- Email: [email protected]
Melkersson-Rosenthal syndrome
Otolaryngology–Head and Neck Surgery (2008) 138, 246-251
ORIGINAL RESEARCH— OTOLOGY AND NEUROTOLOGY
Melkersson-Rosenthal syndrome Mervi Kanerva, MD, Kirsi Moilanen, MSc, Susanna Virolainen, MD, PhD, Antti Vaheri, MD, PhD, and Anne Pitkäranta, MD, PhD, Helsinki, Finland OBJECTIVES: To study characteristics of MelkerssonRosenthal syndrome (MRS) patients with facial palsy (FP) and differences in patients treated at the Departments of Otorhinolaryngology and Dermatology. METHODS: Clinical picture of MRS was studied from patient charts at two departments. Patients with FP received a questionnaire and were examined. Tissue biopsies were searched for nonnecrotizing granulomatous infiltrations typical of MRS and blood DNA for UNC-93B1 gene mutations predisposing to herpesvirus infection. RESULTS: At the Department of Otorhinolaryngology, all 18 MRS patients had FP, 9 the triad form. Two patients revealed non-necrotizing granulomatous infiltrations during acute edema episodes; another two had association with uveitis. Edema was rarely persistent and did not dominate the clinical picture. No UNC-93B1 mutations were found. At the Department of Dermatology, 2 patients had triad MRS and 15 had monosymptomatic granulomatous cheilitis with persistent edema and typical MRS histology. CONCLUSION: The clinical picture of MRS with FP differed from the current knowledge of edema-dominated MRS. More studies focusing on MRS with FP would broaden our understanding of the syndrome. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
M
elkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology, undefined incidence, and inconsistent classification. MRS is classically defined as a triad of recurrent orofacial edema, recurrent peripheral facial palsy (FP), and fissured tongue (lingua plicata, LP).1 All three symptoms are present in a minority of patients. When two symptoms appear, the form is oligosymptomatic,1,2 and many investigators consider cheilitis granulomatosa (CG), an intermittent labial or orofacial edema, as a monosymptomatic MRS form.1,3 This interpretation results from histopathological biopsy findings of edematous tissues in CG and in some other MRS patients being identical, ie, showing non-necrotizing lymphoepitheloid granulomas.1,3 Some investigators suggest that these two are separate diseases because the majority of CG patients never present with other MRS symptoms.4 Most MRS studies are conducted at departments of der-
matology or oral and plastic surgery and comprise patients with monosymptomatic CG or oligosymptomatic forms of MRS in which the leading clinical symptom is edema. Few publications present more than one or two patients with the triad MRS form.1,3,5,6 Studies on patients with FP and fissured tongue without facial edema are very rare and some investigators do not include these patients in MRS at all.7 MRS patients with FP and without problematic edema have, in general, received little attention. In conducting the study at the Department of Otorhinolaryngology (depORL), we assumed that most MRS patients would have a history of FP. Previous studies have shown that the predominant manifestation and the most important diagnostic feature of MRS is facial edema1,3,5,6; however, this finding may lack relevance for our patients, and we hypothesized that it might stem from the bias of different specialties. Edema is also supposed to affect almost all patients and to progress and become persistent over time.1,3 We hypothesized that in our MRS patients with FP, progression of the disease would not be observed. This view was based on the fact that such patients seldom need follow-up in our department. We also searched patient charts at the Department of Dermatology (depDerma) to determine whether MRS patients treated in these two departments would vary in their forms of MRS. The etiology of MRS is unknown and herpesviruses have been suggested in MRS as well as in Bell’s palsy.8 We sought possible susceptibility to herpes simplex virus-1 (HSV-1) infections by determining autosomal recessive single-gene mutations leading to intracellular UNC-93B protein deficiency. Such a deficiency impairs cellular interferon antiviral responses to HSV-1 but does not compromise immunity to other pathogens.9
