Granulomatous Cheilitis/Melkersson-Rosenthal Syndrome (Miesher’s Cheilitis)
Are You Confident of the Diagnosis?
Granulomatous cheilitis (also known as Miescher cheilitis), first described by Miescher in 1945, is a rare inflammatory disorder of unknown etiology characterized by recurrent swelling of the labial tissues. It is regarded as part of the spectrum of orofacial granulomatosis.
Melkersson-Rosenthal syndrome is an uncommon neuromucocutaneous disorder that consists of the triad of orofacial edema, facial palsy, and fissured tongue (lingua plicata). It was first reported by Melkersson in 1928, and few years later Rosenthal added fissured tongue to complete the triad. Most authors regard granulomatous cheilitis as the mono- or oligosymptomatic form of Melkersson-Rosenthal syndrome, although there is a possibility that they are separate diseases. Only 8% to 25% of patients with this syndrome present with the complete triad.
Because granulomatous cheilitis and Melkersson-Rosenthal syndrome share histopathologic and clinical features with disorders such as Crohn’s disease, sarcoidosis, foreign body reaction, chronic granulomatous disease, and mycobacterial infections, the term orofacial granulomatosis was introduced to include all of these related conditions.
Characteristic findings on physical examination
Granulomatous cheilitis clinically presents with lip swelling that may initially be episodic, but can often persist in the long term. Many times, adjacent areas of the cheek are involved. If the swelling is confined to the lip, the lip may swell two to three times normal size. The initial edema usually subsides rapidly, within hours or days, but recurrent attacks lead to a more persistent swelling. The tissue texture may evolve from a soft fullness to a firm, brawny edema.
Melkersson-Rosenthal syndrome may manifest as the classic triad, in an incomplete form, or with sequential appearance of the clinical findings. The orofacial swelling seen is a prominent symptom of the syndrome, involving the eyelid in some cases. The gingival, lingual, and buccal mucosae may also be involved.
Facial palsy, which often cannot be distinguished from Bell’s palsy, is present in 20% to 50% of the cases. This neurologic finding may precede attacks of edema by months or years, especially when the syndrome affects children, but more commonly develops later. The paralysis is usually on the same side that is affected by the swelling. Approximately 50% of the patients report regional lymph node enlargement, and 20% to 40% have fissured tongue (lingua plicata).
Other clinical symptoms that have been reported in patients with Melkersson-Rosenthal syndrome include migraines or other headaches, tinnitus, sudden deafness, dizziness, dry mouth, dysphagia, excessive facial sweating or facial anhidrosis, dry eyes, disturbances of vision, and excessive tearing.
There is no difference in the clinical picture of Melkersson- Rosenthal syndrome in childhood from that in adults, although the sequence of events and the frequency of episodes are significantly different. The most common symptom of Melkersson-Rosenthal syndrome in childhood is a painless nonpruritic orofacial swelling involving the lips, chin, cheeks, and the periorbital region. Lingua plicata presents in only about 30% of cases reported in children, and develops during the course of the disease.
Expected results of diagnostic studies
The main diagnostic tools for granulomatous cheilitis and Melkersson-Rosenthal syndrome remain history and clinical examination, although a biopsy of the areas of swelling may be performed. It is widely accepted that Melkersson-Rosenthal syndrome can only be diagnosed with certainty when there is at least one major sign (recurrent orofacial edema and facial nerve palsy) associated with the histological features of typical noncaseating granulomas.
