Orofacial granulomatosis
Introduction
Orofacial granulomatosis (OFG) is characterized clinically by recurrent or persistent orofacial swelling. The term was first described1 in 1985 as an idiopathic entity requiring exclusion of other known causes of granulomatous inflammation, including mycobacterial infection, deep fungal infection, sarcoidosis, rosacea, and Crohn disease (CD).[2], [3], [4], [5], [6], [7] Recently, OFG has been used to describe multiple entities with varying etiologies responsible for orofacial swelling and granulomatous inflammation. Several processes have been hypothesized to play a role in pathogenesis, including genetic, immunologic, allergic (food or dental materials), and infectious etiologies.[2], [3] OFG encompasses a spectrum of known granulomatous diseases, including localized lip swelling in granulomatous cheilitis or Miescher cheilitis, as well as more extensive inflammation leading to facial nerve palsy and lingua plicata (fissured tongue), a triad known as Melkersson-Rosenthal syndrome.[8], [9], [10], [11], [12], [13], [14], [15]
Section snippets
History and nomenclature
Granulomatous inflammation in the setting of orofacial swelling and facial palsy without an underlying systemic condition was first described by Melkersson in 1928.16 Rosenthal presented a patient with orofacial swelling, facial palsy, and an additional feature, lingua plicata.17 In 1945, the terms cheilitis granulomatosa and Miescher cheilitis were used to describe granulomatous inflammation and swelling confined to the lips,18 In 1949, the concept of the Melkersson-Rosenthal syndrome triad
Epidemiology
Patient demographic characteristics are largely based on cohorts reported from North America and Europe.[1], [4], [10], [21], [22], [23], [24], [25], [26] The prevalence is uncertain. OFG may occur at any age but appears to be most prevalent in young adults. No racial or sex predilection has been consistently reported. Recent literature from Sweden suggests geographic differences in epidemiology may exist.26
Etiology
The etiology and pathogenesis of OFG are not well understood. Numerous studies have been undertaken with varied results, suggesting a multifactorial process. Multiple etiologies have been postulated: genetic, immunologic, allergic, and infectious.
Genetic
A genetic predisposition to OFG has been investigated, but studies are sparse and have reported mixed results. A familial basis has been described with the suggestion of autosomal dominant inheritance with variable penetrance.27 A de novo autosomal t(9;21)(p11;p11) translocation was described in a case report.28 Some observers have suggested OFG is linked with specific human leukocyte antigen (HLA) genotypes and haplotypes.29 HLA-B16 and HLA-Cw3 have also been found in patients with
Immunologic
The noncaseating granulomatous inflammation that occurs in OFG is indistinguishable from that in CD, sarcoidosis, and chronic inflammatory conditions, such as chronic tooth-associated infection and rosacea. Additional histologic features include lymphedema and a perivascular lymphocytic infiltrate, often composed of CD4+ T cells, although other T-cell subsets and B cells have been described and implicated in the pathogenesis of OFG.[32], [33] One study34 found no significant differences in
Allergic
Allergy to foodstuffs, food additives, and dental materials has also been implicated in OFG, but causation versus exacerbation of signs and symptoms in these patients is debated. Strengthening this theory are studies indicating a high prevalence of atopy in patients with OFG.[39], [40], [41], [42] One group43 found a significantly greater prevalence of allergy as determined by a history of asthma, atopic dermatitis, allergic rhinitis, or acute food allergy, as well as positive skin prick tests
Infectious
Microbiologic agents have been associated with chronic granulomatous diseases, including tuberculosis, sarcoidosis, and CD, thus their suspected role in OFG.[58], [59] Studies have primarily focused on Mycobacterium tuberculosis, Mycobacterium paratuberculosis, Saccharomyces cerevisiae, and Borrelia burgdorferi. M tuberculosis has been found in the tissue of OFG patients using amplification techniques on fresh60 and paraffin-embedded61 tissue. Increased serum antibodies to the mycobacterial 65
