Original Article

Journal of Cutaneous Medicine and Surgery

Clinical Profile of Melkersson-­Rosenthal 2021, Vol. 25(4) 390–396

© The Author(s) 2021
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Syndrome/Orofacial Granulomatosis: A ​sagepub.​com/​journals-­​permissions
​DOI: ​10.​1177/​1203​4754​21995132
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Camila FB Gavioli1, Giovanna P Florezi2, Silvia V Lourenço2,

and Marcello MS Nico1

Abstract
Background:  Melkersson–Rosenthal syndrome (MRS) is a rare disease characterized by the triad of granulomatous cheili-
tis, fissured tongue, and facial paralysis. Publications concerning large series are rare in the literature.
Objectives:  To describe the clinical and histopathological characteristics of patients with complete and oligosymptomatic
forms of MRS.
Methods:  A retrospective records review was performed for the diagnoses of Melkersson-­Rosenthal syndrome, granulo-
matous cheilitis, and orofacial granulomatosis at oral Diseases Clinic of the Department of Dermatology, University of São
Paulo, Brazil (2003, 2017).
Results:  A total of 51 patients were included, mean age at presentation 35.69 years. Four patients were younger than 18
years. The complete triad of was observed in 10 patients. The rare findings of granulomatous blepharitis, gingivitis and palati-
tis are presented. Comorbidities included Crohn’s disease (5 patients), migraine headaches (1 patient) and convulsions (2
patients). Granulomatous inflammatory infiltrate was detected in 31 biopsies. Medical therapies included included oral and
intralesional steroids, thalidomide, dapsone, azathioprine, tetracycline, methotrexate, and surgery, with variable responses.
Conclusions:  Our report meant to draw attention to the clinical spectrum of this rare disorder, mainly to oligosymptom-
atic forms and rarer presentations.

Keywords
Melkersson-­
Rosenthal syndrome, fissured tongue, geographic tongue, facial paralysis, granulomatous cheilitis, orofacial
granulomatosis