The characteristic histologic finding is noncaseating granulomas that are formed with epithelioid cells and Langerhans-type giant cells, but their absence does not exclude the syndrome. There may also be mild epithelial hyperplasia overlying the dermis or lamina propria (
Melkersson-Rosenthal syndrome (H&E). Low power. (Courtesy of Bryan Anderson, MD)
The differential diagnosis of granulomatous cheilitis in Melkersson- Rosenthal syndrome includes:
- hereditary angioedema
- infections from pathogens such as herpes simplex, Streptococcus, Staphylococcus
- contact dermatitis
- odontogenic infection
- Crohn’s disease
- Fabry’s disease
- superior vena cava obstruction
- Ascher’s syndrome (upper lip swelling, blepharochalasis, accessory lacrimal gland inflammation, and thyromegaly)
- chelitis glandularis
Facial palsy in Melkersson-Rosenthal syndrome cannot be distinguished from Bell’s palsy, which may also recur, thus making the diagnosis difficult. The clinician should then have to differentiate between Melkersson-Rosenthal syndrome and conditions that cause Bell’s palsy, such as tumors, infections, trauma, and the Ramsay-Hunt syndrome. In case a neoplasm is suspected, computed tomography (CT) scan and magnetic resonance imaging (MRI) of the head should be ordered.
Many authors have assumed that there is a relationship between Melkersson-Rosenthal syndrome and Crohn’s disease on the basis of similar histologic findings and orofacial swelling in both disorders, and the fact that granulomatous cheilitis has been found to precede Crohn’s disease by several years, but there is no evidence so far to support this assumption. In addition, it does not seem justified to recommend routine investigations of the gastrointestinal tract in patients with granulomatous cheilitis or Melkersson-Rosenthal syndrome with a negative history of gastrointestinal complaints.
As sarcoidosis is characterized by noncaseating granulomas similar to Melkersson-Rosenthal syndrome, it should be considered in the differential diagnosis. Sarcoidosis differs, though, as it responds to steroids and it is a self-limiting condition associated with hilar lymphadenopathy, hypercalcemia, positive Kveim test, and raised angiotensin-converting enzyme levels. Also, the lesions in sarcoidosis consist of focal nodular elements on the lips, as opposed to the more diffuse lip swelling in granulomatous cheilitis.
Complement levels and C1 esterase inhibitor levels should be measured to differentiate granulomatous cheilitis/Melkersson-Rosenthal syndrome from hereditary angioedema. Recurrent painless orofacial swelling appears to be a unique characteristic of Melkersson-Rosenthal syndrome.
Who is at Risk for Developing this Disease?
The rarity of granulomatous cheilitis and Melkersson-Rosenthal syndrome, and the fact that granulamatous cheilitis is regarded as a monosymptomatic or incomplete variant of Melkersson-Rosenthal syndrome, make the calculation of incidence of these entities very difficult, although it has been reported at about 0.08% of the general population.
Melkersson-Rosenthal syndrome affects all age groups and usually presents in the second or third decade of life. The median age at onset has been estimated to be in the range of 25 to 40 years.
Most studies have shown that the disorder affects both sexes equally, but a female:male ratio of 2:1 and even male predominance have also been reported.
There is no racial or ethnic predilection observed in any of the studies reviewed.
What is the Cause of the Disease?
The etiology of granulomatous cheilitis and Melkersson-Rosenthal syndrome remains controversial. There are several reports suggesting a genetic predisposition for Melkersson-Rosenthal syndrome (i.e. autosomal dominant inheritance with variable expression with the defect located at 9p11 chromosome) that might also be applicable to granulomatous cheilitis. Atopy and allergies to additives such as monosodium glutamate, cinnamaldehyde, carvone, pepritone, coca, carmosine, sun yellow dye, and cobalt have been implicated as an etiologic mechanism in granulomatous cheilitis.
The association among Melkersson-Rosenthal syndrome, Crohn’s disease, and sarcoidosis is tenuous, as there is no proven common pathophysiologic mechanism or etiology. It is worth mentioning that granulomatous cheilitis has been reported to represent extra-intestinal Crohn’s disease, with oral manifestations of this disease either coinciding with the onset of gastrointestinal symptoms or found after the diagnosis of Crohn’s disease has already been established. Granulomatous cheilitis is found in only 0.5% of patients with Crohn’s disease.
