Cheilitis Granulomatosa

Updated: Apr 20, 2020
Author: Alan Snyder; Chief Editor: William D James, MD 



Cheilitis granulomatosa (or granulomatous cheilitis) is characterized by persistent idiopathic swelling of the lip due to granulomatous inflammation. It is thought to be a subset of orofacial granulomatosa and is frequently used in the literature to describe the monosymptomatic presentation of Miescher cheilitis.[1, 2, 3, 4, 5]

Orofacial granulomatosis (OFG) represents a spectrum of disease characterized by granulomatous inflammation of the oral and maxillofacial region in the absence of systemic disease like Crohn disease.[1, 2, 5, 6] It is rare for patients to progress to symptoms of Crohn disease.[7, 8]

Miescher-Melkersson-Rosenthal syndrome is the term used when the cheilitis occurs as part of a symptomatic triad including facial palsy and plicated (fissured) tongue. The entire triad is not always present.

Miescher cheilitis is a term sometimes used when the granulomatous changes are confined to the lip. Miescher cheilitis is generally regarded as a monosymptomatic form of Miescher-Melkersson-Rosenthal syndrome. See the image below.

Orofacial granulomatosis in a patient with Crohn d Orofacial granulomatosis in a patient with Crohn disease showing showing lip and gingival swelling.



While the actual frequency is unknown, one study estimated its incidence at 0.08% of the general population.[9] Onset of granulomatous cheilitis is usually in young adult life. Both orofacial granulomatosis and Miescher-Melkersson-Rosenthal syndrome have an average age of onset of about 32 years. However, cases may present as early as age 3 years and as late as age 78 years.[10]


The cause of granulomatous cheilitis is unknown.[11] Normal lip architecture is altered by lymphedema and noncaseating granulomas in the lamina propria. Excessive permeability of facial cutaneous vessels resulting from abnormal regulation of the autonomic nervous system has been suggested as a potential cause. Hornstein proposed that nonspecific antigens may stimulate perivascular cells to form granulomas, causing obstruction of the vessels and subsequent facial swelling.[12]

Dietary or other antigens are the most common identified cause of orofacial granulomatosis (OFG).[13, 14] Contact antigens such as cobalt, gold, or mercury are sometimes implicated.[15] OFG may also result from reactions to some foods or medicaments, particularly cinnamon aldehyde and benzoates, but also butylated hydroxyanisole, dodecyl gallate, menthol, and monosodium glutamate.[16] Expression of protease-activated receptor 1 and 2 occurs in orofacial granulomatosis. Th1 immunocytes produce interleukin 12 and RANTES/MIP-1alpha and granulomas. HLA typing may show HLA A*02, HLA*A11, HLA DRB1*11, HLA DRB1*13, and HLA DQB1*03.[17] Low levels of HLA A*01, HLA DRB1*04, HLA DRB1*07, and HLA DQB1*02 may be found as well.[18]

Crohn disease, sarcoidosis, and OFG may present with similar histologic findings. Analogous findings have also been reported after liver transplantation in children.[19] Recent research has attempted to identify related genetic risk factors between Crohn disease and OFG to correlate their similar clinical presentation and sometimes comorbid development.[5, 20] Missense coding in NOD2-variant patients may indicate the concurrent development of OFG with intestinal disease, but not OFG alone.[21] Miescher-Melkersson-Rosenthal syndrome is not usually related to the development of inflammatory bowel disease. However, one longitudinal study tracking 27 patients with a median follow up of 30 years found that one patient with cheilitis granulomatosa developed Crohn disease and two with Miescher-Melkersson-Rosenthal syndrome developed ulcerative colitis.[22] This is still an active area of research.

A genetic predisposition may exist in Miescher-Melkersson-Rosenthal syndrome; siblings have been affected, and a plicated tongue may be present in otherwise unaffected relatives. Paternal and maternal inheritance has been implicated in some cases.[23] A mutation in the FATP1 gene has been found in patients with this syndrome.[24] It may follow a pattern of autosomal dominant inheritance with the responsible gene being located on 9p.[25]

A summary of possibilities follows:

  • Genetics - Debate about link with HLA antigen and inheritance patterns of different subsets of the disease

  • Food allergy - Various food additives thought to cause or precipitant event; 60% of individuals with condition are atopic (eczema, IgE levels); prime causative agents or exacerbation of disease

  • Allergy to dental material - No conclusive evidence

  • Infection - Studies have focused on Mycobacterium tuberculosis, Mycobacterium paratuberculosis, Saccharomyces cerevisiae, and Borrelia burgdorferi but provide insufficient evidence