Introduction
Melkersson-­Rosenthal syndrome (MRS) is a rare neuromu-
cocutaneous disease characterized by the classic triad of
recurrent orofacial edema, relapsing facial paralysis and fis-
sured tongue (lingua plicata).1-4 The complete triad appears
in only 8% to 45% of patients. The most common feature
consists of persistent orofacial swelling, mainly affecting the
lips (granulomatous cheilitis, Miescher’s cheilitis); many
patients present exclusive lip involvement.3,5 The alternative
term orofacial granulomatosis (OFG) has been used as a syn-
onym in some publications.2,6 Some authors include under
the term OFG other granulomatous processes such as
sarcoidosis.2,6
The cause of MRS remains unknown. Local allergies
have been suspected, mainly in the dental literature, nonethe-
less a systemic process with non-­ local causes has been
increasingly considered.1,3,5 Recently, our group demon-
strated statistically significant increase in the expression of
HLA A*02, HLA DRB1*11, and HLA DQB1*03 as well as
low levels of HLA A*01, HLA DRB1*04, HLA DRB1*, and
HLADQB1* in MRS patients compared with controls, indi-
cating both predisposing and protective genes for the dis-
ease.7 A possible association between MRS and Crohn’s
disease is suspected by some authors.2
Although novel information on the disease is gradually
disclosed, the clinical-­pathological aspects of patients are yet
a major toll for MRS diagnosis suspicion. In the present
1
Department of Dermatology, Medical School, Av. Dr. Eneas de Carvalho
Aguiar 255, Brazil1
2
Department of Pathology, Dental School, University of São Paulo- Brazil,
Brazil
Corresponding Author:
Marcello MS Nico, Department of Dermatology, Medical School, Av.
Dr. Eneas de Carvalho Aguiar 255, 3oA, São Paulo-­SP, CEP- 05403-000,
Brazil.
Email: ​mentanico@​hotmail.​com
Gavioli et al
study, we present the clinical and histopathological charac-
teristics of 51 patients with MRS.
Patients and Methods
A retrospective review of our database was performed and
selected patients diagnosed with Melkersson-­Rosenthal syn-
drome (MRS), granulomatous cheilitis (GC), and orofacial
granulomatosis (OFG) at the Oral Diseases Clinic of the
Dermatology Department, Medical School, University of
São Paulo, from January 1, 2003 to December 31, 2017.
Patients with documented systemic disease such as sarcoid-
osis, infectious diseases and lymphedema were not incorpo-
rated in the present cohort.
The medical records of all patients were re-­evaluated and
clinical features such as gender, age of disease onset, and
disease diagnosis, comorbidities, differential diagnostic pro-
cedures, colonoscopical examination, treatments, and family
history were assessed. Review of histopathological speci-
mens was performed by two observers. This study was
approved by the Local Ethics Committee under the protocol
#1.310.600.
Results
A total of 51 patients were included in the analysis (26
female—51%, 25 male—49%). Mean age at the onset was
32.35 years (range 5-57). Mean age at clinical presentation
was 35.69 years (range 8-59). Four patients (three male and
one female) were less than 18 years old at diagnosis (10, 12,
12, 17 years old, consecutively). Mean time from the onset to
a correct diagnosis of MRS was 3.34 years (range 6
months-25 years). The findings are summarized in
Supplemental Table S1.
Figure 1.  Upper lip enlargement and tongue changes. (a) geographic and fissured tongue (patient 16); (b) geographic and fissured
tongue in a pediatric patient (patient 5); (c) geographic tongue only (patient 32).
391
Orofacial edema was present in all cases and the upper lip
was the most frequent location (40/51, 78.4%) ; followed by
lower lip (24/51, 47%), gingivae (21/51, 41.1%), cheeks
(13/51, 25.4%), palate (6/51, 11.7%), eyelids (2/51, 3.9%),
forehead (1/51, 2%), nasolabial fold (1/51, 2%), buccal
mucosa (1/51, 2%), and nose (1/51, 2%) . Several cases pre-
sented more than one affected site, as follows: lips and cheeks
(11/51, 21.56%), chin and lips (4/51, 7.8%), gingiva and lips
(19/51, 37.25%), palate and lips (3/51, 5.8%), face and buc-
cal mucosa (1/51, 2%). Exclusive lip involvement occurred
in 20 patients (39.2%) (Figures 1–3).
We could not find a precise triggering factor for edema-
tous flares in any patient, except in one (case 45, in whom
pregnancy precipitated a severe and intractable crisis).
Fissured tongue was noticed in 26 patients (50.98%); geo-
graphic tongue was present in 40 individuals (Figure 1).
Seven patients presented facial palsy during follow up
(13,6%), and 7 referred to previous episodes of palsy, which
were not verified at clinical inspection. Of these 14 patients,
8 had experienced a single episode of paralysis, and 6 patients
referred recurrent episodes. The complete triad was con-
firmed in only five patients during follow up. Other neuro-
logical symptoms included migraine (one patient) and
non-­epileptic convulsions (two). We did not perform accu-
rate neurological workup in seemingly asymptomatic
patients in order to search for more subtle cranial nerve
alterations.
Twenty-­one patients were investigated with colonoscopy
and bowel biopsy; of these, granulomatous inflammation
was detected and the diagnosis of Crohn’s disease was estab-
lished in 5 patients during follow-­up (1 symptomatic and 4
asymptomatic). Chest X-­rays images were unremarkable in
all patients.
392 Journal of Cutaneous Medicine and Surgery 25(4)

Figure 2.  Extra labial manifestations (a) asymmetric swelling—cheeks, nasolabial fold (patient 17); (b) granulomatous blefaritis,
confirmed by histopathology (patient 19).

Of the 51 patients, 4 refused to be biopsied. We obtained granulomas and epithelioid well-­ formed granulomas.
48 histopathological specimens (27 from upper lip, 11 Diffuse lymphoplasmacytic inflammatory infiltrate, edema,
from lower lip, 6 from gingiva, and 3 from palate, 1 from fibrosis, vasodilation, and congestion were also detected.
the eyelid). The most common findings were ill-­defined In long lasting cases fibrosis predominated. The presence