Orofacial herpes may precede the first episode of Merkelsson-Rosenthal syndrome, thus supporting the hypothesis that the herpes simplex virus may be involved in the etiology. Other infectious conditions, such as periodontitis, hyperplastic inflammatory tonsils, and infected adenoids, support a bacterial origin of the syndrome. A review of literature provides no evidence of a relationship between Melkersson-Rosenthal syndrome and infective agents such as B burgorferi, Toxoplasma gondii, Treponema pallidum or mycobacteria.
Abnormal T cell receptor V gene usage by lesional T lymphocytes and clonal T cell expansion within the granuloma seem to have a role in the pathogenesis of Melkersson-Rosenthal syndrome. Other immunologic or autoimmune disturbances may also be considered as potential etiologic factors of the syndrome.
Systemic Implications and Complications
Multiorgan involvement is possible in patients with Melkersson-Rosenthal syndrome, and dermatologists should be aware of that possibility. Multiple palsies of the olfactory, auditory, glossopharyngeal, and hypoglossal cranial nerves have be described in patients with Melkersson-Rosenthal syndrome. Central nervous system involvement has been reported in the literature, but the resulting symptoms are usually variable and nonspecific (e.g. headaches, weakness, paresthesias) mimicking conditions such as multiple sclerosis. Autonomic disturbances may also occur.
Treatment options are summarized in
Treatment of granulomatous cheilitis/Melkersson-Rosenthal syndrome.
|emollients/cool packs/cooling ointment||corticosteroids/minocycline+systemic corticosteroids/dapsone+triamcinolone injections||reduction cheiloplasty+ post-reduction intralesional corticosteroids||avoidance of foods that contain flavoring agents or preservatives|
|triamcinolone in orabase or clobetasol in orabase||clofazimine||decompression of facial nerve||treatment of odontogenic foci|
|intralesional triamcinolone injections||immunosuppressants: cyclosporine, azathioprine||radiotherapy|
|antibiotics: metronidazole, penicillin, erythromycin, tetracyclines|
Optimal Therapeutic Approach for this Disease
The treatment of granulomatous cheilitis and Melkersson-Rosenthal syndrome remains a challenge and should be based on the severity of the clinical manifestations. Because the etiology is unknown and the nature of the disease includes frequent recurrence and spontaneous resolution, it is very difficult to assess the efficacy of the therapeutic measures. Most therapeutic regimens include corticosteroid therapy—topical, intralesional, or systemic—as an empirical approach to this inflammatory disease, although the response is usually temporary.
Possible trigger factors, including allergic agents, should be identified and eliminated. Approximately 12%-60% of the patients with orofacial granulomatosis are atopic. Avoidance of foods that contain flavoring agents or preservatives has been shown to help in reducing oral swelling. Odontogenic infectious foci should addressed by the oral specialist, as they could represent an identifiable cause of granulomatous cheilitis. Initial treatment with antihistamines may temporarily help some patients.
Acute labial swelling should be treated symptomatically with protective emollients, cool-packs, or cooling ointment. Most patients with granulomatous chelitis have benefited from the long-term use of topical triamcinolone in orabase, or clobetasol in orabase.
Intralesional therapy with triamcinolone acetonide 0.1% into each side of the affected lip is preferred in more severe cases, but the need for multiple injections for many years carries the risk of skin atrophy and hypopigmentation. However, intralesional corticosteroids remain a first-line treatment for granulomatous cheilitis.
The use of mental nerve anesthesia before triamcinolone injections allows the administration of higher volumes and increases patient’s compliance. The injections may initially have to be administered every 2 weeks, and thereafter at monthly intervals once a response plateau has been reached.
Although the use of systemic corticosteroids (methylprednisolone, 1-1.5mg/kg/day, tapering over 3-6 weeks) is recommended by some authors for persistent lip swelling, the side effects related to their long-term use are significant and thus they should not be the first line of treatment.
Noncorticosteroid regimens are alternatives for corticosteroid therapy. Clofazimine, an antileprosy agent with anti-inflammatory and specifically antigranulomatous properties, in a dose of 100mg, twice daily for 10 days, then 100mg, twice to four times per week for 2-12 months, has been reported to be very effective, even in severe granulomatous cheilitis, and results in a complete or partial response in the majority of patients.
