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Clinical characteristics and treatment of Melkersson-Rosenthal syndrome--overview of six patients/ Klinicka prezentacija i tretman kod melkerson-rozentalovog sindroma--pregled sest pacijenata.


In 1928, Melkersson first described the clinical syndrome as an edema of the orofacial region with the facial nerve palsy [1], and in 1931, Rosenthal added fissured tongue as a part of the clinical picture of this syndrome [2]. This was the way of Melkersson/Rosenthal syndrome (MRS) development, which is characterized by a triad of symptoms: lip and face swelling, fissured tongue and peripheral type paresis and/or paralysis of the facial nerve. When it is presented in classical form, it is not difficult to be diagnosed, but oligo- and monosymptomatic forms represent a problem in making the differential diagnosis. Given that lip edema is predominant in the clinical picture, these patients are referred to an allergologist because of a suspected allergic reaction.

Case Report

The patients, who had presented with the referral diagnosis of recurring or persistent lip edema, wens examined at the Department of Allergology and Immunology of the Clinical Center of Serbia, during the period 1994-2012 and were finally diagnosed with MRS.

There were four females and two males, whose mean age was 50.5 years and the average length of symptoms was 6.4 years. Table 1 shows the age, symptom duration and clinical picture of each case.

The patients could not associate occurrence of their lip edemas with some of the incriminating factors such as food and medicaments. In addition, all patients denied having difficulties associated with any organic systems, in the first place the respiratory system or gastrointestinal tract. Three patients reported migraine-type headache and facial nerve paresis.

The complete triad including lip edema, fissured tongue and facial nerve paresis was manifested in three patients, oligosymptomatic form with lip edema and fissured tongue was diagnosed in two patients and one patient had only lip edema (monosymptomatic form). Lip edema, presented in all patients, was clinically manifested differently. It affected either the upper or the lower lip or both lips (Figure 1). A patient with characteristically fissured tongue (lingua plicata s. geographica) is presented in Figure 2.

All patients underwent the following analysis:

Laboratory analyses (erythrocyte sedimentation rate, complete blood count with leucocyte formula, biochemistry analyses, serum protein electrophoresis (SPEP) with immunofixation (IFX), serum angiotensin-converting enzyme (ACE));

Immunoloserological analysis (serum immunoglobulins, chamber count of eosinophils, antinuclear antibodies, complement components--Clq, C3, C4 and C1s inhibitor--qualitative and quantitative analyses, antineutrophil cytoplasmic antibodies, cryoglobulins);

Skin prick tests with standard inhalation and nutrition allergens, X-ray of the lungs, purified protein derivative (PPD) test, throat, nasal and sputum swabs for bacterial and fungal culture isolation;

Neurological and dental examination;

Examination by a maxillofacial surgeon with the biopsy of oral mucosa.

Inflammatory syndrome was absent in all patients, blood count and biohumoral findings including SPEP and IFX and ACE were within limits. The results of immunoserological analyses were regular in all patients. However, lowered C1 inhibitor function and normal quantitative C1 inhibitor, C4, C1q and C3 complement components values were recorded in one patient. Skin prick tests including the inhalation and nutritional allergens, lung X-ray and PPD test findings, the results of throat, nasal and sputum swabs were all negative. Neurological examinations revealed that one patient had left facial nerve paresis, one patient had convergent strabismus and discrete left pyramidal deficit, while other patients wens deficit-free. Odontogenic focus was detected in one patient and antibiotic therapy was prescribed. All patients underwent oral mucosa biopsy and histopathological findings confirmed granulomatous cheilitis (Figure 3).

Treatment included H1 and H2 antihistamines, corticosteroids (topical application in one patient), anabolics and antibiotics in a patient with verified odontogenic focus. No effect to applied oral corticosteroids and H1 and H2 antihistamines was recorded in 4 patients, while one patient had a partial and another a transient favorable response to this therapy. A partial improvement upon danazol treatment was observed in 3 patients, while a transitory favorable effect and long-lasting good effect were recorded in 1 patient each. A significant improvement was noted in one patient upon intralesional application of corticosteroids (triamcinolone). In one patient, antibiotic therapy for odontogenic focus resulted in resolution of the focus, but without any effect to the lip edema. The drug combination and treatment effects in our patients are illustrated in Table 2.


When the complete triad of symptoms is present, it is not difficult to make the diagnosis of MRS. However, the classical triad is evident in only 8%-25% of patients [3]. The oligosymptomatic form is more common (lip edema, fissured tongue), and the most frequent is the monosymptomatic form (lip edema), which makes this syndrome harder to recognize [4]. It is questionable if the monosymtopmatic form of MRS (granulomatous cheilitis), which was found in one patient, is a part of MRS, or it is a part of heterogenous spectrum of orofacial granulomatosis diseases. Some authors believe that MRS is a part of the orofacial granulomatosis spectrum, along with sarcoidosis, tuberculosis and Chron's disease [5, 6].