METHODS A computer search of patient records for MRS (diagnosis code G51.2 according to the international statistical classification of diseases and related health problems, ICD) was performed from January 1, 1996 to June 30, 2007 at depDerma and depORL. LP was defined according to Axell10
Received October 18, 2007; revised November 6, 2007; accepted November 14, 2007.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2007.11.015
Kanerva et al
Melkersson-Rosenthal syndrome
Table 1 Additional episodic symptoms in 17 patients responding to the Melkersson-Rosenthal syndrome study questionnaire Additional symptoms Migraine Headaches other than migraine Tinnitus Sudden deafness Dizziness Dry mouth Contractions or weaknesses of facial muscle Facial dysesthesia or pain Dysphagia Excessive facial sweating Facial anhidrosis Dry eyes Disturbances of vision Excessive tearing
Number of patients (%) 8 10 6 1 10 7 5
(47) (59) (35) (6) (59) (41) (29)
6 (35) 5 (29) 1 (6) 0 5 (29) 5 (29) 4 (24)
as the dorsum or margins of the tongue being crossed by one or several grooves, estimated to be at least 2 mm deep over a minimum total length of 15 mm. If there was any doubt in patient charts about the LP, severity was considered moderate and not recorded as real LP. Patients with a history of FP received a questionnaire by mail. They were asked about the time of onset, side, and number of FPs; about the location, duration, frequency, and persistence of facial edema; and about the existence of edemas in other body parts. They were asked whether any relatives had FP, edemas, or fissured tongue and were questioned about additional symptoms (Table 1). They were asked about allergies, any other diseases, medications, and gastrointestinal symptoms. Finally, they were invited to a clinical examination. If the patient had LP, the tongue was photographed (Fig 1). Facial function was assessed by the House-Brackmann11 and Sunnybrook12 facial grading systems. A tissue sample (lip, cheek, or tongue) was taken with a 4-mm biopsy punch (in cheek and lip from inside the mouth deep to the underlying muscle) for possible granulomatous infiltration diagnosis. The samples were fixed in formalin. Paraffin-embedded samples were then cut and stained with hematoxylin-eosin and periodic acid-Schiff. The slides were examined by a dermatopathologist. A blood sample was drawn for genetic testing from 13 patients. The samples were stored at ⫺20°C until further use. Genomic DNA was isolated using QiaAmp DNA blood mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Mutation (c.1034del4 and c.781G⬎A) locations in chromosome 11q13 for gene UNC93B1 were amplified in two distinct reactions with specific primers using AmpliTaq Gold polymerase enzyme (Applied Biosystems, Foster City, CA). Polymerase chain reaction
247 products were purified by QIAquick Gel Extraction Kit (Qiagen) and sequenced. The study protocol was approved by the Helsinki University Central Hospital Ethics Committee. All patients taking part by questionnaire or examinations gave their written informed consent. The funding source had only a financial role in the study.
RESULTS The study comprised 35 patients; the computer search yielded 26 patients and an additional 9 patients were found by the authors or with help from colleagues. There were 23 women and 12 men. In depDerma, all 17 patients had labial or facial edema as their most frequent or persistent symptom (Table 2). Samples from edematous tissues, taken for diagnostic purposes, had shown lymphocyte clusters surrounding small vessels in 3 patients and non-necrotizing granulomatous infiltrations typical of MRS in 14 patients. Two of these patients with granulomas also had FP and LP (Table 3, patients 1 and 2), hence a complete triad form of MRS. The remaining 15 patients had CG as a monosymptomatic form of MRS. One of the CG patients had Crohn’s disease. All 18 patients in depORL had FP (Tables 2 and 3, patients 3–20). A full triad of symptoms could be seen in nine patients (Table 3, patients 3, 5–12). Five patients had FP with edema (Table 3, patients 4, 13–16), one had FPs with LP (Table 3, patient 17), and one had an episode of FP with LP and several additional symptoms (Table 3, patient 18) (Table 1). One patient had had FP four times and recurring tears and blisters of the mucous membranes of the mouth (Table 3, patient 19). Herpes infection or MRS was
Figure 1
Plicated tongue.