Figure 3.  Intraoral findings. (a) buccal mucosal edema, as evidenced by tooth marks (mucosal indentations). Histopathology revealed
granulomas (patient 17); (b) similar plaque on the hard palate that showed well-­formed granulomas on histopathology (patient 20). These
patients also had granulomatous cheilitis.
Gavioli et al
Figure 4.  (a) Patient 37 before treatment—upper and lower macrocheilia; (b) aspect after treatment with thalidomide 200 mg/day;
only slight enlargement of the medial portion of the upper lip remains; (c) aspect after cheiloplasty- excellent result; (d) Patient 12—
granulomatous gingivitis; (e) aspect after surgical treatment (patient 12). This patient also had granulomatous cheilitis. Other dental
disorders have been ruled out in this patient.
of microorganisms was discarded by special stains in all
cases.
Treatments performed included intralesional triamcino-
lone infiltration (23/51, 45.1%), oral thalidomide (23/51,
45.1%), oral dapsone (21/51, 41.2%), oral prednisone (11/51,
21.6%), systemic immunosuppressants, such as azathioprine
and methotrexate (8/51, 15.68%) and clofazimine (2/51,
3.9%). Many patients required a combination of treatments
(24/51, 47%). Regarding the responses to the proposed treat-
ments, we observed improvement in 72.7%, 66%, and
63.15% of the patients who received thalidomide, intrale-
sional corticosteroid infiltration and dapsone, respectively.
6/51 (11.7%) of the patients underwent surgical treatment.
Three of them underwent cheiloplasty and three underwent
gingivoplasty with excellent results (Figure 4).
Discussion
Large case series of MRS are scarce in the literature, and the
largest series comprise multicentric studies.8,9 The largest
studies conducted in single centers included 72 and 44
patients, respectively.4,10 Ours is the largest series of MRS in
South American patients.
Melkersson-­Rosenthal syndrome affects more commonly
young people as our series and other confirm; there is no sex
predisposition informed in the literature,10-12 except in the
393
pediatic population, in which male patients seem to prevail;
case reports in pediatric population are increasing.13-16
Most patients are usually first seen by professionals not
acquainted with MRS. Hence the initial diagnoses often
include angioedema, allergies, and infections. This might
explain the large lapse between the initial symptoms and the
correct diagnosis (3.34 years). MRS can be clinically con-
fused with other causes of acute and chronic macrocheilia
such as angioedema, lymphedema, erysipelas, salivary gland
tumors, contact dermatitis, and other chronic granulomatous
diseases (leishmaniasis, leprosy, sarcoidosis). Diagnostic
approach to orofacial swellings has been recently reviewed.17
Many cases consist of oligosymptomatic cases (granulo-
matous cheilitis only). The MRS diagnosis should be sus-
pected in this condition in order to avoid diagnosis delay in
the absence of the complete syndrome triad; a lip biopsy
must be performed in suspected cases. Persistent edema of
other orofacial tissues besides the lips should also raise
suspicion.
We did not perform any kind of allergy testing in our
patients since we strongly believe that MRS represents a
local manifestation of a systemic, genetically influenced
inflammatory process that is not related to local allergy.
Clinical experience with MRS proves the occurrence of
the complete triad only in a minority of patients. More inter-
estingly, the triad represents only a fraction of the totality of
394
signs and symptoms that can manifest in MRS patients.1,18 A
list of additional observations are commonly detected in
MRS: (1) granulomatous inflammation may affect many oro-
facial tissues besides the lips (face, eyelids, buccal mucosa,
etc)1; (2) geographic tongue seems to occur more commonly
than fissured tongue as was the case in our series; (3) many
other cranial nerve abnormalities have been described
besides facial palsy in MRS.1,18 Hence, MRS/orofacial gran-
ulomatosis includes a much broader constellation of changes
than those classically defined. The findings in our series
emphasize this interesting concept.
Geographic tongue is an inflammatory condition charac-
terized by the presence of transient or migratory red patches
of depapillation surrounded by a serpiginous, white border.
Histopathology is identical to psoriasis. Interestingly, there is
a significant association between psoriasis and Crohn’s dis-
ease (see below).19 Fissured tongue generally follows long
lasting geographic tongue; these two findings frequently
coexist, and probably represent the same process at distinct
stages.20 We believe that geographic tongue is an overlooked
feature of MRS.
Additional seldomly reported findings in our series
include eyelids,18 gingival, and palatal granulomatous infil-
tration; these have proved to be exceedingly resistant to
treatment (see below).
Neurological findings other than facial palsy may includ-
ing trigeminal neuralgia, paresthesia, ocular palsies, blephar-