Etiopathogenesis of MRS is still unknown. It has been assumed that it is the manifestation of microneurovascular lesion [7]. The association with infections (spirochetes, mycobacteria, herpes simplex virus, odontogenic foci) has been described, while the genetic predisposition has not been confirmed [8-10].

Differential diagnosis frequently implies allergic conditions such as angioneurotic type and hereditary angioedema.

Neurological manifestations, other than facial nerve paralysis/paresis, appearing in about 20% of MRS cases, may present as trigeminal neuralgia or migraine-type headache [7, 11, 12]. Three of our patients had the history of migraine headaches.

No evidence of atopic constitution was found in our patients, such as sensibilization to some of inhalation and nutrition allergens. Moreover, history data on the duration of lip edema and a poor or no response to antihistamines and corticosteroid treatment failed to indicate angioneurotic edema caused by the known provoking factors (medicaments, preservations, additives).

Within the immunological evaluation, one female patient with oligosymptomatic MRS had a decreased function of C1s inhibitor (21.4%, normal value > 40%). Although hereditary angioedema was ruled out, it could have contributed to the clinical presentation of lip edema. Such associations have rarely been described in literature [13].

None of our patients had anamnestic, clinical and laboratory parameters of systemic connective tissue diseases or primary vasculitides. In addition, there were no anamnestic, clinical or laboratory indicators of systemic granulomatosis.

Melkersson-Rosenthal syndrome diagnosis is typically verified by histopathological analysis of oral mucosa specimen. During the early stages of the disease, it shows connective tissue edema and perivascular lymphocytic infiltration, while in cases of long disease duration, lymphocytic infiltration becomes denser and focal non-necrotizing granulomas, consisting of lymphocytes, epithelioid and giant cells, are formed. Histopathologically, these granulomas are indistinguishable from those found in sarcoidosis or Crohn's disease [3, 4, 14]. At the time of biopsy, two of our patients (No. 1 & 4) had a few granulomas, suggesting the early phase of disease, while other patients had findings corresponding to the chronic phase of granulomatous cheilitis.

Treatment of MRS is complex and various treatment modes have been described in literature: corticosteroids (systemic, intralesional), anabolics, antibiotics (metronidazole, tetracyclines, macrolides), clofazimine, dapsone, sulphasalazine, azathioprine, hydroxychloroquine, methotrexate, infliximab, as well as surgical intervention (cheiloplasty), but very rarely [4, 15-17].

According to our experience, treatment should be initiated with combined oral corticosteroids and H1 and H2 antihistamines, and in case of poor response to therapy, oral anabolics should be introduced. In addition, management of odontogenic foci as well as antibiotic treatment of orofacial region infection is mandatory. Intralesional corticosteroid application applied in one patient proved to yield good results.


In differential diagnosis, Melkersson-Rosenthal syndrome diagnosis primarily refers to conditions of angioneurotic and hereditary angioedema. Besides the complete trias, oligo- and monosymptomatic forms are commonly seen. Therefore, diagnosis should be verified by histopathological analysis of oral mucosa biopsy specimen. Evaluation and treatment of Melkersson-Rosenthal syndrome require multidisciplinary approach by an allergologist-immunologist, neurologist, dentist, maxillofacial surgeon and histopathologist. Regular follow-up of these patients is necessary, both for a possible development of complete trias in mono- and oligosymptomatic forms, and for the development of systemic granulomatous disease.


MRS--Melkersson-Rosenthal syndrome

SPEC--serum protein electrophoresis


PPD--purified protein derivative

ACE--angiotensin-converting enzyme


[1.] Melkersson E. Case of recurrent facial paralysis with angioneurotic edema. Hygiea. 1928;90:737-41.

[2.] Rosenthal C. Klinisch-erbbbiologischer Beitrag zur Konstitutions-Pathologie: gemein-sames Auftreten von (rezidivieender familiarer) Facialislahmung, angioneurotischem Geesichtsodem und Lingua plicata in Arthrismus-Familien. Z Neurol Psychiatrie. 1931;131:475-501.

[3.] Greene RM, Rogers RS 3rd. Melkersson-Rosenthal syndrome: a review of 36 patients. J Am Acad Dermatol. 1989;21:1263-70.

[4.] Elias MK, Mateen FJ, Weiter CR. The Melkersson-Rosenthal syndrome: a retrospective study of biopsied cases. J Neurol. 2013;260:138-43.

