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Chapter 3: Diseases and Disorders

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As the gateway to the body, the mouth is challenged by a constant barrage of invaders—bacteria, viruses, parasites, fungi. Thus infectious diseases, notably dental caries and periodontal diseases, predominate among the ills that can compromise oral health. Injuries take their toll as well, with the face and head particularly vulnerable to sports injuries, motor vehicle crashes, violence, and abuse. Less common but very serious are oral and pharyngeal cancers, with a 5-year survival rate of hardly better than 50 percent (Kosary et al. 1995). Birth defects and developmental disorders frequently affect the craniofacial complex. These appear most commonly as isolated cases of cleft lip or palate, but clefting or other craniofacial defects can also be part of complex hereditary diseases or syndromes. Additionally, acute and chronic pain can affect the oral-facial region, particularly in and around the temporomandibular (jaw) joint, and accounts for a disproportionate amount of all types of pain that drive individuals to seek health care.

Many systemic diseases such as diabetes, arthritis, osteoporosis, and AIDS, as well as therapies for systemic diseases, can directly or indirectly compromise oral tissues. The World Health Organization's International Classification of Diseases and Stomatology currently lists more than 120 specific diseases, distributed in 10 or more classes, that have manifestations in the oral cavity (WHO 1992).

This chapter concentrates on six major oral disease categories: dental and periodontal infections; mucosal disorders; oral and pharyngeal cancers; developmental disorders; injuries; and a sampling of chronic and disabling conditions, including Sjögren's syndrome and oral-facial pain.

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DENTAL AND PERIODONTAL INFECTIONS

The most common oral diseases are dental caries and the periodontal diseases. Individuals are vulnerable to dental caries throughout life, with 85 percent of adults aged 18 and older affected. Periodontal diseases are most often seen in maturity, with the majority of adults experiencing some signs and symptoms by the mid-30s. Certain rare forms of periodontal disease affect young people. The major oral health success story of the past half century is that both caries and periodontal diseases can be prevented by a combination of individual, professional, and community measures.

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Dental Caries

The word caries derives from the Latin for rotten, and many cultures early on posited a tooth worm as the cause of this rottenness. By the twentieth century, caries came to describe the condition of having holes in the teeth—cavities. This description, although not incorrect, is misleading. In actuality, a cavity is a late manifestation of a bacterial infection.

The bacteria colonizing the mouth are known as the oral flora. They form a complex community that adheres to tooth surfaces in a gelatinous mat, or biofilm, commonly called dental plaque. A cariogenic biofilm at a single tooth site may contain one-half-billion bacteria, of which species of mutans streptococci are critical components. These bacteria are able to ferment sugars and other carbohydrates to form lactic and other acids. Repeated cycles of acid generation can result in the microscopic dissolution of minerals in tooth enamel and the formation of an opaque white or brown spot under the enamel surface (Mandel 1979). Frequency of carbohydrate consumption (Gustafsson et al. 1954), physical characteristics of food (e.g., stickiness), and timing of food intake (Burt and Ismail 1986) also play a role.

The essential role of bacteria in caries initiation was established in landmark experiments in the 1950s. Investigators observed that germ-free animals fed high-sugar diets remained caries-free until the introduction of mutans streptococci (a particular group of bacterial strains having a number of common characteristics, and which adhere tightly to the tooth). Later experiments demonstrated the transmissibility of the bacteria from mother to litter and from caries-infected to uninfected cage-mates (Fitzgerald and Keyes 1960). Species of Lactobacillus, Actinomyces, and other acid-producing streptococci within the plaque may also contribute to the process (Bowden 1990).

If the caries infection in enamel goes unchecked, the acid dissolution can advance to form a cavity that can extend through the dentin (the component of the tooth located under the enamel) to the pulp tissue, which is rich in nerves and blood vessels. The resulting toothache can be severe and often is accompanied by sensitivity to temperature and sweets. Treatment requires endodontic (root canal) therapy. If untreated, the pulp infection can lead to abscess, destruction of bone, and spread of the infection via the bloodstream.

Dental caries can occur at any age after teeth erupt. Particularly damaging forms can begin early, when developing primary teeth are especially vulnerable. This type of dental caries is called early childhood caries (ECC). Some 6 out of 10 children in the United States have one or more decayed or filled primary teeth by age 5 (U.S. Department of Health and Human Services, National Center for Health Statistics 1997). ECC may occur in children who are given pacifying bottles of juice, milk, or formula to drink during the day or overnight. The sugar contents pool around the upper front teeth, mix with cariogenic bacteria, and give rise to rapidly progressing destruction (Ripa 1988). Other risk factors for ECC include arrested development of tooth enamel, chronic illness, altered salivary composition and volume (resulting from the use of certain medications or malnourishment), mouth breathing, and blockage of saliva flow in a bottle-fed infant (Bowen 1998, Seow 1998).

Although there have been continuing reductions in dental caries in permanent teeth among children and adolescents over the past few decades, caries prevalence in the primary dentition may have stabilized or increased slightly in some population groups (Petersson and Bratthall 1996, Rozier 1995). Reductions in caries in permanent teeth also have been proportionately greater on the smooth surfaces rather than on the pit-and-fissure surfaces characteristic of chewing surfaces. The gingival tissues tend to recede over time, exposing the tooth root to cariogenic bacteria that can cause root caries. An important risk factor for root caries in older people is the use of medications that inhibit salivary flow, leading to dry mouth (xerostomia).

Saliva contains components that can directly attack cariogenic bacteria, and it is also rich in calcium and phosphates that help to remineralize tooth enamel. Demineralization of enamel occurs when pH levels fall as a result of acid production by bacteria. It can be reversed at early stages if the local environment can counteract acid production, restoring pH to neutral levels. Remineralization can occur through the replacement of lost mineral (calcium and phosphates) from the stores in saliva. Fluoride in saliva and dental plaque and the buffering capacity of saliva also contribute to this process. Indeed, it is now believed that fluoride exerts its chief caries-preventive effect by facilitating remineralization. Several studies have demonstrated that remineralization results in an increase in tooth hardness and mineral content, rendering the tooth surface more resistant to subsequent acid attack (Larsen 1987, Linton 1996, Retief 1983, Shannon 1978, Vissink et al. 1985, White 1988).

Overt caries lesions develop when there is insufficient time for remineralization between periods of acidogenesis, or when the saliva production is compromised. Over 400 medications list dry mouth as a side effect, notably some antidepressants, antipsychotics, antihistamines, decongestants, antihypertensives, diuretics, and antiparkinsonian drugs (Sreebny et al. 1992). The effects of xerostomia may be particularly severe in cancer patients receiving radiation to the head or neck because the rays can destroy salivary gland tissue rather than simply inhibiting salivary secretion.

The professional application of dental sealants (plastic films coated onto the chewing surfaces of teeth) is an important caries-preventive measure that complements the use of fluorides. The films prevent decay from developing in the pits and fissures of teeth, channels that are often inaccessible to brushing and where fluoride may be less effective.

The rate of caries progression through enamel is relatively slow (Berkey 1988, Ekanayake 1987, Shwartz et al. 1984) and may be slower in patients who have received regular fluoride treatment or who consume fluoridated water (Pitts 1983, Shwartz et al. 1984). Because a large percentage of enamel lesions remain unchanged over periods of 3 to 4 years, and because progression rates through dentin are comparably slow (Craig et al. 1981, Emslie 1959, Kolehmainen and Rytömaa 1977), the application of infection control and monitoring procedures to assess caries risk status, lesion activity status, evidence of lesion arrest, and evidence of lesion remineralization over extended periods of time is recommended.

Experts believe that the earlier mutans streptococci are acquired in infancy, the higher the caries risk. Most studies indicate that infants are infected before their first birthday, around the time the first incisors emerge. However, one study found the median age of acquisition to be 26 months, coinciding with the emergence of the primary molars (Bowen 1998, Caufield et al. 1993, Seow 1998). DNA fingerprinting has demonstrated that the source of transmission is usually the mother (Caufield et al. 1993).

It is not clear why some individuals are more susceptible and others more resistant to caries. Genetic differences in the structure and biochemistry of enamel proteins and crystals (Slavkin 1988), as well as variations in the quality and quantity of saliva and in immune defense mechanisms are among the factors under study. Analysis of mutans streptococci genomes may also shed light, indicating which species are particularly virulent and which genes contribute to that virulence.