Antibiotics such as penicillin (12,000,000 units, intravenously, per day for 14 days), azithromycin (250mg/day for 10 weeks), roxithromycin (150mg/day for 5 months), and metronidazole (500mg twice a day for 6 months) have a role in the treatment of granulomatous cheilitis, as shown by research studies. Tetracyclines, represented by minocycline (100mg twice daily for 7-9 months), used in combination with corticosteroids (oral prednisone 30mg/day, tapering dose for 2-4 months), have also been proven efficacious.
Dapsone treatment has also shown excellent results, and a study confirmed that therapy with dapsone, 100mg/day for 2 weeks, and then 50mg/day for 25 weeks, combined with triamcinolone injections (10mg every other week for four courses, and then 10mg once a month for three courses) can be a useful and safe method of therapy in granulomatous cheilitis/Melkersson-Rosenthal syndrome, given the satisfying functional and esthetic result in the patient studied (almost complete resolution of swelling of the lips after only 4 weeks of combined therapy).
Other nonsteroidal treatments used in treatment of granulomatous cheilitis/Melkersson-Rosenthal syndrome include hydroxychloroquine, methotrexate, azathioprine, cyclosporine, danazol, and sulfasalazine, when Crohn’s disease is an underlying pathology. Thalidomide and infliximab, an antitumor necrotic factor, are anecdotal alternatives, referred to in the literature recently.
Surgical management with reduction cheiloplasty, which is usually combined with intralesional corticosteroids, is reserved only for persistent swelling, but surgery should be deferred until the patient has been free of disease activity, to avoid stimulation of the granulomatous inflammatory process. Surgical intervention with decompression of the facial nerve is usually needed for persistent facial palsy in patients with Melkersson-Rosenthal syndrome. Radiotherapy has also been used for refractory cases.
Management in Childhood
Management of granulomatous cheilitis of Melkersson-Rosenthal syndrome in childhood is generally based on topical steroids and triamcinolone injections alone or combined with minocycline. Clofazimine has been used in children for the treatment of leprosy and sarcoidosis, but there is limited data for its use in the treatment of granulomatous cheilitis in childhood or adolescence.
The usefulness of pharmacological agents available for adults, such as thalidomide, hydroxychloroquine, and sulfasalazine, is limited in childhood due to their severe adverse effects. Cheiloplasty with postsurgical corticosteroid injections may be considered if medical treatment fails.
Unfortunately, the therapeutic management of granulomatous cheilitis/Melkersson-Rosenthal syndrome is difficult, so treatment remains largely symptomatic and carries a high rate of recurrences. Because of the lack of studies to evaluate the different treatment modalities, management is mainly empirical, and directed by the severity of symptoms.
Maintenance therapy of orofacial swelling is mainly based on local corticosteroid injections , but their long-term use is associated with side effects that the patient should be informed about. Patients should also be informed about the relapsing pattern of the above-mentioned conditions, and the fact that although there are cases of full remission, these are few and not well understood.
There are no reports in the literature of malignant changes associated with granulomatous cheilitis/Melkersson-Rosenthal syndrome. Patients need to be followed on a regular basis, and should orofacial swelling or facial palsy persist, therapy must be changed accordingly by using another drug category, a different combination of medications, or a referral for surgical intervention.
Unusual Clinical Scenarios to Consider in Patient Management
Melkersson-Rosenthal syndrome can present with variable symptoms, and considering the fact that only a small percentage of patients present with the classic triad, diagnosis can be extremely difficult.
A case report in 2011 described a 25-year-old patient with known granulomatous cheilitis, who presented with intermittent diaphragmatic paralysis of unknown etiology. The diaphragmatic paralysis may have been an unusual extracranial neuropathy related to Melkersson-Rosenthal syndrome. The patient underwent diaphragmatic plication through a mini-thoracotomy to reduce hepatic intrathoracic encroachment.