[5.] Van Maarsseveen AC, Van der Waal I, Stam J, Veldhuizen RW, Van der Kwast WA. Oral involvement in sarcoidosis. Int J Oral Surg. 1982;11:21-9.

[6.] Dupuy A, Cosnes J, Revuz J, et al. Oral Crohn disease, clinical characteristics and long-therm follow-up of 9 cases. Arch Dermatol. 1999;135:439-42.

[7.] Desai SD, Dumraliya P, Mehta D. Melkersson-Rosenthal syndrome. J Neurosci Rural Pract.2014;5(1):S112-S114.

[8.] Hornstein OP. Melkersson-Rosenthal syndrome: a neuromuco-cutaneous disease of complex origin.Curr Probl Dermatol. 1973;5:117-56.

[9.] Liu H, Zheng L, Liu H. Spirochetes--the posible etological factor of the cheilitis granulomatosa. Chin Med Sci J. 2001;16:52-5.

[10.] Todokoro T, Ozawa K, Muso Y, et al. Melkersson-Rosenthal syndrome caused by saprodontia: a case report. J Dermatol. 2003;30:679-82.

[11.] Li D, Rozen TD. The clinical characteristics of new daily persistent headache. Neurology. 2001;56(Suppl. 3):A452-3.

[12.] Liu R, Yu S. Melkersson-Rosenthal Syndrome: a review of seven patients. J Clin Neurosci. 2013;20(7):993-5.

[13.] Masson F, Barete S, Fremeaux-Bacchi V, et al. Melkersson-Rosenthal Syndrome and acquired C1 inhibitro deficiency. Dermatology. 2008;217:114-20.

[14.] Raskovic S, Bogic M, Lazic D. Melkerson-Rozentalov sindrom. Srp Arh Celok Lek. 1994;122(7-8):239-41.

[15.] 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. 2002;41(4):225-9.

[16.] Camacho F, Garda-Bravo B, Carrizosa A. Treatment of Miescher's cheilitis granulomatosa in Melkersson-Rosenthal syndrome. J Eur Acad Dermatol Venereol. 2001;15(6):546-9.

[17.] Arias-Santiago S, Orgaz-Molina J, Naranjo-Sintes R. Persistent swollen lip: cheillitis granulomatosa. Lancet. 2013;381:2280.

Rad je primljen 21. I 2015.

Recenziran 14. VI 2015.

Prihvacen za stampu 15. VI 2015.

DOI: 10.2298/MPNS1512401R


University of Belgrade, Faculty of Medicine (1)

Clinical Center of Serbia, Belgrade

Department of Alergology and Immunology (2)

Corresponding Author: Dr Zikica M. Jovicic, Univerzitet u Beogradu, Medicinski fakultet, 11000 Beograd, Dr Subotica 8, E-mail:

Table 1. Main characteristics of each case

Tabela 1. Karakteristike pacijenata

Case                  Age          Sex   Duration of disease (years)
Pacijent        Starost (godine)   Pol    Trajanje bolesti (godine)

1                      32           F                 2
2                      55           M                21
3                      52           F                 3
4                      62           M                 4
5                      52           F                 7
6                      50           F                 2

Case            Clinical findings
Pacijent          Forma bolesti

1                   LE/OU, LP
2                 LE/OU, LP, PF
3                     LE/OU
4                   LE/OU, LP
5                 LE/OU, LP, PF
6                 LE/OU, LP, PF

Legend: M--male; F--female; LE--lip edema; LP--lingua plicata;
PF--paresis facialis

Legenda: M- muski; z--zenski; OU--otok usana; LP--lingua plicata;
PF--pareza facijalisa

Table 2. Effects of various treatment combinations

Tabela 2. Tretman i efekat terapije kod nasih pacijenata

Treatment        No effect    Partly effective   Temporary effect
Terapija        Bez efekta    Delimi?an efekat   Povremen efekat

CS/GK; H1; H2   2, 4, 5, 6           3                  1
DA                                4, 5, 6               2

Treatment        Long term good effect
Terapija        Dugotrajni dobar efekat

CS/GK; H1; H2
DA                         1
iCS/iGK                    2

Legend: CS--corticosteroids; iCS--intralesional corticosteroids,
H1--H1 antihistamines, H2--H2 antihistamines, DA--Danasol

Legenda: GK--glikokortikosteroidi; IGK--intralezionalni
glikokortikosteroidi, H1--H1 antihistaminici, H2--H2 antagonisti,
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Author:Raskovic, Sanvila; Bolpacic, Jasna; Popadic, Aleksandra Peric; Jovicic, Zikica; Miskovic, Rada; Bogi
Publication:Medicinski Pregled
Article Type:Case study
Date:Nov 1, 2015
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