Even the most protective genetic endowment and developmental milieu are unlikely to confer resistance to decay in the absence of positive personal behaviors. These include sound dietary habits and good oral hygiene, including the use of fluorides, and seeking professional care. There are indications, however, that some destructive oral habits are on the rise, such as the use of smokeless (spit) tobacco products by teenage boys. Although the chief concern here lies in the long-term risk for oral cancers, spit tobacco that contains high levels of sugar is also associated with increased levels of decay of both crown and root surfaces (Tomar and Winn 1998).

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Periodontal Diseases

Like dental caries, the periodontal diseases are infections caused by bacteria in the biofilm (dental plaque) that forms on oral surfaces. The basic division in the periodontal diseases is between gingivitis, which affects the gums, and periodontitis, which may involve all of the soft tissue and bone supporting the teeth. Gingivitis and milder forms of periodontitis are common in adults. The percentage of individuals with moderate to severe periodontitis, in which the destruction of supporting tissue can cause the tooth to loosen and fall out, increases with age.

Gingivitis

Gingivitis is an inflammation of the gums characterized by a change in color from normal pink to red, with swelling, bleeding, and often sensitivity and tenderness. These changes result from an accumulation of biofilm along the gingival margins and the immune system's inflammatory response to the release of destructive bacterial products. The early changes of gingivitis are reversible with thorough toothbrushing and flossing to reduce plaque. Without adequate oral hygiene, however, these early changes can become more severe, with infiltration of inflammatory cells and establishment of a chronic infection. Biofilm on tooth surfaces opposite the openings of the salivary glands often mineralizes to form calculus or tartar, which is covered by unmineralized biofilm—a combination that can exacerbate local inflammatory responses (Mandel 1995). A gingival infection may persist for months or years, yet never progress to periodontitis.

Gingival inflammation does not appear until the biofilm changes from one composed largely of gram-positive streptococci (which can live with or without oxygen) to one containing gram-negative anaerobes (which cannot live in the presence of oxygen). Numerous attempts have been made to pinpoint which microorganisms in the supragingival (above the gum line) plaque are the culprits in gingivitis. Frequently mentioned organisms include Fusobacterium nucleatum, Veillonella parvula, and species of Campylobacter and Treponema. But as Ranney (1989) notes, "The complexity of the results defies any attempt to define a discrete group clearly and consistently associated with gingivitis."

Gingival inflammation may be influenced by steroid hormones, occurring as puberty gingivitis, pregnancy gingivitis, and gingivitis associated with birth control medication or steroid therapy. The presence of steroid hormones in tissues adjacent to biofilm apparently encourages the growth of certain bacteria and triggers an exaggerated response to biofilm accumulation (Caton 1989). Again, thorough oral hygiene can control this response.

Certain prescription drugs can also lead to gingival overgrowth and inflammation. These include the antiepileptic drug phenytoin (Dilantin); cyclosporin, used for immunosuppressive therapy in transplant patients; and various calcium channel blockers used in heart disease. Treatment often requires surgical removal of the excess tissue followed by appropriate personal and professional oral health care.

A form of gingivitis common 50 years ago but relatively rare today is acute necrotizing ulcerative gingivitis, also known as Vincent's infection or trench mouth. This aggressive infection is characterized by destruction of the gingiva between the teeth, spontaneous bleeding, pain, and oral odor. People under extreme stress have an increased susceptibility. Spirochetes and other bacteria have been found in the connective tissue of those affected. An association between smoking and this type of gingivitis is well recognized and was demonstrated as early as 1946 (Pindborg 1947, 1949). This condition has been seen in some HIV-positive patients (Murray 1994). Treatment requires a combination of professional periodontal treatment and antibacterial therapy along with professional smoking cessation assistance as appropriate.

Adult Periodontitis

The most common form of adult periodontitis is described as general and moderately progressing; a second form is described as rapidly progressing and severe, and is often resistant to treatment. The moderately progressive adult form is characterized by a gradual loss of attachment of the periodontal ligament to the gingiva and bone along with loss of the supporting bone. It is most often accompanied by gingivitis (Genco 1990). It is not necessarily preceded by gingivitis, but the gingivitis-related biofilm often seeds the subgingival plaque. The destruction of periodontal ligament and bone results in the formation of a pocket between the tooth and adjacent tissues, which harbors subgingival plaque. The calculus formed in the pocket by inflammatory fluids and minerals in adjacent tissues is especially damaging (Mandel and Gaffar 1986).

The severity of periodontal disease is determined through a series of measurements, including the extent of gingival inflammation and bleeding, the probing depth of the pocket to the point of resistance, the clinical attachment loss of the periodontal ligament measured from a fixed point on the tooth (usually the cemento-enamel junction), and the loss of adjacent alveolar bone as measured by x-ray (Genco 1996). Severity is determined by the rate of disease progression over time and the response of the tissues to treatment.

Adult periodontitis often begins in adolescence but is usually not clinically significant until the mid-30s. Prevalence and severity increase but do not accelerate with age (Beck 1996). One view proposes that destruction occurs at a specific site during a defined period, after which the disease goes into remission (Socransky et al. 1984). The current view is that the disease process may not be continuous but rather progresses in random bursts in which short periods of breakdown of periodontal ligament and bone alternate with periods of quiescence. These episodes occur randomly over time and at random sites in the mouth. Part of the difficulty in determining the pattern of progression reflects variation in the sensitivity of the instruments used to measure the loss of soft tissue and bone. The latest generation of probes finds evidence of both continuous and multiple-burst patterns of loss in different patients and at different times (Jeffcoat and Ready 1991).

Most researchers agree that periodontitis results from a mixed infection but that a particular group of gram-negative bacteria are key to the process and markedly increase in the subgingival plaque. The bacteria most frequently cited are Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, Treponema denticola, and Actinobacillus actinomycetemcomitans (Genco 1996). Their role in disease initiation and progression is determined in part by their "virulence factors." These include the ability to colonize subgingival plaque, generate products that can directly injure tissues, and elicit an inflammatory or immune response. The potentially noxious bacterial products include hydrogen sulfide, polyamines, the fatty acids butyrate and propionate, lipopolysaccharide (also known as endotoxin), and a number of destructive enzymes. The interaction of this arsenal with the host response is at the core of periodontal pathology (Genco 1992, Socransky and Haffajee 1991, 1992). Sequencing of the genomes of several key periodontal pathogens is under way and should provide further insight into these pathogens as well as catalyze new treatment approaches.

Delicate Balances. Neutrophils (a type of white blood cell) and antibodies are the major immune defenses against bacterial attack. Neutrophils move to the site of infection, where they engulf bacteria and elaborate antibacterial agents and enzymes to destroy bacteria. Although stimulation of the immune system to attack the offending bacteria is generally protective, immune hyperresponsiveness and hypersensitivity can be counterproductive, leading to the destruction of healthy tissue. Nevertheless, the neutrophil/antibody axis is critical for full protection against periodontal diseases (Genco 1992).

Also important is the release of certain potent molecules called cytokines and prostaglandins, especially prostaglandin E2 (PGE2) which can contribute to tissue destruction. Cytokines are proteins secreted by immune cells that help regulate immune responses and also affect bone, epithelial, and connective tissues. Most prominent in periodontal diseases are interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-gamma), and interferon gamma (IFN-gamma). These cytokines mediate the processes of bone resorption and connective tissue destruction.

Susceptibility and Resistance. PGE2 may play a central role in the tissue destruction that occurs in periodontal diseases. Levels of PGE2 in periodontal tissue are low or undetectable in health, increase in gingivitis, and rise significantly in periodontitis. Now there is increasing evidence that the level of PGE2 produced in response to bacterial challenge (especially by endotoxin) can be used as a measure of susceptibility (Offenbacher et al. 1993).

Presumably, the level of PGE2 production is subject to genetic influence. Studies of identical and fraternal twins, either reared together or apart, provide evidence that genetic factors may indeed influence susceptibility or resistance to the common adult form of periodontitis (Michalowicz 1994). Recently, a commercial test for a genetic marker of susceptibility has been introduced. The marker is associated with increased production of a particular form of interleukin 1-beta (IL-1-beta) when stimulated by periodontopathic bacteria (Kornman et al. 1997). Newman (1996) found that nonsmoking adults who are positive for the marker are 6 to 19 times more likely to develop severe periodontitis.