Clinical manifestations
OFG has a variable presentation. It may affect all facial tissues, with the lips being the most common site of painless and nonpruritic edema. This may be mild and recurrent but may progress to more severe, persistent edema. The edema may be asymmetric, with involvement of one or both lips or involvement of one side greater than the other (Figures 1 and 2). Associated lip scaling can be noted (Figure 1). Additional features may include oral ulceration (Figure 3), gingivitis and gingival
Histopathology
Characteristic histopathologic features include noncaseating granulomas, dilated lymphatics, and a perivascular lymphocytic infiltrate.[1], [2], [75] Granulomatous inflammation is not always present, and a nonspecific inflammatory infiltrate may be the only histopathologic finding.[10], [22] As such, the absence of noncaseating granulomas does not exclude the diagnosis and may represent a sampling variability or be the result of biopsy from an early lesion.8
Diagnostic studies
A diagnosis of OFG should be suspected in patients presenting with recurrent or persistent orofacial swelling not due to angioedema. Clinical history and examination should be used to identify potential causes (Figure 5). Biopsy of an affected area for hematoxylin and eosin staining may be helpful to find histologic evidence of noncaseating granulomas or other characteristic features. Direct immunofluorescence testing of tissue specimens is unlikely to be useful. Additional diagnostic studies (
OFG and Crohn disease
Crohn disease (CD) is a chronic inflammatory disease with the potential to affect the entire gastrointestinal tract, including the oral mucosa. Oral involvement in patients with intestinal CD, or “oral CD,” has been well established. Disease-specific manifestations include granulomatous inflammation with resultant orofacial swelling, granulomatous cheilitis, cobblestoning of the oral mucosa, deep linear ulceration (often of the buccal sulci), aphthous ulcers, mucosal tags, and gingivitis.[77],
Treatment
Treatment of OFG is challenging. A number of treatments have been documented, but evidence is limited. Treatment of odontogenic infection and avoidance of identifiable allergens may lead to resolution.[24], [47] Topical treatments, including topical corticosteroids and calcineurin inhibitors, may have utility in mild disease, and combination therapy has been found to be superior to topical treatment alone.4 Systemic and intralesional corticosteroids have remained a mainstay of therapy for OFG.97
Conclusions
OFG is an uncommon chronic granulomatous condition with a multifactorial etiology and pathogenesis. Genetic, immunologic, allergic, and infectious mechanisms have been implicated. OFG is often used as a descriptor to encompass all entities with orofacial swelling and histologic evidence of noncaseating granulomas. The diagnosis of OFG should prompt evaluation for provocative factors. The cause of most cases of OFG remains obscure. The clinician must consider mycobacterial infections, deep
References (120)
- et al.
Orofacial granulomatosis: clinical features and long-term outcome of therapy
J Am Acad Dermatol
(2010) An update on granulomatous diseases of the oral tissues
Dent Clin North Am
(2013)Melkersson-Rosenthal syndrome and orofacial granulomatosis
Dermatol Clin
(1996)- et al.
Melkersson-Rosenthal syndrome: a review of 36 patients
J Am Acad Dermatol
(1989) - et al.
Orofacial manifestations of Melkersson-Rosenthal syndrome: a study of 42 patients and review of 220 cases from the literature
Oral Surg Oral Med Oral Pathol
(1992) - et al.
Melkersson-Rosenthal syndrome and cheilitis granulomatosa. A clinicopathological study of thirty-three patients with special reference to their oral lesions
Oral Surg Oral Med Oral Pathol
(1982) - et al.
Miescher's cheilitis and lymphocytic clonal expansion: 2 cases
Ann Dermatol Venereol
(2004) - et al.
Oro-facial granulomatosis: a possible allergic basis
Br J Oral Maxillofac Surg
(1985) - et al.
Monosodium glutamate-related orofacial granulomatosis. Review and case report
Oral Surg Oral Med Oral Pathol
(1991) - et al.
Contact orofacial granulomatosis caused by delayed hypersensitivity to gold and mercury
J Am Acad Dermatol
(2003)