  • Immunological - Hypothesis that no single antigen causes disease, rather a random influx of inflammatory cells; delayed sensitivity reaction rather than super antigen; results reflect an immunological nature


Swelling is typically chronic. Morbidity related to the disease depends also on whether an underlying organic disease, such as Crohn disease or sarcoidosis,[26] is present. Patients, especially children and adolescents, presenting with what appears to be granulomatous cheilitis or OFG should be very carefully evaluated for gastrointestinal symptoms, signs, and disease.[27]




Cheilitis granulomatosa is usually seen in orofacial granulomatosis (OFG) as an episodic nontender swelling and enlargement of one or both lips. Occasionally, similar edematous swellings involve other areas, including the periocular region and genitalia.[23, 28, 29]

A fissured or plicated tongue is seen in 20-40% of patients. Its presence from birth (in some patients) may indicate a genetic susceptibility. Patients may lose the sense of taste and have decreased salivary gland secretion.

The first episode of lip edema typically subsides completely in hours or days. After recurrent attacks, swelling may persist and slowly increase in degree, eventually becoming permanent. Recurrences can range from days to years.

Attacks sometimes are accompanied by fever and mild constitutional symptoms (eg, headache, visual disturbance). Miescher-Melkersson-Rosenthal syndrome involves the association with facial nerve palsy and plicated tongue.[30, 31]

Facial palsy of the lower motor-neuron type occurs in about 30% of patients with granulomatous cheilitis. Facial palsy may precede facial swelling by months or years, but it more commonly develops later. Facial palsy is intermittent at first, but it may become permanent. It can be unilateral or bilateral, partial or complete.

Other cranial nerves (eg, olfactory, auditory, glossopharyngeal, hypoglossal) are occasionally affected.

Physical Examination

The earliest manifestation of granulomatous cheilitis is sudden diffuse or occasionally nodular swellings of the lip or the face involving (in decreasing order of frequency) the upper lip, the lower lip, both lips, and one or both cheeks.[32] The forehead, the eyelids, or one side of the scalp may be involved (less common).[29, 33] As previously mentioned, a fissured or plicated tongue is seen in 20-40% of patients.

The lip swelling may feel soft, firm, or nodular on palpation. Once chronicity is established, the enlarged lip appears cracked and fissured, with reddish brown discoloration and scaling. The fissured lip becomes painful and eventually acquires the consistency of firm rubber. Swelling may regress very slowly after some years. Regional lymph nodes are enlarged (usually minimally) in 50% of patients.

Orofacial lesions of orofacial granulomatosis (OFG) and of Crohn disease may include facial or labial swelling, “cobblestone” proliferation of mucosa or mucosal tags, and/or ulcers. An initial presentation of probable OFG does not necessarily predict the development of Crohn disease, but this is more likely in childhood.[7, 8]

Facial palsy of the lower motor-neuron type occurs in up to 30% of patients. It can be unilateral or bilateral, partial or complete. Other cranial nerves (eg, olfactory, auditory, glossopharyngeal, hypoglossal) are occasionally affected.

Central nervous system involvement has been reported, but the significance of resulting symptoms is easily overlooked because they are very variable (sometimes simulating multiple sclerosis but often with a poorly defined association of psychiatric and neurologic features). Autonomic disturbances may occur.



Diagnostic Considerations

Conditions to consider in the differential diagnosis of granulomatous cheilitis include the following:

  • Acquired angioedema due to C1 inhibitor deficiency
  • Acute complications of sarcoidosis
  • Atopic reaction to ACE inhibitors [1]
  • Blepharochalasis [29]
  • Cheilitis glandularis [3]
  • Crohn disease
  • Dental abscess or infection
  • Dermatologic manifestations of leprosy
  • Dermatologic manifestations of sarcoidosis
  • Foreign body reaction
  • Hereditary angioedema
  • Histoplasmosis [1]
  • Leishmaniasis [34]
  • Leprosy
  • Lymphoma
  • Orofacial granulomatosis
  • Polyangiitis
  • Sarcoidosis
  • Thyroid orbitopathy [29]
  • Trauma
  • Tuberculosis
  • Wegener granulomatosis [1]

Differential Diagnoses



Approach Considerations

Laboratory studies

Serum angiotensin-converting enzyme (SACE) testing may be performed to help exclude sarcoidosis. Patch tests may be used to help exclude reactions to metals, food additives, or other oral antigens[35] ; some cases of granulomatous cheilitis may be associated with such sensitivities. If found, avoidance of the implicated allergen is recommended. Decreased iron, hemoglobin, ferritin, folate, and elevated C-reactive protein, celiac antibodies, serum IgE, and alkaline phosphatases have been documented to be associated with orofacial granulomatosis (OFG); however, evidence is insufficient that any of these are consistent markers of the disease.[5]

Imaging studies

OFG is the term given to granulomatous lesions similar to those of Crohn disease, found on oral biopsy, but where there is no detectable systemic Crohn disease, though this may be detected later.[36] Gastrointestinal tract endoscopy, radiography, and biopsy may be used to help exclude Crohn disease. Chest radiography or gallium or positron emission tomography (PET) scanning may be performed to help exclude sarcoidosis and tuberculosis. Panorex dental films may be obtained to assess for the presence of a chronic dental abscess.