Susceptibility to adult periodontitis has also been explored in relation to a variety of behavioral and demographic variables as well as to the presence of other diseases. One of the strongest behavioral associations is with tobacco use. The risk of alveolar bone loss for heavy smokers is 7 times greater than for those who have not smoked (Grossi et al. 1995). Cigarette smoking also may impair the normal host response in neutralizing infection (Seymour 1991), resulting in the destruction of healthy periodontal tissues adjacent to the site of infection (Lamster 1992). Smokers also have decreased levels of salivary and serum immunoglobulins to Prevotella intermedia and Fusobacterium nucleatum (Bennet and Reade 1982, Haber 1994) and depressed numbers of helper T cells as well (Costabel et al. 1986). Finally, smoking alters the cells that engulf and dispose of bacteria—neutrophils and other phagocytes—affecting their ability to clear pathogens (Barbour et al. 1997).

Epidemiologic studies have found that such additional factors as increasing age, infrequent dental visits, low education level, low income, co-morbidities, and inclusion in certain racial or ethnic populations are associated with increased prevalence of periodontitis (Page 1995). It is important that epidemiologic studies also take into consideration the fact that tobacco use, oral hygiene, professional prophylaxis, and routine dental care are correlated to socioeconomic status, as are race and ethnicity. Sex is another factor. Males tend to have higher levels of periodontal diseases, presumably because of a history of greater tobacco use and differences in personal care and frequency of dental visits. However, female hormones may play a protective role (as they do in protecting against osteoporosis) (Genco 1996).

Certain systemic diseases heighten susceptibility. Epidemiological studies have confirmed that patients with diabetes mellitus, both type 1 and type 2, are more susceptible to periodontal diseases (Genco 1996). Measures such as the gingival index, pocket depth, and loss of attachment are more severe if the diabetic patients are smokers (Bridges et al. 1996). The likelihood of periodontal disease increases markedly when diabetes is poorly controlled. In contrast, periodontal diseases respond well to therapy and can be managed successfully in patients with well-controlled diabetes. Such therapy can result in improvements in the diabetic condition itself (Mealey 1996) (see Chapter 5).

There is some evidence that osteoporosis may be a risk factor for periodontal disease. More clinical attachment loss and edentulousness have been reported in osteoporotic than in nonosteoporotic women (Jeffcoat and Chestnut 1993). Two studies in 1996 showed that estrogen replacement therapy in postmenopausal women not only gives protection against osteoporosis, but also results in fewer teeth lost to periodontal disease (Grodstein et al. 1996, Jacobs et al. 1996).

The less common rapidly progressive form of adult periodontitis typically affects people in their early 20s and 30s. It is characterized by severe gingival inflammation and rapid loss of connective tissue and bone. Many patients have an inherent defect in neutrophil response to infection. Several systemic diseases have been associated with this form of periodontal disease, including type 1 diabetes, Down syndrome, Papillon-Lefevre syndrome, Chediak-Higashi syndrome, and HIV infection (Caton 1989). Specific bacteria associated with rapidly progressive disease include Porphyromonas gingivalis, Prevotella intermedia, Eikenella corrodens, and Wolinella recta (Scheutz et al. 1997). Most recently, mutations in the cathepsin C gene have been associated with the Papillon-Lefevre syndrome (Hart et al. 1999) and how the defect can result in periodontal disease (Toomers et al. 1999).

Refractory Periodontitis. Refractory periodontitis is not a specific form of disease, but refers to cases in which patients continue to exhibit progressive disease at multiple sites despite aggressive mechanical therapy to remove biofilm and calculus, along with the use of antibiotics. Refractory sites exhibit elevated levels of a number of different bacteria, with the dominant species different in different subjects. It is not known whether variations in pathogenicity of the bacteria, defects in the subject's defense systems, or combinations of these factors are responsible for the refractory nature of the disease (Haffajee et al. 1988). The adoption of new diagnostic technology to detect predominant bacterial species, followed by selective antibiotic treatment, may help resolve infection and disease in these patients.

Early-onset Periodontitis

The forms of periodontitis occurring in adolescents and young adults generally involve defects in neutrophil function (Van Dyke et al. 1980). Localized juvenile periodontitis (LJP) mainly affects the first molar and incisor teeth of teenagers and young adults, with rapid destruction of bone but almost no telltale signs of inflammation and very little supragingival plaque or calculus. Actinobacillus actinomycetemcomitans has been isolated at 90 to 100 percent of diseased sites in these patients, but is absent or appears in very low frequency in healthy or minimally diseased sites (Socransky and Haffajee 1992). It is possible that the bacteria are transmitted among family members through oral contacts such as kissing or sharing utensils, because the same bacterial strain appears in affected family members. However, evidence of a neutrophil defect argues for a genetic component. Another organism frequently associated with LJP is Capnocytophaga ochracea. Neither of these bacteria dominate in the generalized adult form of the disease, where Porphyromonas gingivalis is considered of greatest significance (Schenkein and Van Dyke 1994).

Prepubertal periodontitis is rare and can be either general or localized. The generalized form begins with the eruption of the primary teeth and proceeds to involve the permanent teeth. There is severe inflammation, rapid bone loss, tooth mobility, and tooth loss. The localized form of the disease is less aggressive, affecting only some primary teeth. The infection involves many of the organisms associated with periodontitis, but the mix may differ somewhat, with Actinobacillus actinomycetemcomitans, Prevotella intermedia, Eikenella corrodens, and several species of Capnocytophaga implicated (Caton 1989). Defects in neutrophil function noted in both forms of the disease (Schenkein and Van Dyke 1994) may explain why patients are highly susceptible to other infections as well (Suzuki 1988).

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SELECTED MUCOSAL INFECTIONS AND CONDITIONS

Like the skin, the mucosal lining of the mouth serves to protect the body from injury. This lining is itself subject to a variety of infections and conditions, ranging from benign canker sores to often fatal cancers.

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Oral Candidiasis

Chronic hyperplastic candidiasis is a red or white lesion that may be flat or slightly elevated and may adhere to soft or hard tissue surfaces, including dental appliances. It is caused by species of Candida, especially Candida albicans, the most common fungal pathogen isolated from the oral cavity. Normally, the fungi are present in relatively low numbers in up to 65 percent of healthy children and adults and cause no harm (McCullough et al. 1996). Problems arise when there is a change in oral homeostatis—the normal balance of protective mechanisms and resident oral flora that maintain the health of the oral cavity—so that defense mechanisms are compromised (Scully et al. 1994). Under these circumstances the fungal organisms can overgrow to cause disease. A primary disruption in homeostasis occurs with the use of antibiotics and corticosteroids, which can markedly change the composition of the oral flora. Deficiencies in the immune and endocrine systems are also important. Indeed, the diagnosis of candidiasis in an otherwise seemingly healthy young adult may be the first sign of HIV infection. Other causes of candidiasis include cancer chemotherapy or radiotherapy to the head and neck, xerostomia resulting from radiation to the head and neck, medications, chronic mucosal irritation, certain blood diseases, and other systemic conditions. Also, tobacco use has been identified as a cofactor.

Candidiasis often causes symptoms of burning and soreness as well as sensitivity to acidic and spicy foods. Patients may complain of a foul taste in the mouth. However, it can also be asymptomatic. Genomic analysis of the Candida albicans genome is helping investigators identify numerous genes that code for virulence factors, including enzymes that can facilitate adhesion to and penetration of mucous membranes. At the same time, researchers are exploring novel gene technologies to increase production of a family of native salivary proteins, the histatins, that have known anticandidal and other antimicrobial effects.

The most common form of oral candidiasis is denture stomatitis. It occurs when tissues are traumatized by continued wearing of ill-fitting or inadequately cleaned dental appliances and is described as chronic erythematous candidiasis. Another form, candidal angular cheilosis, occurs in the folds at the angles of the mouth and is closely associated with denture sore mouth (Tyldesley and Field 1995). Other common forms of Candida infection are pseudomembranous candidiasis (thrush), which may affect any of the mucosal surfaces, and acute erythematous candidiasis, a red and markedly painful variant commonly seen in AIDS patients.

In most cases, Candida infection can be controlled with antifungal medications used locally or systemically. Control is difficult, however, in patients with immune dysfunction, as in AIDS, or other chronic debilitating diseases. Often the organisms become resistant to standard therapy, and aggressive approaches are necessary (Tyldesley and Field 1995). The spread of oral candidiasis to the esophagus or lungs can be life-threatening and is one of the criteria used to define frank AIDS (Samaranayake and Holmstrup 1989).