Another study reported a case of Melkersson-Rosenthal syndrome in a patient with Down syndrome, although no evidence of this association was ever described in the literature.
A rare manifestation of Melkersson-Rosenthal syndrome has been reported in a 64-year-old man with fissured tongue, who also complained of persistent chronic right upper eyelid edema for 15 years prior to diagnosis. Biopsy revealed non-necrotizing granulomatous inflammation adjacent to blood and lymphatic vessels.
A suggestion has been recently made that granulomatous cheilitis could present as a rare paraneoplastic manifestation of chronic monomyelocytic leukemia, but a fortuitous association could not be excluded.
An unusual clinical presentation of Melkersson-Rosenthal was described in a 48-year-old nonobese male with marked macroglossia and obstructive sleep apnea that could not be attributed to any other established causes. As the swelling of the tongue had been unresponsive to immunosuppressive pharmacotherapy, the patient was finally treated by continuous positive airway pressure therapy.
Finally, very rarely, Melkersson-Rosenthal syndrome can present with bilateral facial nerve palsy that is usually responsive to systemic steroids and physiotherapy.
What is the Evidence?
van der Waal, RI, Schulten, EA, van der Meij, EH, van de Scheur, MR, Starink, TM, van der Waal, I. "Cheilitis granulomatosa: overview of 13 patients with long-term follow up—results of management". Int J Dermatol. vol. 41. 2002. pp. 225-9.(A retrospective case study of the clinical features, histopathology, association with Crohn’s disease, and results of nonsurgical and surgical therapy in thirteen patients with granulomatous cheilitis (mean follow-up period of 8.2 years). The study showed a low chance for patients with granulomatous cheilitis to develop Crohn’s disease, and the authors suggested that there is no need to expose patients to routine investigations of the gastrointestinal tract if there is no history of gastrointestinal complaints. Intralesional corticosteroid injections represented the main treatment modality in this study, with satisfactory results in most cases.)
Zeng, W, Geng, S, Niu, X, Yuan, J. "Complete Melkersson-Rosenthal syndrome with multiple cranial nerve palsies". Clin Exp Dermatol. vol. 35. 2010. pp. 272-4.(The article reports a 27-year-old man with a 3-year history of relapsing, progressive orofacial edema spreading to the chin and forehead, and a 1-year history of facial palsy to the point that he was unable to open his mouth or close his eye. Histopathology confirmed the diagnosis of Melkersson-Rosenthal syndrome and patient was started on prednisone, dapsone, and vitamin B1 for 1 month, with no improvement. The repeated low white blood cell count and multiple cranial nerve palsies implied multiorgan involvement.)
Sobjanek, M, Wlodarkiewicz, A, Zelazny, I, Nowicki, R, Michajlowski, I, Sokolowska-Wojdylo, M. "Successful treatment of Melkersson-Rosenthal syndrome with dapsone and triamcinolone injections". J Eur Acad Dermatol Venereol. vol. 22. 2008. pp. 1028-9.(In this letter to the editor, Sobjanek et al., based on their experience with a 40-year-old man with Melkersson-Rosenthal syndrome that was treated successfully with dapsone and triamcinolone injections, report that this combination can be useful and safe. The antibacterial and anti-inflammatory properties of dapsone are not fully understood, but the authors support its use, as it seems to heighten the mode of action of corticosteroids.)
Ziem, PE, Pfommer, C, Goerdt, S, Orfanos, CE, Blume-Peytavi, U. "Melkersson-Rosenthal syndrome in childhood: a challenge in differential diagnosis and treatment". Br J Dermatol. vol. 143. 2000. pp. 860-3.(Although Melkersson-Rosenthal syndrome is very rare in childhood, this article describes a 9-year-old female with episodic swelling of the upper lip and complete peripheral facial palsy, associated with herpes and recurrent bacterial infections. The patient was treated with prednisolone for 2 months, with good results, although she had a mild relapse that responded to another course of systemic steroids.The authors also include data from various studies for the treatment of Melkersson-Rosenthal syndrome in children and suggest that corticosteroids alone or in combination with minocycline are usually effective. The use of other medications that are prescribed in adults, such as methotrexate, hydroxychloroquine, danazol, and thalidomide, is limited in children due to the drugs’ adverse effects.)
