 98(2):196-208. [Medline].

  321. Kaur G, Verhamme KM, Dieleman JP, Vanrolleghem A, van Soest EM, Stricker BH, et al. Association between calcium channel blockers and gingival hyperplasia. J Clin Periodontol. 2010 Jul. 37(7):625-30. [Medline].

  322. Silverstein LH, Koch JP, Shatz PC. Nifedipine-induced gingival hyperplasia. Am Fam Physician. 1996 Mar. 53(4):1069-70. [Medline].

  323. Wahlstrom E, Zamora JU, Teichman S. Improvement in cyclosporine-associated gingival hyperplasia with azithromycin therapy. N Engl J Med. 1995 Mar 16. 332(11):753-4. [Medline].

  324. Livada R, Shiloah J. Calcium channel blocker-induced gingival enlargement. J Hum Hypertens. 2014 Jan. 28 (1):10-4. [Medline].

  325. Mavrogiannis M, Ellis JS, Thomason JM, Seymour RA. The management of drug-induced gingival overgrowth. J Clin Periodontol. 2006 Jun. 33 (6):434-9. [Medline].

  326. van Boven JF, de Jong-van den Berg LT, Vegter S. Inhaled corticosteroids and the occurrence of oral candidiasis: a prescription sequence symmetry analysis. Drug Saf. 2013 Apr. 36 (4):231-6. [Medline].

  327. Ullah A, Iqbal Z, Anwar A. Frequency of Oral Candidiasis in Asthma Patients using Inhaled Corticosteroids by Different Inhaler Devices. Pakistan J Chest Med. 2016. 22(1):8-11.

  328. Ankit S, Raj YS, Mahip S, Shailendra S, Shifali N, Siddharth T. Incidence of Oral Candidiasis in Patients with Stable Obstructive Airway Disease on Inhaled Corticosteroids. Internat J Contemp Med. 2014. 2(2):164-9.

  329. Williams DW, Kuriyama T, Silva S, Malic S, Lewis MA. Candida biofilms and oral candidosis: treatment and prevention. Periodontol 2000. 2011 Feb. 55 (1):250-65. [Medline].

 
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Table 1.Oral Manifestation of Water-Soluble Vitamin Deficiencies
Vitamin Deficiency Oral Manifestations References
Vitamin B-2 (riboflavin, lactoflavin) deficiency
  • Erythema of pharyngeal and oral mucous membranes
  • Atrophic glossitis, often with a magenta hue
  • Glossodynia
  • Cheilosis
  • Angular cheilitis
Schlosser et al[41]
Vitamin B-3 (niacin, nicotinic acid) deficiency (pellagra)
  • Mucosal edema
  • Cheilosis
  • Angular cheilitis
  • Bright red glossitis
  • Burning mouth
  • Gingival erythema
  • Dental caries
Schlosser et al,[41] Boyd and Palmer[43]
Vitamin B-6 (pyridoxine, pyridoxal, pyridoxamine) deficiency
  • Atrophic glossitis
  • Cheilosis
  • Angular stomatitis
  • Gingival erythema
Schlosser et al[41]
Vitamin B-9 (folic acid, folate) deficiency
  • Atrophic glossitis with erythema and swelling of the tongue
  • Angular cheilitis
  • Glossodynia
  • Dysphagia
  • Recurrent aphthous stomatitis
Schlosser et al,[41] Kozlak et al[44]
Vitamin B-12 (cobalamin, cyanocobalamin) deficiency
  • Generalized stomatitis
  • Taste disturbance
  • Red, atrophic, beefy, burning tongue with bald appearance due to loss of filiform papillae
  • Recurrent aphthous stomatitis
Schlosser et al,[41] Kozlak et al,[44] Field et al[45]
Vitamin C (ascorbic acid, L-ascorbic acid, ascorbate) deficiency, also known as scurvy
  • Mucosal petechiae
  • Hemorrhagic gingivitis
  • Gingival bleeding
  • Gingival hypertrophy
  • Interdental infarcts
  • Loosening or loss of teeth
Schlosser et al,[41] Leggott et al,[46] Yasui et al[47]
Table 2. Oral Manifestation of Fat Soluble Vitamin Deficiencies and Toxicities
Vitamin Deficiency/Toxicity Oral Manifestations References
Vitamin A (retinol) deficiency
  • Xerostomia
  • Periodontal disease
  • Increased intraoral infection
  • Impaired tooth development in children
Schlosser et al[41]
Vitamin A (retinol) toxicity
  • Cheilitis
  • Gingivitis
  • Impaired healing
Schlosser et al[41]
Vitamin D (calciferol, cholecalciferol, ergocalciferol) deficiency
  • Periodontal attachment
  • Recurrent aphthous stomatitis
Schlosser et al,[41] Khabbazi et al,[49] Holick and Chen[50]
Vitamin K (phylloquinone) deficiency
  • Submucosal hemorrhage
  • Gingival bleeding
Schlosser et al[41]
Table 3. Oral Manifestation of Mineral Deficiencies
Iron deficiency
  • Angular cheilitis
  • Atrophic glossitis
  • Glossodynia
  • Recurrent Aphthous Stomatitis
Schlosser et al,[41] Sun et al,[52] Zimmermann and Hurrell[53]
Zinc deficiency
  • Burning mouth syndrome
  • Recurrent aphthous stomatitis
  • Perioral or intraoral erosions
  • Dysgeusia (taste alteration)
Cho et al,[54] Orback et al,[55] Nakano et al,[56] Epstein and Barasch,[57] Hambidge and Krebs[58]
Table 4. 2012 SLICC Clinical and Immunologic Criteria for SLE Diagnosis
Clinical Criteria
Acute cutaneous lupus, including:
  • Lupus malar rash (do not count if malar discoid)