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Herpes Simplex Virus Infections

In any given year, about one-half-million Americans will experience their first encounter with the herpes simplex virus type 1 (HSV-1), the cause of cold sores. That first encounter usually occurs in the oral region and may be so mild as to go unnoticed. But in some people, particularly young children and young adults, infection may take the form of primary herpetic stomatitis, with symptoms of malaise, muscle aches, sore throat, and enlarged and tender lymph nodes, prior to the appearance of the familiar cold sore blisters. These blisters usually show up on the lips, but any of the mucosal surfaces can be affected. Bright-red ulcerated areas and marked gingivitis may also be seen (Tyldesley and Field 1995).

Herpes viruses also cause genital infections, which are transmitted sexually. Both HSV-1 and HSV-2 have been found in oral and genital infections, with HSV-1 predominating in oral areas and HSV-2 in genital areas (Wheeler 1988). Herpes viruses have also been implicated as cofactors in the development of oral cancers. Crowded living conditions can result in greater contact with infected individuals, which aids in transmission of HSV (Whitley 1992).

Normally, the immune system mounts a successful attack on the viruses, with symptoms abating by the time neutralizing antibodies appear in the bloodstream, in about 10 days. However, herpes viruses are notorious for their ability to avoid immune detection by taking refuge in the nervous system, where they can remain latent for years. In oral herpes the virus commonly migrates to the nearby trigeminal ganglion, the cluster of nerve cells whose fibers branch out to the face and mouth. In about 20 to 40 percent of people who are virus-positive, the virus may reactivate, with infectious virus particles moving to the oral cavity to cause recurrent disease (Scott et al. 1997).

The usual site of a recurrent lesion is on or near the lips. Recurrences are rarely severe, and lesions heal in 7 to 10 days without scarring (Higgins et al. 1993). The recurrences may be provoked by a wide range of stimuli, including sunlight, mechanical trauma, and mild fevers such as occur with a cold. Emotional factors may play a role as well.

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Oral Human Papillomavirus Infections

There are more than 100 recognized strains of oral human papillomavirus (HPV), a member of the papovavirus family, implicated in a variety of oral lesions (Regezi and Sciubba 1993). Most common are papillomas (warts) found on or around the lips and in the mouth. HPV is found in 80 percent of these oral squamous papillomas (de Villiers 1989). The virus has also been identified in 30 to 40 percent of oral squamous cell carcinomas (Chang et al. 1990) and has been implicated in cervical cancer as well. Whether a cancer or nonmalignant wart develops may depend on which virus is present or on which viral genes are activated.

Oral warts are most often found in children, probably as a result of chewing warts on the hands. In adults, sexual transmission from the anogenital region can occur (Franchesi et al. 1996).

In general, viral warts spontaneously regress after 1 or 2 years. The immune system normally keeps HPV infections under control, as evidenced by the increased prevalence of HPV-associated lesions in HIV-infected patients and others with immunodeficiency.

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Recurrent Aphthous Ulcers

Recurrent aphthous ulcers (RAU), also referred to as recurrent aphthous stomatitis, is the technical term for canker sores, the most common and generally mild oral mucosal disease. Between 5 and 25 percent of the general population is affected, with higher numbers in selected groups, such as health professional students (Axéll et al. 1976, Embil et al. 1975, Ferguson et al. 1984, Kleinman et al. 1991, Ship 1972, Ship et al. 1967).

The disease takes three clinical forms: RAU minor, RAU major, and herpetiform RAU. The minor form accounts for 70 to 87 percent of cases. The sores are small, discrete, shallow ulcers surrounded by a red halo appearing at the front of the mouth or the tongue. The ulcers, which usually last up to 2 weeks, are painful and may make eating or speaking difficult. About half of RAU patients experience recurrences every 1 to 3 months; as many as 30 percent report continuous recurrences (Bagan et al. 1991).

RAU major accounts for 7 to 20 percent of cases and usually appears as 1 to 10 larger coalescent ulcers at a time, which can persist for weeks or months (Bagan et al. 1991). Herpetiform RAU has been reported as occurring in 7 to 10 percent of RAU cases. The ulcers appear in crops of 10 to 100 at a time, concentrating in the back of the mouth and lasting for 7 to 14 days (Bagan et al. 1991, Rennie et al. 1985).

RAU can begin in childhood, but the peak period for onset is the second decade (Lehner 1968). About 50 percent of close relatives of patients with RAU also have the condition (Ship 1965), and a high correlation of RAU has been noted in identical but not fraternal twins. Associations have been found between RAU and specific genetic markers (Scully and Porter 1989).

RAU has also been associated with hypersensitivities to some foods, food dyes, and food preservatives (Woo and Sonis 1996). Nutritional deficiencies—especially in iron, folic acid, various B vitamins, or combinations thereof—have also been reported, and improvements noted with suitable dietary supplements (Nolan et al. 1991).

The two factors that have been found to have the strongest association with RAU are immunologic abnormality, possibly involving autoimmunity, and trauma (Lehner 1968, Ship 1996, Woo and Sonis 1996).

Volunteers with and without a history of RAU were studied for their reaction to the trauma of a needle prick to the inner cheek tissue. No ulcers developed in non-RAU subjects, but nearly half of those prone to canker sores had a recurrence (Wray et al. 1981).

RAU also can occur in a number of systemic diseases, including HIV infection, ulcerative colitis, Crohn's disease, and Behçet's disease (Ship 1996). In general, people who are immunocompromised are more susceptible to RAU, as are people with a variety of blood diseases.

RAU itself does not give rise to other illnesses but is uncomfortable. Symptomatic treatment includes topical analgesics, antibacterial rinses, topical corticosteroids, and a new prescription medication that reduces pain and healing time (Khandwala et al. 1997, Ship 1996).

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ORAL AND PHARYNGEAL CANCERS AND PRECANCEROUS LESIONS

In 2000, oral or pharyngeal cancer will be diagnosed in an estimated 30,200 Americans and will cause more than 7,800 deaths (Greenlee et al. 2000). Over 90 percent of these cancers are squamous cell carcinomas—cancers of the epithelial cells. The most common oral sites are on the tongue, the lips, and the floor of the mouth. Oral cancer is the sixth most common cancer in U.S. males and takes a disproportionate toll on minorities; it now ranks as the fourth most common cancer among African American men (Kosary et al. 1995). The prominent role of tobacco use, especially in combination with alcohol, in causing these cancers is a major incentive to develop effective health promotion and disease prevention efforts.

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Heightening the Risk

Oral cancer develops as a clone from a single genetically altered cell (Solt 1981). It generally has a long latency period and invariably develops from a precancerous lesion on the oral mucosa, such as a white leukoplakia, or more commonly, a reddish erythroplakia (Mashberg 1978, Shklar 1986). Both kinds of lesions are usually induced by tobacco use alone or in combination with heavy use of alcohol. The development of squamous cell carcinoma from initial erythroplakia lesions has been well demonstrated experimentally. Silverman (1998) reported rates of malignant transformation for leukoplakias of between 0.13 and 17.5 percent. However, there is considerable debate as to the actual malignant potential of the leukoplakia lesion associated with the use of smokeless (spit) tobacco. Meaningful data for determining a specific malignant transformation rate or relative risk of oral cancer due to smokeless tobacco use are difficult to obtain because of the confounding effects of other habits such as concurrent smoking and alcohol consumption and because of the variations in smokeless (spit) products and how they are used.

Another oral precancerous lesion that has received attention is submucous fibrosis. It is commonly seen in India and Southeast Asia and is related to betel nut use (Canniff et al. 1986).

Early epidemiologic studies identified behaviors such as smoking and environmental factors such as exposure to solar radiation and x-rays as causes of intraoral and lip cancers (Pindborg 1977). Researchers then sought experimentally to explain the mechanisms of initiation. In the 1980s and 1990s, investigators exploited the techniques of molecular biology and genetics to probe what was going on deep inside the cell. These studies revealed an abundance of systemic and local factors, including viral and fungal infections, that affect cell behavior. Some factors stimulate cell division and others inhibit it—even to the point of initiating a program of cell "suicide," called apoptosis. How a given cell behaves at any given time in its life cycle is the net result of the signals it receives from neighboring cells and molecules, from circulating factors in the blood or immune system, and from its own internal controls. The following sections provide a brief description of these factors and how they may participate in enhancing the risk for the development of oral cancers.

