Key points

In 2000, the US Surgeon General’s report Oral Health in America highlighted ways in which oral health and systemic conditions are associated with each other. An oral examination can reveal signs and symptoms associated with immunologic diseases, endocrinopathies, hematologic conditions, systemic infections, and nutritional disorders. In this article, multiple systemic diseases and associated oral symptoms are discussed.

Sickle cell anemia

A single point mutation to the β-globin gene can alter the structure of hemoglobin, shifting the molecule’s tendency to aggregate and subvert the biconcavity of the red blood cell (RBC) into a sickled cell, with the potential to reap profound morbidity and mortality.

Sickle cell disease (SCD) describes syndromes that produce sickled RBCs. The molecular genetic etiologies of SCD can vary. For instance, the homozygous inheritance of the point mutation (a missense, glu-val) that results in sickle hemoglobin causes sickle cell anemia (SCA). Alternatively, a coinherited sickle β-hemoglobin with alleles that render it genetically dominant, such as sickle β-thalassemia, hemoglobin SC, hemoglobin SD, and hemoglobin SE, can also cause SCD.

Hemolytic anemia and vaso-occlusion drive the diverse and varied clinical manifestations of SCD. Acute features include chest syndrome, stroke, infection, asplenia, bone pain, and priapism. Chronic features can include bone necrosis, nephropathy, heart, lungs, and skin disorders.

Hemolytic anemia of SCA, when severe, can cause pallor of mucous membranes, specifically and most commonly observed in the palpebral conjunctiva and oral mucosa.

Hemolytic anemia can cause an elevation in serum bilirubin, resulting in jaundice, a diffuse and generalized yellowish color change to skin and mucosa. The degree of color change is dependent on the serum level of bilirubin and tissue composition. Elastin fibers bind well to bilirubin. Sclera, lingual frenum, and soft palate have a high concentration of elastin and, therefore, are sites of prominent color change.

The craniofacial morphologies attributed to SCD are variable and controversial. Most consistently reported is a protruding maxilla, skeletal class II malocclusion. Other abnormalities include overjet, overbite, and retrusion of the mandible. It is hypothesized that the some morphologic changes are caused by hyperplasia, and expansion of the bone marrow occurs to compensate for the short half-life of RBCs maintaining larger volumes of hematopoietically active marrow.

Radiographic findings in the sickle cell patient include hair-on-end appearance of the diploic space of the cranial vault, coarse trabecular pattern, loss of alveolar bone height, pronounced lamina dura (as seen Fig. 1 A ), generalized osteoporotic appearance due to bone marrow hyperplasia, and radiopaque lesions corresponding to areas of vaso-occlusive phenomena and infarctions. Bone pain from vaso-occlusive, hypoxia-inducing attacks are more common in the posterior mandible.

( A ) Panoramic radiograph showing enamel hypomineralization, cavitated teeth, missing teeth, and decreased trabeculation of bone. ( B ) Periapical radiograph tooth showing trabeculation of bone.

( From [ A , B ] Kawar N, Alrayyes S, Aljewari H. Sickle cell disease: an overview of orofacial and dental manifestations. Dis Mon. 2018;64(6):293; with permission.)

Individuals with SCA are at risk for systemic osteomyelitis, head and neck osteomyelitis is less common. When osteomyelitis does occur, it occurs most frequently in the posterior mandible.

Other possible manifestations of SCA include mucosal damage due to anemia, papillary atrophy of the tongue, and fungal infections due to multiple antibiotic therapies often prescribed to SCA patients. Additionally, loss of sensation to the lips, chin, and teeth has been observed and is thought to be caused by infarction to the vasculature supporting branches of the inferior alveolar nerve. Loss of sensitivity is often coincident with sickle cell crisis; the duration of neuropathy has been reported to be temporary or permanent.

