Elsevier

Clinics in Dermatology

Volume 34, Issue 4, July–August 2016, Pages 505-513
Clinics in Dermatology

Orofacial granulomatosis

https://doi.org/10.1016/j.clindermatol.2016.02.024Get rights and content

Abstract

Orofacial granulomatosis (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 fungal infections, sarcoidosis, rosacea, and Crohn disease (CD). In addition, OFG should be considered synonymous with previously described conditions, including granulomatous cheilitis and Miescher cheilitis, as well as Melkersson-Rosenthal syndrome and its monosymtomatic or oligosymptomatic variants. The relationship of OFG to CD is currently debated, with recent evidence suggesting the possibility of three entities: classic oral CD (established gastrointestinal CD with oral involvement), OFG with gastrointestinal involvement (OFG with subclinical or asymptomatic gastrointestinal endoscopy changes), and OFG without bowel involvement. Childhood onset, presence of certain phenotypic features, laboratory abnormalities, or gastrointestinal symptoms may indicate the need for further evaluation to assess for concurrent or future CD. Although multiple therapies have been found to be effective in small numbers of patients, treatment should be tailored to each patient.

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)

  • D.K. Armstrong et al.

    Contact hypersensitivity in patients with orofacial granulomatosis

    Dermatitis

    (1997)
  • S.A. Saboor et al.

    Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction

    Lancet

    (1992)
  • G. Ficarra et al.

    Oral Crohn's disease and pyostomatitis vegetans: an unusual association

    Oral Surg Oral Med Oral Pathol

    (1993)
  • W.R. Tyldesley

    Oral Crohn's disease and related conditions

    Br J Oral Surg

    (1979)
  • N. Worsaae et al.

    Melkersson-Rosenthal syndrome and Crohn's disease

    Br J Oral Surg

    (1980)
  • E.A. Field et al.

    Oral Crohn's disease revisited—a 10-year-review

    Br J Oral Maxillofac Surg

    (1989)
  • A.P. Zbar et al.

    Oral Crohn's disease: is it a separable disease from orofacial granulomatosis? A review

    J Crohns Colitis

    (2012)
  • S. Harty et al.

    A prospective study of the oral manifestations of Crohn’s disease

    Clin Gastroenterol Hepatol

    (2005)
  • C.B. Lynde et al.

    Cheilitis granulomatosa treated with intralesional corticosteroids and anti-inflammatory agents

    J Am Acad Dermatol

    (2011)
  • M. Mignogna et al.

    Effectiveness of small-volume, intralesional, delayed-release triamcinolone injections in orofacial granulomatosis: a pilot study

    J Am Acad Dermatol

    (2004)
  • D. Wiesenfeld et al.

    Oro-facial granulomatosis—a clinical and pathological analysis

    Q J Med

    (1985)
  • B. Grave et al.

    Orofacial granulomatosis—a 20-year review

    Oral Dis

    (2009)
  • W. Tilakaratne et al.

    Orofacial granulomatosis: review on aetiology and pathogenesis

    J Oral Pathol Med

    (2007)
  • A. Bouaziz et al.

    Oral involvement in sarcoidosis: report of 12 cases

    Q J Med

    (2012)
  • V. Ramesh

    Orofacial granulomatosis due to tuberculosis

    Pediatr Dermatol

    (2009)
  • R. Rogers

    Granulomatous cheilitis, Melkersson-Rosenthal syndrome, and orofacial granulomatosis

    Arch Dermatol

    (2000)
  • R. van der Waal et al.

    Cheilitis granulomatosa

    J Eur Acad Dermatol Venereol

    (2001)
  • K. Al Johani et al.

    Onset and progression of clinical manifestations of orofacial granulomatosis

    Oral Dis

    (2009)
  • D.K. Armstrong et al.

    Orofacial granulomatosis

    Int J Dermatol

    (1995)
  • W.A. Critchlow et al.

    Cheilitis granulomatosa: a review

    Head Neck Pathol

    (2014)
  • C. Scully et al.

    Orofacial granulomatosis

    Lancet

    (1991)
  • E. Melkersson

    Ett fall av recidiverande facialispares i samband med angioneurotiskt ödem

    Hygiea

    (1928)
  • C. Rosenthal

    Klinisch-erbbiologischer Beitrag zur Konstitutionspathologie

    Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr

    (1931)
  • G. Miescher

    Über die essentielle granulomatöse Makrocheilie (granulomatöse cheilitis)

    Dermatology (Basel, Switzerland)

    (1945)
  • E. Luscher et al.

    Schweiz Med Wochenschr

    (1949)
  • M. Daoud et al.

    Melkersson-Rosenthal syndrome

    Semin Dermatol

    (1995)
  • J.J. Sciubba et al.

    Orofacial granulomatosis: presentation, pathology and management of 13 cases

    J Oral Pathol Med

    (2003)
  • B.E. McCartan et al.

    Characteristics of patients with orofacial granulomatosis

    Oral Dis

    (2011)
  • M. Mignogna et al.

    The multiform and variable patterns of onset of orofacial granulomatosis

    J Oral Pathol Med

    (2003)
  • G. Gale et al.

    Characterisation of a Swedish cohort with orofacial granulomatosis with or without Crohn's disease

    Oral Dis

    (2015)
  • A. Goto et al.

    A case of typical Melkersson-Rosenthal syndrome with possible autosomal dominant inheritance

    Rinsho Shinkeigaku

    (1999)
  • E. Smeets et al.

    Melkersson-Rosenthal syndrome and de novo autosomal t(9;21)(p11;p11) translocation

    Clin Genet

    (1994)
  • J. Gibson et al.

    Human leucocyte antigen typing in orofacial granulomatosis

    Br J Dermatol

    (2000)
  • N. Stosiek et al.

    HLA typing in patients with Melkersson-Rosenthal syndrome

    Z Hautkr

    (1987)
  • M. Meisel-Stosiek et al.

    Family study on Melkersson-Rosenthal syndrome. Some hereditary aspects of the disease and review of literature

    Acta Derm Venereol

    (1990)
  • G. Gale et al.

    Immunophenotype in orofacial granulomatosis with and without Crohn's disease

    Med Oral Patol Oral Cir Bucal

    (2014)
  • P. Patel et al.

    Subepithelial dendritic B cells in orofacial granulomatosis

    Inflamm Bowel Dis

    (2010)
  • F. Facchetti et al.

    Non-specific influx of T-cell receptor alpha/beta and gamma/delta lymphocytes in mucosal biopsies from a patient with orofacial granulomatosis

    J Oral Pathol Med

    (2000)
  • A. Giovannetti et al.

    Skewed T-cell receptor variable β repertoire and massive T-cell activation in idiopathic orofacial granulomatosis

    Int J Immunopathol Pharmacol

    (2012)
  • S.H. Lim et al.

    Molecular analysis of T cell receptor beta variability in a patient with orofacial granulomatosis

    Gut

    (1997)
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