A biopsy of the swollen lip or orofacial tissues is indicated but often shows only lymphoedema and perivascular lymphocytic infiltration during the early stages and may only later show granulomas. A biopsy may help to exclude Crohn disease, sarcoidosis, lymphoma, and other conditions in the differential diagnosis.

Histologic Findings

Histologic changes are not always conspicuous or specific in many cases of long duration; the infiltrate becomes denser and pleomorphic, and small, focal, noncaseating, sarcoidal granulomas are formed that are indistinguishable from Crohn disease or sarcoidosis.

The inflammatory response is probably mediated by cytokines such as tumor necrosis factor-alpha and by protease-activated receptors (PARs), matrix metalloproteinases (MMPs), and cyclo-oxygenases (COXs). There is submucosal chronic inflammation with many Th1 and mononuclear, interleukin 1–producing cells; large, active, dendritic B cells; and noncaseating granulomas.[37] Small granulomas occur in the lymphatic walls in some cases. Similar changes may be present in cervical lymph nodes.



Approach Considerations

Treatment is difficult and unsatisfactory. In severe cases of labial swelling, medication or surgical intervention may be required, but most respond to more conservative measures.[32] Exclusion of offending substances may help facial swelling resolve. Up to 40% of orofacial granulomatosis (OFG) patients may have positive reactions to patch tests. Half of these benefit from antigen exclusion.[38]

Granulomatous cheilitis or OFG may improve with implementation of a cinnamon- and benzoate-free diet. Benefit has been reported in 54-78% of patients.[39]

Intralesional corticosteroids may be helpful in some patients,[40] and their use in combination with antibacterial drugs such as metronidazole has been an effective treatment in several instances.[41, 42] Success with other treatments has been reported anecdotally, including intralesional pingyangmycin plus dexamethasone.[43] Simple compression for several hours daily may produce sustained improvement. Compression devices can be worn overnight to reduce lip edema.

Extensive labial swelling can be disfiguring and have serious social consequences for the patient; therefore, changes in personal affect should be taken into consideration when choosing treatment options for patients with cheilitis granulomatosa.[32] Furthermore, comorbid psychiatric diseases and other affective phenomena may be linked to relapse frequency of Miescher-Melkersson-Rosenthal syndrome.[44] In one case, targeted psychotherapeutic intervention resulted in both decreased relapse frequency of the syndrome and remission of depression.[44]

Surgical care

Surgery and radiation have been used in treating cheilitis granulomatosa. Surgery alone is relatively unsuccessful. Reduction cheiloplasty with intralesional triamcinolone and systemic tetracycline offers the best results.[45] Medical therapy is necessary to maintain the results of reductive cheiloplasty during the postoperative period.[32] Give corticosteroid injections periodically after surgery to avoid an exaggerated recurrence.

Nerve decompression has been successful in the treatment of recurrent facial nerve palsy.[46]


Patients with lesions apparently restricted initially to the mouth may progress to exhibit frank intestinal Crohn disease.[47, 48, 49] Therefore, consult a gastroenterologist, an immunologist, a dietician, and an oral medicine specialist.


Follow-up care is indicated particularly to exclude the development of Crohn disease and possibly ulcerative colitis.



Medication Summary

None of the agents listed below has been systematically evaluated.

Immunomodulatory agents are tried as follows:

  • Nonsteroidal anti-inflammatory agents (NSAIDs)
  • Mast cell stabilizers [41]
  • Clofazimine [50]
  • Methotrexate [51]
  • Tacrolimus
  • Biologics such as infliximab [52]
  • Dapsone
  • Triamcinolone and dapsone injections [53]

Antimicrobials are as follows:

  • Tetracycline (used for anti-inflammatory activity)
  • Azithromycin [54]
  • Metronidazole [41, 42]
  • Minocycline [55]
  • Roxithromycin [56]
  • Antibiotic treatment of dental abscess - Resulted in remission in anecdotal cases

Intralesional corticosteroid (triamcinolone) injections may reduce swelling. Systemic corticosteroids are rarely indicated and not all patients respond. Clofazimine, dapsone, tacrolimus, thalidomide, or antitumor necrosis factor biologics may be needed.[36] No large randomized, controlled trials have been recorded with potential therapies such as tacrolimus, thalidomide, or infliximab.