ospasm, epiphora, keratitis, psychotic episodes, uveitis,
changes in sweating, and migraine.1,21 Unfortunately, we did
not perform a complete neurological analysis in our cases,
and we feel that some of these findings might have been
missed. Seizures occurred in cases 19 and 21, and were con-
sidered as non-­epileptic by the neurology team; we strongly
suspect that their seizures were related to MRS, as well as
relapsing migraine in case 12.
The association between MRS and Crohn’s disease (CD)
has been suspected.2,13,22 We confirmed this association in
five patients, who had a clinical dermatological picture iden-
tical to the other patients. These patients have been included
in the previous HLA study by our group, all of them had one
or more alleles similar to those in the MRS group (HLA A *
02, HLA DRB1 * 11, HLADRB1 * 13, and DQB1 * 03). In
addition, in three of these five patients with CD and MRS
harbored HLA DQB1 * 05, an allele that has been linked to
the susceptibility to Crohn disease in American Caucasian
patients (therefore, these three patients with CD and MRS
had a gene already described in the genetic profile of CD).
The HLA DQB1 * 05 allele was expressed similarly in the
syndrome and control groups (18 % × 20 %, respectively),
increasing only in patients with associated MRS and CD.
Therefore, based on our genetic results, it is speculated that
these diseases are distinct entities, but might be linked.7 In
fact, some authors hypothesize the existence of 3 distinct
clinical settings: classical oral CD (when patients present
Journal of Cutaneous Medicine and Surgery 25(4)
intestinal CD with orofacial involvement), OFG with gastro-
intestinal asymptomatic involvement, and OFG without
intestinal involvement.13
We have recommended that patients presenting with MRS
should be screened for CD at regular intervals, since three of
our five cases developed CD many years after the diagnosis
of MRS. Unfortunately, we did not get colonoscopic exam-
ination of all patients from the baseline.
Family history has only been reported in 1 case; nonethe-
less, we suspect that familial history was not actively
searched in our retrospective series.
Granulomatous inflammation is considered a typical histo-
logic finding in MRS but it is not required to establish a diagno-
sis of the disorder.23 We recently published the detailed
histopathological findings in our case series.24 We found differ-
ent histopathological patterns depending on the stage of the dis-
ease. In the early stages there was only marked edema and
non-­diagnostic diffuse inflammatory infiltrate. As the disease
progressed, ill-­formed granulomas developed, as well as well-­
formed granulomas. In later stages, granulomatous inflamma-
tion was replaced by fibrosis. This continuum of changes might
explain the fact that we did not find granulomatous inflamma-
tion in 34% of our patients.
No single therapeutic approach has been universally suc-
cessful in MRS. There are no controlled studies on the available
treatments. Response to a given drug is unpredictable; at present
there is no effective clue that might indicate the election of a
particular drug to resolve all cases. We believe that the selected
drug should be employed for at least 3 months before it is con-
sidered a failure since clinical response is very slow.
Our approach has been empirical, and with time we have
favored thalidomide over other drugs. In adult patients, we start
with 200 mg at bedtime. Women of childbearing age should be
tried on dapsone 100 mg/day. Oral and intralesional corticoste-
roids should be used only in acute flares. Oral metronidazole
and azathioprine seem interesting options in refractory cases;
the first of these is also used in CD. Other therapies such as
clofazimine or minocycline did not prove effective in our hands.
We have not used immunobiological therapy in MRS,
although we feel that their use might be of help and they
should be further studied.25,26
We employed surgical treatment in 3 situations: complete
resistance to oral medications, residual lip enlargement after
disease control (a common situation, in which lip consis-
tency softens but the lip remains enlarged) (Figure 4a and b
& c), and in severe gingival compromise (a presentation that
almost never improves with medical treatment only)
(Figure 4d & e).27
In conclusion, it is necessary to pay attention to seldomly
described manifestations of MRS. Additionally, it is import-
ant to notice that the absence of granulomas on histopathol-
ogy does not exclude MRS, and that intestinal manifestations
are more commonly absent, but these can occur even after
several years after control of orofacial symptoms.
Gavioli et al
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
13. Lazzerini M, Bramuzzo M, Ventura A. Association between
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: FAPESP
Grant - (2017/26990-8), and FUNADERSP Grant - (29/2016).
Supplemental Material
Supplemental material for this article is available online.
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