Tobacco and Alcohol

Tobacco and alcohol are the major risk factors for oral cancers, and their effects have been studied for many years (Rothman and Keller 1972, Decker and Goldstein 1982). Tobacco contains substances that are frankly carcinogenic or act as initiators or promoters of carcinogenesis. Among these are N-nitrosonornicotine, 4-nitroquinoline-N-oxide, and benzpyrene. The most damaging carcinogens are found in the tars of tobacco smoke, but many forms of smokeless (spit) tobacco, including snuff, have been implicated in the development of mouth cancer (Advisory Committee to the Surgeon General 1986, International Agency for Research on Cancer 1985, Winn 1984). Other habits that have been related to oral cancer include chewing betel nut in the presence of tobacco, as is done primarily in Southeast Asia (Hirayama 1966, Mehta et al. 1981), and, more recently, using marijuana (Donald 1986).

The role of alcohol in oral carcinogenesis has been demonstrated experimentally (Wight and Ogden 1998) and appears to be related to its damaging effect on the liver. Major metabolites of alcohol, such as acetaldehyde—a known carcinogen in animals—may also be important. Alcohol is also thought to act as a solvent that facilitates the penetration of tobacco carcinogens into oral tissues. That observation may partly explain why the combined use of tobacco and alcohol produces a greater risk for oral cancer than use of either substance alone. Indeed, tobacco and alcohol, working in tandem, are thought to account for 75 to 90 percent of all oral and pharyngeal cancers in the United States (Blot et al. 1988).

Viruses

The role of viruses in causing cancer in animals was established early in the century when Rous showed that a virus, later named the Rous sarcoma virus (RSV), caused tumors in chickens. The issue of whether viruses could cause cancer in humans remained unexplored until the mid-1970s, when Varmus and Bishop showed that RSV had a special gene, which they called src (for sarcoma), that could transform the cell it infected into a malignant cell (Bishop et al. 1978). It was an oncogene, or cancer-causing gene. The researchers subsequently, and surprisingly, discovered that src was not native to the virus, but had been picked up by some ancestor virus from a chicken cell's own genome, where src had presumably played a role in the chicken cell's normal growth and development. Somehow RSV was able to subvert src when it infected a chicken cell to cause the cell to divide uncontrollably. Varmus and Bishop called the normal cellular src gene a proto-oncogene, meaning that it had the potential to be converted to an oncogene. Subsequent research led to the discovery of other viruses that could cause tumors in animals and revealed the presence of proto-oncogenes in birds and mammals. These genes could also be converted to oncogenes, behaving exactly like those carried by cancer viruses. In 1982 an oncogene isolated from a human bladder cancer turned out to be virtually identical to ras, the oncogene found in a rat sarcoma virus (Parada et al. 1982).

Viruses that have been implicated in oral cancer include herpes simplex type 1 and human papillomavirus. Epstein-Barr virus, also a herpes virus, is now accepted as an oncogenic virus responsible for Burkitt's lymphoma, occurring primarily in Africa, and nasopharyngeal carcinoma, occurring primarily in China. HPV is a major etiologic agent in cervical cancer (Howley 1991), and has been found in association with oral cancer as well (Sugerman and Shillitoe 1997). HPV DNA sequences have been found in oral precancerous lesions as well as in squamous cell carcinomas (Adler-Storthz et al. 1986, Syrjanen et al. 1988), and experimental evidence has shown that HPV-16 can be an important cofactor in oral carcinogenesis (Park et al. 1991, 1995). Herpes simplex type 1 antibodies were demonstrated in patients with oral cancer, and herpes was found to induce dysplasia (abnormal cellular changes) in the lips of hamsters when combined with the application of tobacco tar condensate (Park et al. 1986).

More recently, human herpes virus 8, a newly identified member of the herpes virus family, has been found in Kaposi's sarcoma, an otherwise rare cancer occurring in patients with AIDS. These tumors often appear initially within the oral cavity (Epstein and Scully 1992). Other uncommon oral malignant tumors, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma, can also occur in the mouths of AIDS patients.

In addition to viruses, infection with strains of the fungus Candida albicans has been linked to the development of oral cancers via the fungal production of nitrosamines, which are known carcinogens.

Genetic Derangements

Of the more than 50 known oncogenes, many have been reported to be present in oral cancer, and multiple oncogenes have been reported in oral and pharyngeal cancer (Spandidos et al. 1985). Some of these are Bcl-1, c-erb-B2, c-myc, ins-2, and members of the ras family (Berenson et al. 1989, Bos 1989, Riviere et al. 1990, Somers et al. 1990, 1992).

The genetic derangements that can give rise to oral cancer, including many mutations associated with the transformation of proto-oncogenes, have received notable attention (Sidransky 1995, Wong et al. 1996). In some instances a change in a single nucleotide base—a point mutation—in a gene encoding a proto-oncogene is enough to transform it into an oncogene. Cancerous changes may also involve alterations, deletions, and break points in chromosomes that affect the position of genes.

Mutations that disarm the cell's DNA repair mechanisms, as well as mutations in tumor suppressor genes, which inhibit abnormal cell growth, play a major role in cancer development. If an individual inherits or acquires a mutation in one or more tumor-suppressor genes, for example, the loss of this protective mechanism reduces the number of other deleterious changes needed for cancer to develop.

Tumor suppressor genes suspected to be mutated in oral and pharyngeal cancers include those for Rb, p16 (MTS1, CDKN2, or IN4a), and p53. Todd et al. (1995) recently reported a novel oral tumor suppressor gene, named "deleted in oral cancer-1 (doc-1)." Of the group of tumor suppressor genes, that coding for p53 is considered of major importance, with mutations in the p53 gene detected in many types of cancer (Greenblatt et al. 1994, Hollstein et al. 1991), including oral and pharyngeal cancer (Langdon and Partridge 1992, Somers et al. 1992). The p53 gene has been called the "guardian of the genome" (Lane 1992) because of its ability to recognize damage to a cell's DNA and stop the process of growth and division until the damage is repaired. If repair is not possible, p53 can trigger apoptosis. Mutations in the p53 gene in oral cancer have been linked to smoking and alcohol use (Brennan et al. 1995).

Loss of Immunosurveillance and Control

The immune system can, as first noted by Paul Ehrlich in 1909, seek and destroy initial clones of transformed cancer cells (Ehrlich 1957). Ehrlich called this process immunosurveillance, and it has been confirmed in experimental animals (Burnet 1970, Shklar et al. 1990) and in humans with induced immunosuppression (Penn 1975).

One mechanism of immunosurveillance involves stimulating cytotoxic macrophages and lymphocytes to migrate to the tumor site and release tumor necrosis factors alpha and beta (Shklar and Schwartz 1988). Another mechanism operative in oral cancer appears to be stimulation of Langerhans cells, a special group of immune cells, in the oral mucosa (Schwartz et al. 1985). Other immune cells implicated in tumor rejection are natural killer cells and lymphokine-activated killer cells (Reif 1997).

There is an increased incidence of cancer in patients with AIDS or other immunodeficient conditions or with induced immunosuppression prior to organ transplantation.

In addition, there is evidence that smoking depresses the immune system (Chretien 1978), and this may be one of the ways in which smoking acts as a major risk factor in oral cancer.

Growth Factors

Immune cells are potent generators of growth factors and other molecules that can stimulate other cells to migrate and proliferate. This capacity is important in normal cell growth and turnover, in wound healing, and in coping with infection. Unfortunately, the release of growth factors can contribute to oral cancer by stimulating keratinocyte (oral epithelial cell) proliferation (Aaronson 1991, Issing et al. 1993, Wong 1993). Increased levels of transforming growth factor alpha (TGF-alpha) and epidermal growth factor have been found in oral and pharyngeal cancers and therefore could serve as markers for malignancy (Grandis and Tweardy 1993). Nicotine at high doses stimulates the release of growth hormones, among other endocrine effects (Pomerleau and Pomerleau 1984, Seyler et al. 1984, 1986).

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Prevention and Management

Studies of experimental carcinogenesis are elucidating the role of micronutrients in tumor development and progression. Alpha tocopherol (vitamin E) also has been studied as an antioxidant in nutritional approaches to the prevention or control of oral cancer. Antioxidants can trap free radicals, the highly reactive molecules that build up in cells and can damage DNA. The control of oral cancer and precancerous lesions has been demonstrated experimentally using a variety of antioxidant micronutrients, such as retinoids, carotenoids, and glutathione, as well as alpha tocopherol. For example, it was found that alpha tocopherol inhibited tumor development and tumor angiogenesis (blood vessel formation) in hamsters, as well as the expression of TGF-alpha, a potent angiogenesis stimulator (Shklar and Schwartz 1996). Animal research and tissue culture studies using animal- and human-derived cancer cell lines have shown combinations of micronutrients to be more effective than single micronutrients and to work synergistically. The nutrients not only were able to inhibit experimental carcinogenesis, but also could completely prevent tumor development and cause established squamous cell carcinomas to regress (Shklar and Schwartz 1993). The mechanisms of cancer control by micronutrients are gradually becoming clarified and involve common pathways of activity at the molecular level (Shklar and Schwartz 1994). Clinical studies in humans have shown an inhibitory effect on oral leukoplakia (Benner et al. 1993, Blot et al. 1993, Garewal 1993, Garewal et al. 1990, Hong et al. 1986), suggesting a potential role for nutrients in the overall prevention and management of early oral cancer and precancerous leukoplakia. However, a recommendation to employ such approaches clinically at this time is premature.