248
Otolaryngology–Head and Neck Surgery, Vol 138, No 2, February 2008 revealed non-necrotizing granulomatous infiltration. Another patient (Table 3, patient 4) had had edemas recurring in the right cheek for a year. Again, a tissue sample taken during an acute edema episode demonstrated non-necrotizing granulomas consisting of histiocytic cells and small lymphocytes. Samples taken without acute edema from six other patients (Table 3) displayed no specific findings. UNC-93B1 gene mutations (13 patients, Table 3) were not found. Ten of the 14 patients with multiple FPs (Table 3) had them on both sides of the face. The median time between episodes was 6.5 (range 1–50) years. Eight of the 14 patients examined received a reduced grade in facial grading (Table 4). In the FP group, three triad patients had constant facial edema and patient 1 (Table 3) had had cheiloplasty of the upper and lower lip. In other MRS FP patients, edema was not the dominating feature of the syndrome; it appeared seldom, and it was mostly moderate in nature. The first symptom of the syndrome in the FP group was FP in 12 patients, edema in 3 patients, and FP and edema simultaneously in 5 patients. In the CG group, 12 of the 15 patients had developed persistent edema. The most common site in both groups was the upper lip, but both lips, cheeks, and tongue were also common. Other sites included the neck, eyelids, larynx, and vulva; patient 1 (Table 3) had biopsyconfirmed vulvitis granulomatosa. Two triad MRS patients were siblings (Table 3, patients 8 and 9). To their knowledge, no one else in the family had any of the symptoms. One triad patient (Table 3, patient 7) had a father with FP, a mother with facial edemas, and four siblings with LP. She was also a symptomless carrier of a gene mutation in chromosome 10q24 for infantile onset spinocerebellar ataxia, which is a severe autosomal recessively inherited neurodegenerative disorder. One triad patient had a brother with FP (Table 3, patient 3), another triad
Table 2 Frequency of symptoms in 35 Melkersson-Rosenthal syndrome patients in two specialty departments Otorhinolaryngology Dermatology (n ⫽ 17) (n ⫽ 18) Number of patients Number of patients (%) (%)
Symptom Facial palsy Triad of symptoms* Edema Lingua plicata (LP) LP or moderately plicated tongue
18 (100) 9 (50)
2 (12) 2 (12)
16 (89) 11 (61)
17 (100) 2 (12)
12 (67)
5 (29)
*Facial palsy, lingua plicata, and edema
suspected. One patient had recurrent edema of the cheek and weakness of the marginal branch of the facial nerve (Table 3, patient 20). The median age was 47 (range 19 –75) years: 45.5 years for the FP group and 47 years for the CG group. The median age at symptom onset was 21.5 years and 34 years, respectively. The difference was not statistically significant (Mann-Whitney U test, P ⫽ 0.26). Of the 20 patients with FP receiving the questionnaire, 17 replied and 14 were able to attend the clinical examination. Patients 1 and 2 (Table 3) had previously had a tissue sample showing typical granuloma-infiltrating edematous tissue. For several years, patient 3 (Table 3) had in the upper lip short episodes of edema, which gradually became more persistent. Tissue biopsies had been taken without specific findings but biopsies taken during an acute edema episode
Table 3 Melkersson-Rosenthal syndrome (MRS) patients (n ⴝ 20) with facial palsy (FP) Patients 1
2
3
4
5
6
7
F 50 22 1 ● ● ● ● ⫺ ⫹
F 37 10 2 ● ● ● ● ⫺ ⫹
M 59 39 1 ● ● ● ●
F 47 12 1 ⫺ ● ● ● ⫺ ⫹
M 36 24 2 ● ● ● ● ⫺ ⫺
M 39 21 2 ● ● ● ● ⫺ ⫺
F 60 23 3 ● ● ● ● ⫺ ⫺
MRS Gender Age Age at onset Number of FP Lingua plicata Facial edema Questionnaire Examination Mutations* Histology ⫹/⫺
⫹
8 9 Proven M 41 31 1 ● ● ● ● ⫺ ⫺
F 40 21 2 ● ● ● ● ⫺
10
11
12
13
14
15
F 36 21 2 ● ● ●
F 74 48 3 ● ●
F 34 15 4 ● ●
F 48 13 4 ⫺ ● ● ● ⫺
F 54 47 2 ⫺ ● ●
M 36 20 3 ⫺ x1 ● ● ⫺ ⫺
16 17 18 19 20 Probable Possible F 47 43 2 j x1 ● ● ⫺
M 72 20 3 ● ⫺ ●
M 44 44 1 ● ⫺
F 59 12 4 ⫺ j ● ● ⫺
F 67 67 1 ⫺ ● ● ● ⫺ ⫺
Patients 1 and 2 from the Department of Dermatology; Patients 3–20 from the Department of Otorhinolaryngology F, female; M, male; ●, yes; j, mild symptom; ⫺, no *Leading to UNC-93B protein deficiency: ⫺, mutations not found; Histology: ⫹, non-necrotizing granulomas; ⫺, atypical finding
Kanerva et al
Melkersson-Rosenthal syndrome
249
Table 4 House-Brackmann (H-BFGS) and Sunnybrook (SFGS) facial grading system results in 14 Melkersson-Rosenthal syndrome patients with facial palsy (FP) Patients (numbers according to Table 3) 1
2
3
4
5
6
7
8
9
13
15
16
19
20
FP* 1 2 1 1 2 2 3 1 2 4 3 2 4 1 H-BFGS† 1 2 1 1 2 2-3 2 1 1 2 2 2 3-4 1 100/100 97/100 100/100 100/100 79/95 100/70 97/97 100/100 100/100 85/85 93/98 100/91 49/85 100/100 SFGS‡ right/ left *Number of episodes †Grade 1– 6: 1 ⫽ full function, 6 ⫽ total paralysis ‡Grade 0 –100: 100 ⫽ full function, 0 ⫽ total paralysis