Sciubba, JJ, Said-Al-Naief, N. "Orofacial granulomatosis: presentation, pathology and management of 13 cases". J Oral Pathol Med. vol. 32. 2003. pp. 576-85.(Sciubba et al., in the above article, grouped together Melkersson-Rosenthal syndrome, Crohn’s disease, granulomatous cheilitis, and sarcoidosis under the term orofacial granulomatosis because of their similar clinical and histopathologic features. Based on the thorough examination and detailed history from thirteen patients with diagnosed orofacial granulomatosis, the authors concluded that oral manifestations of Crohn’s disease may be classified as an oligosymptomatic form of Melkersson-Rosenthal syndrome. The article also summarizes possible causes of granulomatous cheilitis and treatment options.)
van der Waal, RI, Schulten, EA, van de Scheur, MR, Wauters, IM, Starink, TM, van der Waal, I. "Cheilitis granulomatosa". J Eur Acad Dermatol Venereol. vol. 15. 2001. pp. 519-23.(This article, from the Netherlands, is an overview of the clinical features, histopathology, differential diagnosis, management strategies, and prognosis of granulomatous cheilitis. After a thorough literature review, the authors emphasize the treatment of the disease, providing details about dosages, duration of use of specific medications, and results .)
Ang, KL, Jones, NS. "Melkersson-Rosenthal syndrome". J Laryngol Otol. vol. 116. 2002. pp. 386-8.(This paper describes a 21-year-old female with the monosymptomatic form of Melkersson-Rosenthal syndrome (recurrent swelling of her lips), which was treated with intralesional steroid injections that produced only short-term improvement. The authors also discuss other diagnoses that can mimic Melkersson-Rosenthal syndrome, and conclude with the observation that there are no reports in the literature that associate orofacial granulomatosis with malignancy.)
Rogers, RS. "Melkersson-Rosenthal syndrome and orofacial granulomatosis". Dermatol Clin. vol. 14. 1996. pp. 371-9.(This is a review article that describes the causes, clinical features, histopathology, management, and prognosis of Melkersson-Rosenthal syndrome and orofacial granulomatosis.)
Kanerva, M, Moilanen, K, Virolainen, S, Vaheri, A, Pitkäranta, A. "Melkersson-Rosenthal syndrome". Otolaryngol Head Neck Surg. vol. 138. 2008. pp. 246-51.(This research study, from Finland, focused on the characteristics of Melkersson-Rosenthal syndrome patients with facial palsy and the differences in patients treated at the Departments of Otorhinolaryngology and Dermatology. The presence of the mutation UNC-93B1, responsible for susceptibility to herpes simplex virus-1, was also studied in thirteen patients, as herpes simplex virus has been suggested as an etiologic factor of Melkersson-Rosenthal syndrome and facial palsy, and none of the patients had the mutation.At the Department of Otorhinolaryngology, all of the eighteen patients had facial palsy and nine had the complete triad, whereas at the Department of Dermatology, of the seventeen patients, two had the complete triad and and the rest presented with monosymptomatic granulomatous cheilitis. A table of additional clinical characteristics of Melkersson-Rosenthal syndrome in patients with facial palsy is included in the study.)
Rogers, RS. "Granulomatous cheilitis, Melkersson-Rosenthal syndrome, and orofacial granulomatosis". Arch Dermatol. vol. 136. 2000. pp. 1557-8.(In this editorial, the author focuses on the causes of Melkersson-Rosenthal syndrome and orofacial granulomatosis by reviewing the literature. He reports that there is no evidence of a relationship between Melkersson-Rosenthal syndrome and infective agents such as B burgorferi, Toxoplasma gondii, Treponema pallidum, mycobacteria or herpes simplex virus.)
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