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DEVELOPMENTAL DISORDERS

The importance of the face as the bearer of identity, character, intelligence, and beauty is universal. Craniofacial birth defects, which can include such manifestations as cleft lip or palate, eyes too closely or widely spaced, deformed ears, eyes mismatched in color, and facial asymmetries, can be devastating to the parents and child affected. Surgery, dental care, psychological counseling, and rehabilitation may help to ameliorate the problems but often at great cost and over many years.

Although each developmental craniofacial disease or syndrome is relatively rare, the number of children affected worldwide is in the millions. In addition, craniofacial defects form a substantial component of many other developmental birth defects, largely because they occur very early in gestation, when many of the same genes that orchestrate the development of the brain, head, face, and mouth are also directing the development of the limbs and many vital internal organs, such as the heart, lungs, and liver.

By about the third week after fertilization, the three germ layers of the embryo—the ectoderm, endoderm, and mesoderm—have formed, as well as the first of four sets of paired swellings—the branchial arches—that appear at the sides of the head end of the embryo. (See Chapter 2 for more details on this process.) Some craniofacial defects result from failure of the arches to complete their morphogenetic development. Other craniofacial defects are the result of the abnormal differentiation of cells derived from the ectoderm and endoderm or from ectomesenchyme cells, which originate in a part of the ectoderm (the neural crest), in interaction with future connective tissue (the mesenchyme).

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Craniofacial Anomalies Caused by Altered Branchial Arch Morphogenesis

Cleft Lip/Palate and Cleft Palate

The most common of all craniofacial anomalies—and among the most common of all birth defects—are clefts of the lip with or without cleft palate and cleft palate alone; these occur at a rate of 1 to 2 out of 1,000 births, resulting in over 8,000 affected newborns every year. Cleft lip/palate and cleft palate are distinct conditions with different patterns of inheritance and embryological origins (Lidral et al. 1997, Murray et al. 1997). The male to female ratio of cleft lip/palate is 2:1; the ratio for cleft palate alone is just the reverse, 1:2.

These anomalies result from the failure of the first branchial arches to complete fusion processes (Murray 1995, Robert et al. 1996). Clefting can occur independently or as part of a larger syndrome that may include mental retardation and defects of the heart and other organs. Not all cases of clefting are inherited; a number of teratogens (environmental agents that can cause birth defects) have been implicated, as well as defects in essential nutrients such as folic acid. Smoking by the mother during pregnancy also increases the risk. It is becoming increasingly evident that most diseases and disorders, not just craniofacial anomalies, result from interactions involving multiple genes and environmental factors.

Infants with clefts have difficulty with vital oral functions such as feeding, breathing, speaking, and swallowing. They are also susceptible to repeated respiratory infections. As these children grow, they must cope with the social consequences of a facial deformity, delayed and altered speech, frequent illness, and repeated surgeries that may persist through late adolescence.

Current molecular epidemiology investigations have examined both syndromic and nonsyndromic (isolated) cleft lip/palate and cleft palate. Linkage studies have identified a number of candidate genes (Lewanda and Jabs 1994), including MSX1, RAR, an X-linked locus, and the genes for TGF-beta-3 and TGF-alpha. The pattern of inheritance in cleft lip/palate and cleft palate suggests that between 2 and 20 genes may be involved, with one gene representing a major component in the development of the cleft. One of the common syndromic forms of cleft lip/palate, the Van der Woude syndrome, is caused by an autosomal dominant form of inheritance at a locus on chromosome 1 (Sander et al. 1995). Future molecular genetic studies will be needed to provide the information necessary for prenatal diagnosis, calculation of risk, and potential gene therapy.

The Treacher Collins Syndrome—Mandibulofacial Dysostosis

Children with the Treacher Collins syndrome have downward-sloping eyelids; depressed cheekbones; a large fishlike mouth; deformed ears with conductive deafness; a small, receding chin and lower jaw; a highly arched or cleft palate; and severe dental malocclusion (Dixon 1996). These defects result from defective cranial neural crest cell differentiation, migration, and proliferation (see Chapter 2). Consequently, the first branchial arch structures are deficient, and all derivative craniofacial components are affected.

The underdeveloped facial structures can contribute to airway blockage and repeated upper respiratory infections, either of which can be fatal. The faulty development of the ears leads to a conductive deafness. The severe facial deformities exacerbate the psychological difficulties these youngsters face.

Investigators have identified the gene involved in an autosomal dominant form of the syndrome (Wise et al. 1997). The function of the gene is not yet known, but its identity will provide opportunities for prenatal diagnosis, gene therapy, and further understanding of craniofacial development.

The Pierre Robin Syndrome

Deficient development of the first-branchial-arch-derived mandibular portion results in the lower jaw's being set far back in relation to the forehead. As a result, the tongue is set back and may obstruct the posterior airway, compromising respiration (Elliott et al. 1995, Tomaski et al. 1995) and, in severe cases, leading to inadequate aeration and failure to thrive. The infant is also at risk for the development of cor pulmonale, an enlargement of the right ventricle of the heart that occurs secondarily to a chronic lung condition. Cleft palate may be another consequence.

The DiGeorge/Velocardiofacial Syndrome

The primary defect in the DiGeorge syndrome results from altered development of the fourth branchial arch and the third and fourth pharyngeal pouches (Goldmuntz and Emanuel 1997). Deficiencies affecting the thymus, parathyroid glands, and the great vessels that derive from these structures result. The facial features are subtle and include a squared-off nasal tip, small mouth, and widely spaced eyes. Similar facial features, along with heart defects, are seen in the velocardiofacial syndrome. Both syndromes are associated with deletions on the long arm of chromosome 22 (22q11) (Gong et al. 1997, Gottlieb et al. 1997). Further characterization of this chromosomal deletion region will provide information on the specific gene(s) affected and its function in craniofacial development.

The thymus defects severely compromise cellular immunity, depriving the body of thymus-derived T cells and paving the way for severe infectious disease. Inadequate or missing parathyroid glands cause severe hypocalcemia (low blood calcium levels) and seizures. The great vessel abnormalities alter cardiac output and lead to compromised circulation to heart tissues.

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Cranial Bone and Dental Anomalies

Defects in the timing of developmental events can cause premature fusion of cranial bones. Impairments of tooth development can result from interruptions of the developmental sequence at several different stages.

Craniosynostoses

Some craniofacial anomalies are associated with so-called master genes that orchestrate a program by which the embryo assumes its basic shape. Craniosynostosis, which occurs in approximately 1 out of 3,000 births, is one such anomaly. It results in the premature fusion of the cranial sutures, a dangerous condition that puts pressure on the developing brain. A number of diseases and syndromes, including Crouzon's, Apert's, Boston-type craniosynostosis, Pfeiffer's, and Saethre-Chotzen, share this anomaly, but differ in other features, which can include structural defects such as webbing of the hands and feet as well as mental retardation. Boston-type craniosynostosis has been linked to MSX2, one of the master genes. Several of the other syndromes involve point mutations at one or another locus in genes that code for fibroblast growth factor receptors (FGFR 1, 2, and 3) (Howard et al. 1997, Meyers et al. 1996). Collectively, these genes are associated with cell regulation, either through mediating growth factor effects or by serving as transcription factors (Cohen 1997).

Hereditary Hypodontia or Anodontia

Conditions of underdeveloped teeth (hypodontia) or their complete absence (anodontia) have been correlated with specific genes, such as MSX1 and LEF1. The complete absence of teeth alters the bony development of the mandible and maxilla.

Amelogenesis Imperfecta and Dentinogenesis Imperfecta

Amelogenesis imperfecta and dentinogenesis imperfecta are linked to defects in structural genes that code for proteins essential to the development of tooth enamel (amelogenesis imperfecta) or dentin (dentinogenesis imperfecta). The teeth are weak and extremely sensitive to temperature and pressure. The ordinary forces of chewing are painful and can lead to further wear and pain.