patient had a sister and a grandfather with LP (Table 3, patient 2), and one patient had an uncle with FP (Table 3, patient 16). Two triad MRS patients had recurring acute anterior uveitis (Table 3, patients 1 and 5). Patient 5 had anterior uveitis unilaterally three times, and he had laser treatment for small retinal ablation in the same eye preceding the first attack. Patient 1 had bilateral uveitis that recurred in one eye. Examinations did not reveal sarcoidosis or diseases other than MRS. Both patients were HLA-B27 negative. Table 1 lists additional episodic (ie, inconsistent) symptoms inquired about in the questionnaire and the number of patients affected by them. Five patients had gastrointestinal symptoms, two with specific diagnosis: diverticulitis (Table 3, patient 7) and ulcerous colitis (Table 3, patient 15).
DISCUSSION Symptoms of MRS patients treated in the two departments varied greatly according to the specialty: FP was always present in the patient history in depORL, while edema was seen in depDerma patients. These findings support our hypothesis that the existing knowledge regarding MRS is influenced by most studies being from the departments of dermatology and oral or plastic surgery, which treat MRS patients troubled by edema. Most of our patients in depORL had never visited a doctor because of edema. This study has several shortcomings. In depORL, the computer search yielded only MRS patients with a specific diagnosis code. More patients might have been found under the diagnosis of FP, but with over 300 FP diagnoses a year, we were unable to examine most of the charts. Thus, the actual number of MRS patients is likely greater than that presented here. The same shortcomings apply to depDerma. Only patients with positive histology were coded under MRS (as is correct with monosymptomatic CG), and thus, we missed all suspected MRS patients. The classification
may also have influenced the MRS forms found in depDerma. Two triad MRS patients in our study had acute uveitis. To our knowledge, only one report exists of uveitis in association with triad MRS.13 One of our two patients had an eye operation as a predisposing factor to uveitis, but the longstanding nature of the disease and recurrences after two years suggest additional etiological factors. These findings might be associated with immunologic or autoimmune disturbances, which are considered potential etiological factors in MRS.2 MRS affects all age groups.1 In our study, the median age at onset was 24 years, which is close to previous findings of 25 to 40 years.3,5,14 Our female:male ratio was 2:1, in accordance with previous studies,5,14 while equal presentation3 or male predominance6 have also been reported. Edema was the most common initial symptom in our study as it is in the literature.3,5,6,14 However, MRS patients with FP had FP as the most common initial symptom, as also described previously.1 The most common site of edema was the upper lip, then both lips, cheeks, and tongue, in accordance with earlier reports.3,5,6,14 FP has most commonly been estimated to appear in 20% to 30%3-5,14,15 of all MRS cases, but reviews with 50%16 or 90%17 existences have also been published. The triad form is found in up to 20% of all MRS cases.3-6 In our study, combining the patients of both departments, FP was present in 57% and the triad form in 31% of all cases. Zimmer et al14 postulated that FP episodes in MRS are initially short, later lasting longer or becoming permanent. That was not the case with most of our patients, although more than half had residual symptoms from FP. LP can be found on average in 6% of the general population, with an increasing prevalence with age.10 About half of the patients have had LP in previous studies,3,5,6,14 compared to about one third in our study. The rarity of the disease makes assumptions about incidence difficult. Hornstein15 estimated an incidence of 80 in
250
Otolaryngology–Head and Neck Surgery, Vol 138, No 2, February 2008
100,000 per year, with MRS FP patients accounting for 25%. In a 25-year prospective study of peripheral FP etiology,18 the incidence of MRS with FP was 0.36 in 100,000 per year, corresponding to total incidence of 0.7 to 1.8 in 100,000 per year if FP is evident in 20% to 50% of all cases. The incidence of idiopathic peripheral FP (Bell’s palsy) is 20 to 30 in 100,000 per year18 worldwide, and in this respect the incidence of MRS with FP in Hornstein15 (20/100,000/ year) may be excessive. In our retrospective material, the annual incidence of MRS with FP was 0.2 in 100,000 per year and of all cases 0.3 in 100,000 per year. We probably missed undiagnosed patients, and only biopsy-proven cases of MRS from the depDerma were