  • Bullous lupus

  • Toxic epidermal necrolysis variant of SLE

  • Maculopapular lupus rash

  • Photosensitive lupus rash in the absence of dermatomyositis
  • OR subacute cutaneous lupus (nonindurated psoriasiform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias)

Chronic cutaneous lupus, including:
  • Classic discoid rash
  • Localized (above the neck)
  • Generalized (above and below the neck)
  • Hypertrophic (verrucous) lupus
  • Lupus panniculitis (profundus)
  • Mucosal lupus
  • Lupus erythematosus tumidus
  • Chilblains lupus
  • Discoid lupus/lichen planus overlap
Oral ulcers
  • Palate
  • Buccal
  • Tongue
  • OR nasal ulcers, in the absence of other causes, such as vasculitis, Behçet disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic food exposure

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
Serositis
  • Typical pleurisy for more than 1 day OR pleural effusions OR pleural rub
  • Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day OR pericardial effusion OR pericardial rub OR pericarditis by electrocardiography in the absence of other causes, such as infection, uremia, and Dressler pericarditis
Urine protein–to-creatinine ratio (or 24-h urine protein) representing 500 mg protein/24 hours OR red blood cell casts

Neurologic
  • Seizures
  • Psychosis
  • Mononeuritis multiplex in the absence of other known causes such as primary vasculitis
  • Myelitis
  • Peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus
  • Acute confusional state in the absence of other causes, including toxic/metabolic, uremia, drugs
Hemolytic anemia
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

Immunologic Criteria
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:
  • Positive test result for lupus anticoagulant
  • False-positive test result for rapid plasma reagin
  • Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)
  • Positive test result for anti–β 2-glycoprotein I (IgA, IgG, or IgM)
Low complement
  • Low C3

  • Low C4

  • Low CH50

Direct Coombs test in the absence of hemolytic anemia
Table 5. Causes of Drug-Associated Xerostomia
Dehydrating Agents
  • Diuretics
Anticholinergic Agents
  • Tricyclic antidepressants
  • Muscarinic agonists
  • Alpha-receptor antagonists
  • Antipsychotics
  • Antihistamines
Sympathetic Effectors
  • Antihypertensives
  • Selective serotonin reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants
  • Appetite suppressants
  • Decongestants
  • Bronchodilators
  • Muscle relaxers
  • Antimigraine medications
Drugs of Abuse
  • Opioids
  • Benzodiazepines
  • Cannabis
  • 3,4-Methylenedioxymethamphetamine (MDMA) (ecstasy)
Other
  • Anti-HIV drugs
  • Retinoids
  • Cytotoxic drugs
  • Proton-pump inhibitors and H2 receptor antagonists
  • Caffeinated and alcoholic beverages/products
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