The enamel matrix genes include tuftelin, ameloblastin, and amelogenin; researchers have begun to link mutations in these genes with amelogenesis imperfecta. Similarly, genes labeled DSP and DPP have been characterized for dentin matrix and are associated with the inheritance of dentinogenesis imperfecta.

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Craniofacial Defects Secondary to Other Developmental Disorders

A number of genetic diseases occur in which craniofacial defects are secondary to a more generalized structural or biochemical defect.

Osteogenesis Imperfecta

Inherited mutations of collagen genes lead to a number of "brittle bone" diseases characterized by defects in mineralized tissues that form from a collagen-rich matrix. Osteogenesis imperfecta presents a spectrum of deficiencies that includes fragile bones, clear or blue sclera, deafness, loose ligaments, and painful dentinogenesis imperfecta-like changes in the teeth.

Epidermolysis Bullosa—Recessive Dystrophic Type

The gene defect in epidermolysis bullosa—recessive dystrophic type—manifests as blisters or bullae that appear shortly after birth on skin areas following minor trauma. Mutations in keratin genes that contribute to the epithelial cell cytoskeleton have been correlated with this condition.

The oral manifestations include both mucosal bullae and altered teeth. Altered teeth with hypoplastic enamel develop and exhibit an increased susceptibility to caries. Oral bullae develop from even the slightest mucosal trauma. The condition is painful and dangerous because of the constant risk that the bullae will become infected.

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Craniofacial Manifestations of Single-Gene Defects

In many craniofacial defects, mutations within a single gene manifest as complex syndromes with varied organ and limb defects as well as facial anomalies.

Ectodermal Dysplasias

The ectodermal dysplasias (EDs) are a family of hereditary diseases first observed by Charles Darwin over a century ago. They involve defects in two or more tissues derived from the ectoderm—skin, hair, teeth, nails, and sweat glands. The ectodermal structures fail to differentiate properly owing to altered epithelial-mesenchymal signaling. A gene, EDA, at an X-linked locus has been linked to the syndrome, and ongoing research is aimed at determining the function of the gene and the molecular mechanism of the syndromes (Kere et al. 1996, Zonana et al. 1994). More recently, investigators have discovered genes linked to autosomal (i.e., non-sex-linked) forms of ED, displaying both dominant and recessive inheritance (Monreal et al. 1999).

Oral manifestations of the ectodermal dysplasias are associated with the teeth. Alterations in tooth development can include hypodontia, anodontia, and conically shaped teeth.

The Waardenburg Syndrome

The Waardenburg syndrome has been subdivided into several types. All involve a variety of abnormalities in the position and appearance of the nose and eyes, with pigment changes that may cause one eye to differ in color from the other. Other signs include deafness, a mildly protruding jaw, cleft lip and palate, and skeletal deformities (Reynolds et al. 1995). The syndrome is inherited in an autosomal dominant manner with complete penetrance and variable expression. Specific genes associated with this syndrome are members of the homeobox family that regulate the transcription of other genes: Waardenburg type 1 with PAX3; Waardenburg type 2 with MITF, 3q14.1; and Waardenburg type 3 with PAX3, 2q35 (Asher et al. 1996).

Cleidocranial Dysplasia

The inheritance of a regulatory gene defect in cleidocranial dysplasia leads to features that include delayed tooth eruption, supernumerary teeth, altered or missing collarbones, short stature, and possible failure of cranial suture closure. The exact mechanism of the associated gene, CBFA1, located on chromosome 6, has not been determined but appears to be essential for bone development.

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INJURY

The common perception is that injuries are random occurrences that are unpredictable and hence unpreventable. In actuality, experts in the field make the point that there are no basic scientific distinctions between injury and disease (Haddon and Baker 1981). Injuries have been categorized as "intentional" and "unintentional." People identified as being at risk for certain injuries, as well as the causes of those injuries, can be targeted for appropriate prevention strategies. Such an approach is broadly applicable to sports, falls, and motor vehicle injuries (unintentional) as well as to injuries caused by abusive and violent behaviors (intentional).

Injuries are a major public health problem, outranking cancer and heart disease as a leading cause of death in some age groups of the population (Kraus and Robertson 1992). Cranial injuries in particular are a leading cause of mortality. Oral-facial injuries can bring disfigurement and dysfunction, greatly diminishing the quality of life and contributing to social and economic burdens (Reisine et al. 1989).

The leading causes of oral and craniofacial injuries are sports, violence, falls, and motor vehicle collisions (Kraus and Robertson 1992). Oral cavity injuries may also be caused by foreign objects in food (Hyman et al. 1993).

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Sports

Craniofacial sports injuries occur not only in contact sports, but also in individual activities such as bicycling, skating, and gymnastics, especially on trampolines. Each sport predisposes its participants to a specific array of extrinsic risk factors (Pinkham and Kohn 1991). These include physical contact, projectiles such as balls and pucks, and the quality of the playing field and equipment. In contact sports the absence of protective equipment such as headguards and mouthguards is a major risk factor. In a recent survey of school-aged children in organized sports, football was the only sport in which the majority of participants used mouthguards and headgear (Nowjack-Raymer and Gift 1996).

There are intrinsic risk factors as well, relating to characteristics of the individual participant. These include age, sex, injury history, body size, aerobic fitness and muscle strength, central motor control, and general mental ability (Taimela et al. 1990).

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Falls

Falls are a major cause of trauma to teeth, primarily to incisors. Unlike bone fractures, fractures of the crowns of the teeth do not heal or repair, and affected teeth often have an uncertain prognosis. Problems may develop later due to damage to the pulp.

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Motor Vehicle Collisions

The effects of motor vehicle collisions may range from minor and reversible effects to long-term medical, surgical, and rehabilitative consequences. Post-traumatic headaches and chronic oral-facial pain can occur. Neuromuscular and glandular damage may cause short- or long-term problems with chewing, swallowing, and tearing or result in facial tics or paralysis.

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Violence

The family is the single most frequent locus of violence in Western society. Domestic violence includes child abuse, spousal and elder abuse, and abuse of the disabled. Child abuse is of particular concern to the oral health community because 65 percent of cases involve head and oral-facial trauma (Mathewson 1993, Needleman 1986) and dentists are required to report suspected cases of child abuse. In the young child, head injury is the most common cause of death. Psychological trauma from abuse can result in sleep disturbances, eating disorders, developmental growth failure in young children, and nervous habits such as lip and fingernail biting and thumb sucking. Effects may also include chronic underachievement in school and poor peer relationships (Mathewson 1993). In abusive families, physical neglect is commonplace, with inadequate provision of basic needs, including medical and oral health care (Mathewson 1993).

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SELECTED CHRONIC AND DISABLING CONDITIONS

Oral, dental, or craniofacial signs and symptoms play a critical role in autoimmune disorders such as Sjögren's syndrome and in a number of chronic and disabling pain conditions.

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Sjögren's Syndrome

Sjögren's syndrome is one of several autoimmune disorders in which the body's own cells and tissues are mistakenly targeted for destruction by the immune system. Like other autoimmune conditions, Sjögren's syndrome is more prevalent among women. The ratio of females to males affected is 9:1, with symptoms usually developing in middle age. There are an estimated 1 to 2 million individuals in the United States with Sjögren's syndrome (Talal 1992).

The disease occurs in two forms. Primary Sjögren's involves the salivary and lacrimal (tear) glands. In secondary Sjögren's the glandular involvement is accompanied by the development of a connective tissue or collagen disease, most often rheumatoid arthritis, lupus erythematosis, scleroderma, or biliary cirrhosis.

The glandular involvement causes a marked reduction in fluid secretion, resulting in xerostomia and xerophthalmia (dry eyes). The constant oral dryness causes difficulty in speaking, chewing, and swallowing; the dry eyes often itch and feel gritty. There is no cure for Sjögren's, and patients often carry eyedrops and water bottles or saliva substitutes in an attempt to provide symptomatic relief. Clinically, the reduction in salivary flow changes the bacterial flora, which, in addition to the reduction in salivary protective components, increases the risk of caries and candidiasis (Daniels and Fox 1992). Recent studies have indicated that there is a reduction in masticatory function (Dusek et al. 1996) and an increased prevalence of periodontal disease (Najera et al. 1997). In advanced stages the salivary glands may swell because of obstruction and infection or lymphatic infiltration. In both forms of the disease, other systems may eventually become affected. Nasal, laryngeal, and vaginal dryness may occur, as well as abnormalities in internal organs (Oxholm and Asmussen 1996).