included. The etiology of MRS remains unsolved. The relation of the monosymptomatic CG form with sarcoidosis and Crohn’s disease has particularly been studied because of the common finding of non-necrotizing granulomas1,4; no definite association exists. One patient in depDerma had had Crohn’s disease for over 10 years, after which she developed CG. One of the FP patients had ulcerative colitis. We did not find similar cases in the literature. MRS with FP resembles Bell’s palsy in which herpesviruses are considered possible etiologic factors.19 Such an etiology is also suggested for MRS with FP.8 MRS is sometimes associated with herpes infection–type blisters at the beginning of edema.3,8,15 We searched for mutations that would predispose the patient to HSV-1 infection, but to no avail. Casrouge et al9 found these mutations in two otherwise healthy children with HSV-1 encephalitis. None of our patients had serious infections recorded in their patient histories. Hornstein et al suggested diagnostic criteria for MRS in their work in 19875 and in an adjusted version in 1997.2 In the 1987 version, complete form is not a synonym for triad form; LP was not necessary for a diagnosis of complete form, and one episode of edema combined with FP was sufficient with a typical biopsy finding. In the 1997 version of the complete form, LP is included and recurrent edema with typical histology is required, whereas recurrence of FP is not necessary. Typical MRS histology shows lymphoepitheloid granuloma infiltrations, which might also be replaced by small lymphoplasmocytic clusters or mononuclear infiltrates surrounding small vessels.2 Edema has previously been shown to be the most common feature in MRS, affecting almost all patients and eventually becoming persistent.1,3,5,6 This could also be seen in depDerma patients in our study, but not in depORL MRS patients. All patients from depDerma with persistent edema had typical biopsy findings. Negative histological findings in typical clinical MRS are common,14 and repeated biopsies in persistent edema cases are recommended.3 One of our patients had slight persistent edema in the upper lip with unspecific previous biopsy results. New biopsies were taken during an acute edema episode, revealing typical MRS histology. Some
investigators have suspected the need for persistent edema and advanced disease before granulomatous infiltrations develop.1 Another patient had nonpersistent edema symptoms for only a year with non-necrotizing granulomatous infiltrations found during an acute edema episode. These two patient findings suggest that taking biopsies during the acute edema phase is beneficial. Most MRS patients with FP in our study had mild edema symptoms or edema attacks were far apart. Thus, emphasizing the importance of edema episodes in MRS diagnostics might underestimate the prevalence and forms of MRS in patients treated in otorhinolaryngology departments. As major signs of MRS, Hornstein2 included palsies of other cranial nerves apart from the facial nerve. One triad patient in our study had experienced sudden deafness. Additional criteria suggested for MRS by Hornstein2 include minor signs of unilateral or bilateral sensory, motor neuron, or autonomous disturbances. These symptoms have been found in 80% of the patients2,5 and have been considered as additions to the diagnosis in incomplete, oligosymptomatic forms of the disease.2 Of the patients answering the questionnaire in our study, all but one reported at least one additional symptom (Table 1). Migraine was very common in our patients (47%), as reported previously (41%).5 In two other MRS studies,1,16 by contrast, the prevalence of migraine did not exceed the figure of 10(-20)% in the general population.20
CONCLUSION The clinical picture of MRS varied according to the department specialty where the patient was treated. MRS apparently could be divided into two separate forms according to the aggressiveness of the edema. Moreover, patients with monosymptomatic CG differed from the other MRS patients as though it were a distinct, separate disease. Our findings support taking tissue biopsies during acute edema episodes to reveal non-necrotizing granulomatous infiltrations. UNC93B1 gene mutations predisposing to HSV-1 infections could not be found. Even though the etiology of MRS is unknown and treatments (not discussed here) are often unsatisfactory, it is a relief to the patient to have MRS diagnosed and the odd separate symptoms explained. We suspect MRS is more frequent than diagnosed in cases of nondominating edema. More studies, especially from departments of otorhinolaryngology, could clarify the clinical picture and the incidence of different forms of MRS, providing us with a better understanding of this mystery.