Dental findings can include delayed tooth eruption, hypomaturation and hypomineralization of enamel and dentin ( Fig. 1 ), hypercementosis, and pulp stones ; high frequency of caries has been observed. A high frequency of dental malocclusions have been reported in SCD populations; however, causality is inconclusive. Symptomatic or asymptomatic necrosis, possibly the result of abnormal pupil perfusion sickle cells, have been observed in pulp vasculature possibly obstruction blood flow.

Plummer-Vinson syndrome

Plummer-Vinson syndrome (PVS), also known as Paterson-Kelly syndrome, is a rare condition with a triad of findings, including iron deficiency anemia (IDA), dysphagia, and cervical esophageal web formation. Historically, a majority of patients with PVS have been women of Scandinavian or Northern European descent in their third to fifth decades of life. The etiology and pathogenesis has not been definitively elucidated. IDA plays an important role, along with other possible contributing factors, including genetic predisposition, autoimmunity, and malnutrition.

There has been a decline in reported cases of PVS; this decline is thought to be due to improvements in nutrition, hygiene, and iron supplementation and a reduction in parasitic infestations.

Dysphagia in PVS has a gradual onset, on the order of multiple years; it is usually painless and intermittent. Anemia precipitates fatigue, exertional dyspnea, weakness, tachycardia, and pallor. When visualized with gastrointestinal endoscopy, esophageal webs appear in the proximal part of the esophagus—they are smooth, thin, and gray, with eccentric or central lumen.

The mucosa of the oral cavity is commonly pale, consistent with IDA. Tongue findings include glossitis, atrophy of the fungiform, and filiform papillae. Other findings include angular cheilitis ( Fig. 2 ), dryness of the mouth; stomatitis , atrophic mucosa of the oral cavity, hypopharynx, and the esophagus and enlargement of the thyroid.

An example of atrophic glossitis with angular cheilitis ( arrow ).

( From McCord C, Johnson L. Oral manifestations of hematologic disease. Atlas Oral Maxillofac Surg Clin North Am. 2017;25(2):155; with permission.)

PVS is considered a premalignant condition predisposing patients to oral, esophageal, or pharyngeal squamous cell carcinoma. Therefore, it is critical to be aware of the symptoms indicative of malignancy—for example, odynophagia, change in voice, nasal regurgitation of ingested solids and liquids, anorexia, and weight loss.

Scurvy

Scurvy is a nutritional disease caused by a deficiency of l -ascorbic acid (vitamin C). Ascorbic acid is an essential nutrient that is involved in many processes critical for healthy physiology, such as collagen synthesis, fatty acid transport, neurotransmitter formation, wound healing, and immunity. If left untreated, this deficiency can lead to death.

Today scurvy is uncommon in developed nations; however, there remain populations at risk for an altered nutritional status that may lead to scurvy, for example, populations with low socioeconomic status, isolated elderly persons, alcoholics with poor nutrition, diet faddists, those with unusual dietary habits, and those with psychiatric illness.

Children at risk for scurvy typically have predisposing factors, including neurodevelopmental disabilities, autism spectrum disorder, intellectual disability, selective eating, and dietary insufficiency. Within the special needs population, dental/oral pain and limitations in oral motor function can lead to dietary limitations, likely increasing their risk for nutritional deficiencies.

The clinical signs of scurvy are primarily due to defective collagen synthesis. With a collagen deficiency, walls of the body’s vasculature become weak and thus underlie spontaneous petechial hemorrhage and ecchymosis. Additional findings include impaired wound healing, gingivitis, perifollicular hemorrhages, petechiae, purpura, follicular hyperkeratosis, and corkscrew-shaped hairs on the lower limbs. Symptoms include weakness, fatigue, and depression. Scurvy can also resemble rheumatologic disorders, such as pseudovasculitis or chronic arthritis, arthralgia, and mild to severe bone pain.

The oral manifestations of scurvy can include generalized gingival swelling, gingival hypertrophy and gingival friability, spontaneous gingival hemorrhage, intraoral ulceration, tooth mobility, increased severity of periodontal infection and periodontal bone loss, halitosis, and loss of teeth, as seen in Fig. 3 . Scorbutic gingivitis is the term used to describe the gingival lesions specific to patients with scurvy.

