A Review of Non-plaque-related Gingival Conditions. Part One: Genetic/Developmental Disorders, Specific Infections and Inflammatory and Immune Conditions

Hereditary gingival fibromatosis

Hereditary gingival fibromatosis (HGF) is a rare developmental condition that presents as widespread, slow-growing and progressive enlargement of the maxillary and mandibular gingivae (Figure 1). It is regarded as a benign condition although the exact aetiology is unknown. It has been suggested that platelet-derived growth factor (PDGF) isoforms and transforming growth factor beta (TGF-beta) isoforms and their receptors are involved.^2,3

The gingival enlargement may present alone or as a component of other recognized syndromes. Diagnosis is made on the presenting clinical signs and history. Treatment will require specialist restorative involvement in view of the complex impact on the dentition.

Necrotizing gingivitis

Necrotizing gingivitis (NG) represents an infection associated with increased numbers of periodontal bacteria, in particular Treponema species, Fusobacterium species, Selenomonas species and Prevotella intermedia.⁴ Predisposing factors proposed include tobacco smoking, emotional stress and immunosuppression.^5,6,7 The condition is characterized by the rapid onset of erythema and necrosis of the marginal gingivae accompanied by grey sloughing of the interdental papillae (Figure 2).⁸ Plaque will usually be present, as even though it is not the initial causative factor, the ability to maintain oral hygiene will be compromised once the gingivae are uncomfortable to brush. There is a characteristic marked halitosis.

The diagnosis of NG is made from the history and clinical appearance. However, a smear of the gingival margin stained by Gram's method will demonstrate high numbers of inflammatory cells, spirochetes and fusobacteria (Figure 3). In the first instance, a supra-gingival scale combined with the use of a chlorhexidine 0.2% or hydrogen peroxide 1.5% rinse is helpful to reduce bacterial load.^9,10 If severe, metronidazole 400 mg (reduced in children) taken every 8 hours for 3 days is indicated.¹¹ It is essential to eliminate any precipitating factor by stopping smoking, reducing stress and improving oral hygiene. Once the acute infection has resolved, sub-gingival cleaning under local anaesthetic is required.¹² The possibility of HIV infection should be considered if NG is prolonged or recurrent.

Primary herpetic gingivostomatitis

The mouth is the most frequent site for first exposure to the herpes simplex virus type 1 (HSV-1), causing primary herpetic gingivostomatitis (PHGS). The virus is acquired through direct contact; usually via saliva from an individual who is experiencing reactivation of the latent virus, in particular recurrent herpes labialis, or asymptomatic shedding in their mouth.¹³ PHGS is characteristically seen in early childhood, although can be experienced in teenage years. Symptoms are usually subclinical and often mistaken for an episode of teething.¹⁴ However, some children will demonstrate significant clinical manifestations, including blood crusted lips, mucosal erythema, gingival swelling (Figure 4), oral blistering, multiple ulcers, fever, malaise and cervical lymphadenopathy.¹⁵ There is often a reduced appetite, poor oral hygiene, halitosis and a white coating of the tongue.¹³

The vast majority of cases of PHGS are diagnosed from the history and clinical features; however, molecular-based special investigations can be used to provide a rapid diagnosis if there is uncertainty.^16,17 Necrotizing gingivitis and erythema multiforme should be considered in the differential diagnosis.¹⁸

In an otherwise healthy individual, PHGS will resolve within 2 weeks. Oral analgesia, soft diet, adequate fluid intake and bedrest should be provided. In young children, chlorhexidine 0.2% mouthwash applied on a cotton bud to clean the teeth is helpful. Benzydamine hydrochloride 0.15% mouthwash or spray can also provide symptomatic relief. Family members of the patient should be warned about the high infectivity of HSV-1 and advised to avoid kissing or sharing bath towels with the patient. It is particularly important to avoid transmission of HSV-1 in saliva to the eye since this can cause herpetic keratitis and potential blindness.^13,19,20

Systemic aciclovir should be prescribed in severe cases or if the patient is immune-compromised because this will reduce the duration of symptoms.^21,22 The adult dose of 200 mg taken five times daily can be given from the age of 2 years. Once PHGS resolves, HSV-1 remains latent within the tissues with the potential for periodic reactivation.

Plasma cell gingivitis

Although not fully understood, plasma cell gingivitis is thought to be a hypersensitivity reaction to various substances, including ingredients of toothpaste, chewing gum and foodstuffs.^23,24,25 Desquamative gingivitis with a velvety texture and sharp demarcation along the muco-gingival border is the typical clinical presentation (Figure 5). Histopathological examination of biopsy material will show a dense infiltrate of plasma cells in the lamina propria. It is important to exclude other conditions that may present with similar clinical features, in particular, forms of leukaemia and myeloma.²⁶

Management should focus on an attempt to identify the causative agent, which may be achieved by cutaneous patch testing, and if found, subsequent avoidance.²⁶ This alone should improve symptoms, but often topical steroid treatment may be required to achieve resolution.^27,28

Pemphigus vulgaris

Pemphigus vulgaris (PV) is an autoimmune condition in which antibodies are produced against specific components of epithelial desmosomes, resulting in loss of attachment between epithelial cells and blister formation (Figure 6). Vesicles and bullae develop within the oral mucosa, but since these are fragile, rupture occurs to leave erosion as the usual presenting feature. Any oral site may be affected by PV, but the non-keratinized mucosa is most susceptible.²⁹ Desquamative gingivitis is also a frequent oral manifestation.³⁰ PV may also affect the skin, causing erythematous erosions and crusts.^31,32

Diagnosis can be confirmed using an incisional biopsy, usually of tissue taken immediately adjacent to affected mucosa, to detect an intra-epithelial split on routine histopathology, or inter-epithelial IgG on direct immunofluorescence.³⁰ Indirect immunofluorescence using a blood sample may detect the presence of circulating auto-antibodies.³³ Treatment will depend on the severity of symptoms and involve corticosteroid therapy, both topical and systemic, steroid-sparing immunosuppressant drugs and biologic agents.^31,34 Multidisciplinary care, involving ophthalmology and dermatology may be necessary. Maintenance of good oral hygiene is important to eliminate plaque-induced inflammation.

Mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is an autoimmune condition in which antibodies are produced against specific components of the epithelial hemidesmosomes, resulting in loss of attachment between the epithelium and underlying connective tissue to produce blistering. MMP predominantly affects the mouth, although any mucosal site may be involved, especially the eyes and genitals.³⁵ The gingivae are the tissues most frequently affected intra-orally, usually presenting as a painful desquamative gingivitis (Figure 7) or blood-filled bullae (Figure 8).^36,37 Other oral mucosal sites may also be affected, with erosions, ulceration or bullae. Skin may be involved in MMP, but to a lesser extent than the mucosal sites.

Diagnosis can be made from an incisional biopsy, usually taken from mucosa adjacent to affected tissues to demonstrate a sub-epithelial split on routine histopathology. Direct immunofluorescence on tissue will show IgG and C3 at the basement membrane.²⁹ Indirect immunofluorescence on a blood sample may reveal the presence of circulating auto-antibodies.³⁸ The treatment of MMP will involve topical and systemic corticosteroid therapy, steroid-sparing immunosuppressant drugs and biologic agents.^39,40 Multidisciplinary care involving ophthalmology and dermatology is essential.

Lichen planus

Lichen planus (LP) is an immune-mediated mucocutaneous condition involving T cell mediated destruction of basal keratinocytes and hyperparakeratinization of the epithelium.⁴¹ The specific trigger for LP is not fully understood.⁴² There is evidence that there may be a link with hepatitis C virus infection.^43,44,45

LP may affect mucous membranes, skin and nails.⁴⁶ The oral presentation is characteristically bilateral and symmetrical, affecting the buccal mucosa, tongue and gingivae. LP most frequently presents as a ‘reticular’ form, with white reticular striae on an underlying erythema (Figure 9). Other presentations can be white plaques, erosions, areas of atrophy or rarely, bullae.^47,48 Regarding the gingivae, LP may present with desquamative gingivitis; highly reddened gingivae, often velvety in texture and with overlying white striae. Gingival LP may present in isolation^49,50 or alongside other oral sites (Figure 10). LP has a long duration and may persist for many years, although symptoms vary with time, sometimes being exacerbated by emotional stress.⁵¹

Diagnosis of the majority of cases of LP can be made from the characteristic clinical presentation and history. However, a biopsy should be carried out in cases of doubt to exclude lupus erythematosus, lichenoid reaction, leukoplakia, pemphigus and mucous membrane pemphigoid.⁵² The management of the oral manifestations of LP depends on the severity of symptoms. First-line treatment is with topical steroids and the location and severity of mucosal involvement will determine the potency and format of steroid prescribed (cream, gel, mouthwash, spray). A vacuum-formed soft acrylic splint can be used to hold steroid cream against the gingivae. Patients with LP that is unresponsive to topical treatment may require systemic medication. Regular monitoring is required since oral LP is classified as a potentially malignant disorder.⁵³

Orofacial granulomatosis

Orofacial granulomatosis (OFG) is generally believed to involve a hypersensitivity to dietary factors, in particular benzoates and cinnamon.^54,55 There is debate as to whether OFG represents an early manifestation of inflammatory bowel disease (notably Crohn's disease) or if it is a separate clinical entity.^56,57,58 Characteristically, OFG presents initially in childhood or early teenage years as recurrent or persistent painless swelling of one or both lips. Intra-orally there is likely to be full thickness gingivitis (Figure 11a), aphthous-type ulceration, ‘cobblestone’ swelling of the buccal mucosa and mucosal tags.⁵⁹ The presence of deep linear ulceration in the lower buccal sulcus is suggestive of Crohn's disease.⁶⁰

Diagnosis can usually be made on the history and clinical features; however; it is important to question the patient about gastrointestinal symptoms and, if present, refer for exclusion of Crohn's disease. An intra-oral biopsy down to muscle can be performed to detect the diagnostic presence of multiple non-caseating granulomas.⁵⁹ Cutaneous patch testing is extremely helpful in the identification of any hypersensitivity reaction.⁶¹ Haematological testing can help to exclude other granulomatous conditions such as sarcoidosis, which may present with similar clinical or histological features.⁵⁹

Avoidance of benzoates and cinnamon in the diet should be carried out whenever OFG is suspected since it may significantly reduce clinical signs and symptoms (Figure 11b).⁶² Topical steroids can relieve symptoms of oral ulceration and topical calcineurin inhibitors may be of benefit for the orofacial swelling and erythema.^63,64 Injection of corticosteroid into the lip can reduce swelling and improve cosmetic appearance.^65,66,67 Systemic steroids, thalidomide, immunosuppressants and biologics are reserved for more severe cases, or for known Crohn's disease.^59,68,69,70 Patients should be informed about the potential link to inflammatory bowel diseases.