Diagnosis is difficult in the early stages, and women often report that it took many years and consultations with many specialists before they received the correct diagnosis. Diagnosis involves demonstration of specific antibodies in the blood characteristic of an autoimmune disorder, a labial (minor) salivary gland biopsy, and a series of eye tests to measure flow rate and tissue characteristics. Confirmatory tests include an evaluation of salivary flow and chemistry.

Patients with Sjögren's syndrome are at some risk of developing diseases such as non-Hodgkin's lymphoma; clinical data indicate that such lymphomas develop in 5 percent of patients with Sjögren's syndrome (Moutsopoulos et al. 1978).

Histological examination shows that immune cells infiltrate the glands and cluster around the secretory elements, resulting in a breakdown of the normal structure of the gland. The mechanisms by which this occurs involve immune-cell-mediated inflammation and stimulation of the salivary gland cells themselves to produce tissue-destructive molecules such as cytokines. Another hypothesis is that a viral infection of the glands may trigger the immune response that leads to autoimmunity, whereas genetic or regulatory alterations might lead to abnormalities in apoptosis (Fox and Speight 1996).

In addition to saliva substitutes and artificial tears, some medications, such as pilocarpine and cevimeline, are prescribed to increase salivary flow from the residual healthy gland tissue, again providing symptomatic relief only. The problems that develop in the other organ systems are also treated symptomatically. At advanced stages, steroids are employed intermittently to alleviate problems.

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Acute and Chronic Oral-Facial Pain

Since the nineteenth century, when two dentists, Horace Wells and Frederick Morton, demonstrated the analgesic powers of nitrous oxide and ether, oral health investigators have been recognized leaders in the field of pain management worldwide. Their analyses of the cells, pathways, and molecules involved in the transmission and modulation of pain have given rise to a growing variety of medications, often combined with other approaches, that can control acute and chronic pain. Pain researchers today stress that chronic pain can become a disease in itself, causing long-term detrimental changes in the nervous system. These changes may affect resistance to other diseases as well as effectively destroy quality of life. Most people have experienced acute pain involving teeth and the oral tissues at one time or another.

Atypical Facial Pain

Atypical facial pain is characterized by a continuous dull ache on one or both sides, most frequently in the region of the maxilla (the upper jaw). The pain tends to be episodic and is aggravated by fatigue, worry, or emotional upset. It is often accompanied by pain elsewhere in the body and depression. Once a dental cause can be ruled out, pain resolution depends on the successful use of antidepressants, psychotherapy, or both (Tyldesley and Field 1995).

Tic Douloureux

The oral-facial region is also subject to pain that can be paroxysmal or continuous along a distinct nerve distribution. The most frequently encountered of these oral facial neuralgias is tic douloureux, or trigeminal neuralgia, a disease of unknown etiology affecting one, two, or all three branches of the trigeminal nerve. The pain is highly intense and of a stabbing nature, and lasts for a few seconds. This transient attack may be repeated every few minutes or several hours. There may be no precipitating factor, or it may occur in response to a gentle touch or a breeze wafting across the face—a condition experts call allodynia, the feeling of pain in response to a normally nonpainful stimulus. On other occasions, there may be a specific trigger zone. Although spontaneous remission for weeks or months may occur, it is rarely permanent. Given the unknown, unpredictable nature of tic douloureux, it is not surprising that fear of pain comes to dominate these patients' lives, as they avoid doing anything that might trigger an attack.

Trigeminal neuralgia generally occurs in later life, but also occurs in younger individuals affected by multiple sclerosis, where it is assumed to be associated with lesions (multiple sclerosis "plaques") in the brain stem. Medical treatment depends largely on the use of a drug that has become a virtual specific, the antiepileptic drug carbamazepine. For those patients with no consequential adverse effects, it can control the disease. An alternative for chronic sufferers is the surgical removal of a small vein or artery that may be exerting pressure on the nerve root or the selective destruction of the nerve fibers themselves using chemical or electrical methods. In many cases, these procedures can produce complete relief from pain (Tyldesley and Field 1995).

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Temporomandibular Disorders

Various etiological factors, including trauma, can give rise to pain and dysfunction in the temporomandibular joint and surrounding muscles, conditions collectively called temporomandibular disorders (TMDs). The pain may be localized or radiate to the teeth, head, ears, neck, and shoulders. Abnormal grating, clicking, or crackling sounds, known as crepitus, in the joint often accompany localized pain. Pain is also found in response to clinical palpation of the affected structures. TMDs are common, occurring in as many as 10 million Americans. Although surveys indicate that both sexes are affected, the majority of individuals seeking treatment are women of childbearing age, a phenomenon suggesting that hormonal influences should be investigated.

Several factors can contribute to the onset or exacerbation of TMD symptoms. These factors include certain developmental anomalies; injury to the jaw from accidents or abuse; oral habits that greatly stress the joint and musculature, such as tooth grinding (bruxism); jaw manifestations of systemic diseases such as fibromyalgia and arthritic diseases; and some irreversible treatments for initial signs and symptoms.

The multiplicity of factors that may cause or contribute to TMDs has unfortunately led to a multiplicity of treatments. Most of these treatments have not been tested in randomized controlled clinical trials. During the 1970s and 1980s, many individuals underwent surgery, which proved unsuccessful in many cases.

Leading investigators have proposed standardized research diagnostic criteria to clarify the kinds of pathology that can give rise to TMDs and to classify the most common forms of TMDs. Such criteria could be used in designing clinical trials and could ultimately lead to better diagnostics, treatments, and prevention. The criteria use two dimensions or axes: axis I delineates various forms of joint or muscle pathology; axis II explores pain-related disability and psychological status. The approach requires detailed clinical examinations and patient histories (Dworkin and LeResche 1992).

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A MIRROR, A MODEL, AND A BETTER UNDERSTANDING OF DISEASES AND DISORDERS

Studying the diseases and disorders that affect craniofacial tissues can provide scientists with models of systemic pathology. Because some craniofacial tissues, such as bones, mucosa, muscles, joints, and nerve endings, have counterparts in other parts of the body and these tissues are often more accessible to research analysis than deeper-lying tissues, researchers studying craniofacial tissues can gain valuable insights into how cancer develops, the role of inflammation in infection and pain, the effects of diet and smoking, the consequences of depressed immunity, and the changes that can arise from a mutated gene.

Other craniofacial tissues—teeth, gingiva, tongue, salivary glands, and the organs of taste and smell—are unique to the craniofacial complex. Study of the diseases affecting these tissues has revealed a wealth of information about their special nature as well as the molecules and mechanisms that normally operate for the protection, maintenance, and repair of all the oral, dental, and craniofacial tissues. When factors perturb these nurturing elements, the oral health scale can tip toward disease. When those factors stem from systemic diseases or disorders, the mouth can sometimes mirror the body's ill health. Similarly underscoring the connection between oral and general health are studies suggesting that poor dental health, mainly due to chronic dental infections, may heighten the risk for both cardiovascular disease and stroke independently of factors such as social class and established cardiovascular risk factors (Grau et al. 1997). The interplay between craniofacial and systemic health and disease has become a lively focus of interest and research, as discussed in Chapter 5.

Current research on developmental disorders and diseases affecting the craniofacial complex is facilitating and complementing the intense effort of the Human Genome Project to map and sequence all 100,000 genes. This goal should be accomplished early in the twenty-first century and should begin to yield information on the genetic program that governs morphogenesis, organ development, and disease etiology and pathogenesis, with the potential for interventions that can correct errors in the program. The continued sequencing of the genomes of microbial pathogens involved in oral diseases also should lead to new diagnostic and preventive approaches.

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FINDINGS

  • Microbial infections, including those caused by bacteria, viruses, and fungi, are the primary cause of the most prevalent oral diseases. Examples include dental caries, periodontal diseases, herpes labialis, and candidiasis.

  • The etiology and pathogenesis of diseases and disorders affecting the craniofacial structures are multifactorial and complex, involving an interplay among genetic, environmental, and behavioral factors.

  • Many inherited and congenital conditions affect the craniofacial complex, often resulting in disfigurement and impairments that may involve many body organs and systems and affect millions of children worldwide.

  • Tobacco use, excessive alcohol use, and inappropriate dietary practices contribute to many diseases and disorders. In particular, tobacco use is a risk factor for oral cavity and pharyngeal cancers, periodontal diseases, candidiasis, and dental caries, among other diseases.

  • Some chronic diseases, such as Sjögren's syndrome, present with primary oral symptoms.

  • Oral-facial pain conditions are common and often have complex etiologies.

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