Scurvy, gingivitis.

( From James WD, Elston DM, Treat J, et al. Nutritional diseases. In: Andrews’ diseases of the skin. 13th ed. Philadelphia: Elsevier; 2020. p. 475–84.e2; with permission.)

Treatment of scurvy involves the supplementation of l -ascorbic acid. On supplementation, the prognosis for this condition is good. Additional steps, possibly with the help of allied health professionals, may need to be taken in specific at risk populations, such as children, the elderly, and those with special needs, involving diet modification and education for the individuals, their caretakers, and others responsible for the health of the patient.

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic condition. The STK11(LKB1) gene encodes a serine/threonine kinase and mutation of this gene is responsible for most cases of PJS. PJS has a prevalence of approximately 1 in 50,000 to 200,000 births.

PJS is characterized by melanotic macules of the hands, perioral skin, and oral mucosa, in conjunction with multiple gastrointestinal hamartomatous polyps and predisposition for affected individuals to develop various neoplasms.

In early childhood, the melanotic macules of PJS typically develop around the orifices of the body in areas, such as oral, nasal, anal, genital regions. In approximately half of patients, the skin of the peripheral extremities exhibits melanotic macules.

The intestinal polyps can be found most commonly in the jejunum and ileum. Polyps can cause intestinal obstruction with intussusception. The polyps’ role in cancer development is controversial ; however, it is estimated that that gastrointestinal cancer can developed in 9% to 14% of individuals by the age of 40 and 33% to 42% by the age of 60.

Other tumors may develop in other tissues, including pancreas, gallbladder, bronchi, genital tract, breast, and ovary, among others.

Mucocutaneous pigmented lesions in and around the oral cavity can be found in approximately 95% of patient with PJS. They range in size from approximately 1 mm to 4 mm in diameter; they can be brown to blue-gray; they localize around the vermilion border, as seen in Fig. 4 ; and they can be found on the buccal mucosa (as seen in Fig. 4 ), labial mucosa, and the tongue. The number, distribution, and color can vary. Mucocutaneous lesions may fade after puberty but often persist in the buccal mucosa. The histology of the pigmented lesions reveals basal cells with increased melanin possibly due to disrupted melanin migration from melanocyte to keratinocyte. Improvement in the appearance of mucocutaneous pigmented lesions has been reported using intense pulse light (590-nm), Q-switched ruby laser, and CO ₂ -based laser therapies.

PJS. A 12-year-old girl with melanotic macules on her face, in particular her lips. Melanotic macules were also present on her extremities, trunk, and mucous membranes.

( From Mavropoulos JC, Cohen BA. Disorders of pigmentation. In: Cohen BA, editor. Pediatric dermatology. 4th ed. Philadelphia: Saunders/Elsevier; 2013. p. 148–68; with permission.)

Addison disease (hypoadrenocorticism)

Addison disease, also known as hypoadrenocorticism, is a disorder of the adrenal glands caused by the destruction of the adrenal cortex that results in the underproduction of adrenal corticosteroid hormones.

The incidence of new cases is approximately 110 to 140 per million population per year in the western hemisphere. The underlying causes of the adrenal cortex destruction are varied and include autoimmune destruction, infections, and trauma. Other rarer causes include metastatic tumors, sarcoidosis, hemochromatosis, and amyloidosis, among others.

A related disorder, secondary hypoadrenocorticism, can develop if the pituitary gland is dysfunctional, causing decreased production of adrenocorticotropic hormone, the hormone that regulates serum levels of cortisol.

The clinical features include fatigue, irritability, depression, weakness, and hypotension and can occur over a time period of months. As serum corticosteroid levels drop, this induces the production of corticotropin and α-melanoctye stimulating hormone (MSH). α-MSH is thought to directly stimulate melanocytes and increase melanin production, causing the mucocutaneous hyperpigmentation; on the skin it is described as bronzing.