Antibiotics, Other

Class Summary

Therapy must be comprehensive and should cover all likely pathogens in the clinical setting.

Azithromycin (Zithromax, Zmax)

Azithromycin inhibits bacterial growth by binding to the 50S subunit of bacterial ribosome, preventing assembly of the ribosome complex and inhibiting translation during protein synthesis.

Clofazimine (Lamprene)

Clofazimine inhibits mycobacterial growth, binding preferentially to mycobacterial deoxyribonucleic acid (DNA). It has antimicrobial properties, but the mechanism of action is unknown.


Dapsone is bactericidal and bacteriostatic against mycobacteria. Its mechanism of action is similar to that of sulfonamides in which competitive antagonists of para-aminobenzoic acid (PABA) prevent the formation of folic acid, inhibiting bacterial growth.

Metronidazole (Flagyl, Flagyl ER, Flagyl IV RTU)

Metronidazole is used to treat a number of microbial infections, exerting is greatest effects in reducing cellular environments. Reduction of its nitro group results in the creation of cytotoxic intermediates that inhibit deoxyribonucleic acid synthesis.

Penicillin G (Pfizerpen)

Penicillin G interferes with the synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Doxycycline (Doryx, Adoxa, Ocudox, Vibramycin, Oraxyl)

Doxycycline is a broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations.

Doxycycline inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly the 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Erythromycin (E.E.S., Ery-Tab, Erythrocin, PCE, EryPed)

Erythromycin covers most potential etiologic agents, including Mycoplasma species. The oral regimen may be insufficient to adequately treat Legionella species, and this agent is less active against Haemophilus influenzae. Although the standard course of treatment is 10 days, treatment until the patient has been afebrile for 3-5 days seems a more rational approach. Erythromycin therapy may result in GI upset, causing some clinicians to prescribe an alternative macrolide or change to a thrice-daily dosing.

Erythromycin is a macrolide that inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Mast Cell Stabilizers

Class Summary

Mast cell stabilizers inhibit the degeneration of sensitized mast cells when exposed to specific antigens by inhibiting the release of mediators from the mast cells. These agents block calcium ions from entering the mast cell.

Ketotifen, ophthalmic

Ketotifen is an H1-receptor antagonist and mast cell stabilizer. This agent inhibits the release of mediators from cells involved in hypersensitivity reactions.


Class Summary

These agents decrease inflammatory responses and systemically interfere with events leading to inflammation.

Sulfasalazine (Azulfidine)

Sulfasalazine decreases the inflammatory response and systemically inhibits prostaglandin synthesis.


Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Triamcinolone (Aristospan, Kenalog)

Triamcinolone is used to treat inflammatory dermatosis that is responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.


Class Summary

These agents inhibit key factors that mediate immune reactions, which, in turn, decrease inflammatory responses.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, ribonucleic acid (RNA), and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity.


Questions & Answers


What is cheilitis granulomatosa?

What is the prevalence of cheilitis granulomatosa?

What causes cheilitis granulomatosa?

What is the prognosis of cheilitis granulomatosa?


Which clinical history findings are characteristic of cheilitis granulomatosa?

Which physical findings are characteristic of cheilitis granulomatosa?


Which conditions should be included in the differential diagnoses of cheilitis granulomatosa?

What are the differential diagnoses for Cheilitis Granulomatosa?


What is the role of lab testing in the diagnosis of cheilitis granulomatosa?

What is the role of imaging studies in the diagnosis of cheilitis granulomatosa?

What is the role of biopsy in the diagnosis of cheilitis granulomatosa?

Which histologic findings are characteristic of cheilitis granulomatosa?


How is cheilitis granulomatosa treated?

What is the role of surgery in the treatment of cheilitis granulomatosa?

Which specialist consultations are beneficial to patients with cheilitis granulomatosa?

What follow-up care is needed for patients with cheilitis granulomatosa?


Which immunomodulatory agents are used in the treatment of cheilitis granulomatosa?

Which antimicrobials are used in the treatment of cheilitis granulomatosa?

Which medications in the drug class Immunosuppressants are used in the treatment of Cheilitis Granulomatosa?

Which medications in the drug class Corticosteroids are used in the treatment of Cheilitis Granulomatosa?

Which medications in the drug class Salicylates are used in the treatment of Cheilitis Granulomatosa?

Which medications in the drug class Mast Cell Stabilizers are used in the treatment of Cheilitis Granulomatosa?

Which medications in the drug class Antibiotics, Other are used in the treatment of Cheilitis Granulomatosa?