Symptoms may include gastrointestinal upset with anorexia, nausea, vomiting, diarrhea, weight loss, salt cravings, hypotension, easy bruising, fatigue, mood swings, depression, and weakness.

In the oral cavity, the hyperpigmentation can manifest as diffuse or patchy, brown, macular pigmentation of the oral mucosa. The oral mucosal changes can be the earliest manifestation of the disease; skin hyperpigmentation can present as a late finding. Sites of hyperpigmentation include areas of friction, recent scars, and the vermilion border of the lips. The buccal mucosa, periodontal soft tissues ( Fig. 5 A), and tongue ( Fig. 5 B) can also exhibit patchy macular areas of hyperpigmentation ( Fig. 5 C).

( A ) Generalized hyperpigmentation of face with increased pigmentation of acne scars and lips. ( B ) Tongue—patchy macular areas of hyperpigmentation. ( C ) Periodontal and buccal mucosal hyperpigmentation.

( From [ A , C ] Nieman LK, Chanco Turner ML. Addison’s disease. Clin Dermatol. 2006;24:278, with permission; and [ B ] Nieman LK, Chanco Turner ML. Addison’s disease. Clin Dermatol. 2006;24:279; with permission.)

Addison disease is treated with corticosteroid replacement therapy. The body may need additional corticosteroid hormones during stressful events, such as surgery. Without treatment, this condition can be fatal. With treatment this condition has a good prognosis.

Gardner syndrome

Gardner syndrome (GS), or familial colorectal polyposis, is an autosomal dominant disorder. The incidence of GS ranges between 1 in 4000 and 1 in 12,000, depending on the region. Multiple polyps in the colon along with tumors outside the colon characterize the disorder. The tumors outside the colon may include osteomas of the skull, epidermoid cysts, fibromas, and thyroid cancer.

There is a high association between GS and familial adenomatous polyposis. This association may manifest as aggressive fibromatosis (desmoid tumors). The numerous polyps in the colon predispose the individual to colon cancer (adenocarcinomas). Removal of the colon decreases the likelihood of developing colon cancer.

GS can be identified based on head, neck, and oral findings, including many impacted teeth, multiple supernumerary teeth, odontomas, osteomas of maxilla and mandible, causing a radiographic cotton-wool appearance. There also is a congenital hypertrophy of the retinal pigment epithelium.

Osteomas typically are asymptomatic, presenting without pain, and these lesions can cause expansile facial asymmetry and are radiographically radiopaque. The osteomas often are observed during puberty and this can be prior to the gastrointestinal symptoms of bowel polyps. Indication for removal of jaw osteomas and epidermoid cysts is for cosmetic reasons. The prognosis for the patient depends on the behavior of the bowel adenocarcinomas.

Brown tumors of renal osteodystrophy

Renal osteodystrophy can result in brown tumors. The brown tumors are linked to secondary hyperparathyroidism in patients with chronic renal failure. The rate of brown tumors in patients with secondary hyperparathyroidism related to chronic kidney disease ranges from 1.5% to greater than 13%. The brown tumors derive its name from the color of the tissue on gross dissection. The tissue is a dark red-brown, thought to be due to hemorrhage and hemosiderin found within the tumor. Radiographically, these lesions are well defined as unilocular or multilocular radiolucencies.

The brown tumors are brought about through breakdown of a focus of bone. The most common locations relate to areas where bone resorption is common and rapid. A cycle of hemorrhage followed by infiltration with granulation tissue containing multinucleated giant cells that eventually displaced the healthy bone marrow, resulting in a brown tumor. The lesions often are expansible and often affect the mandible, clavicles, ribs, and pelvis.

Browns tumor is more likely to be found in the mandible compared with the maxilla. The locations of the tumors can vary; patients present typically without pain; however, pain has been reported. Patients with secondary hyperparathyroidism can help prevent brown tumors with restriction of dietary phosphate binders and vitamin D; surgical removal of the brown tumor mass sometimes may be required.