ACKNOWLEDGMENTS We thank Kaija Haukka, IT coordinator; Heli Hyry, MD, PhD; and Juhani Rinne, MD, PhD at the Department of Dermatology for assisting with data collection; and Eija Nenye and Leena Juvonen, medical laboratory tech-
Kanerva et al
Melkersson-Rosenthal syndrome
nologists at the research laboratory of the Department of Otorhinolaryngology, for their help with patient samples.
AUTHOR INFORMATION From the Department of Otorhinolaryngology, Helsinki University Central Hospital (M. Kanerva and A. Pitkäranta); and the Departments of Virology (K. Moilanen and A. Vaheri) and Pathology (S. Virolainen), Haartman Institute, University of Helsinki. Corresponding author: Mervi Kanerva, MD, Department of Otorhinolaryngology, Helsinki University Central Hospital, POB 220, FIN-00029 HUS, Helsinki, Finland. E-mail address: [email protected]. “Melkersson-Rosenthal syndrome and UNC-93B protein” was presented as a research forum poster at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Washington, DC, September 16-19, 2007.
AUTHOR CONTRIBUTIONS Mervi Kanerva, study design and conduct, data collection, main writer; Kirsi Moilanen, gene analysis, writer; Susanna Virolainen, tissue histology analysis, writer; Antti Vaheri, study design, gene analysis and supervision, manuscript preparation; Anne Pitkäranta, study design and supervision, manuscript preparation.
FINANCIAL DISCLOSURE This study was supported in part by a grant from the Helsinki University Central Hospital Research Fund.
REFERENCES 1. Greene RM, Rogers RS 3rd. Melkersson-Rosenthal syndrome: a review of 36 patients. J Am Acad Dermatol 1989;21:1263–70. 2. Hornstein OP. Melkersson-Rosenthal syndrome—a challenge for dermatologists to participate in the field of oral medicine. J Dermatol 1997;24:281–96.
251 3. Worsaae N, Christensen KC, Schiodt M, et al. Melkersson-Rosenthal syndrome and cheilitis granulomatosa. A clinicopathological study of thirty-three patients with special reference to their oral lesions. Oral Surg Oral Med Oral Pathol 1982;54:404 –13. 4. van der Waal RI, Schulten EA, van der Meij EH, et al. Cheilitis granulomatosa: overview of 13 patients with long-term follow-up— results of management. Int J Dermatol 2002;41:225–9. 5. Hornstein OP, Stosiek N, Schonberger A, et al. Classification and scope of clinical variations of Melkersson-Rosenthal syndrome. Z Hautkr 1987;62:1453– 66. 6. Rintala A, Alhopuro S, Ritsila V, et al. Cheilitis granulomatosa—the Melkersson-Rosenthal syndrome. Scand J Plast Reconstr Surg 1973; 7:130 – 6. 7. Mair IW, de Graaf AS. Peripheral facial palsy in sub-arctic Norway. Acta Otolaryngol 1974;77:119 –25. 8. Ziem PE, Pfrommer C, Goerdt S, et al. Melkersson-Rosenthal syndrome in childhood: a challenge in differential diagnosis and treatment. Br J Dermatol 2000;143:860 –3. 9. Casrouge A, Zhang SY, Eidenschenk C, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 2006;314:308 – 12. 10. Axell T. A prevalence study of oral mucosal lesions in an adult Swedish population. Odontol Revy 1976;27:1–103. 11. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg 1985;93:146 –7. 12. Ross BG, Fradet G, Nedzelski JM. Development of a sensitive clinical facial grading system. Otolaryngol Head Neck Surg 1996;114:380 – 6. 13. Ates O, Yoruk O. Unilateral anterior uveitis in Melkersson-Rosenthal syndrome: a case report. J Int Med Res 2006;34:428 –32. 14. Zimmer WM, Rogers RS 3rd, Reeve CM, et al. Orofacial manifestations of Melkersson-Rosenthal syndrome. A study of 42 patients and review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 1992;74:610 –9. 15. Hornstein OP. Melkersson-Rosenthal syndrome. A neuro-muco-cutaneous disease of complex origin. Curr Probl Dermatol 1973;5:117–56. 16. Vistnes LM, Kernahan DA. The Melkersson-Rosenthal syndrome. Plast Reconstr Surg 1971;48:126 –32. 17. Alexander RW, James RB. Melkersson-Rosenthal syndrome: review of literature and report of case. J Oral Surg 1972;30:599 – 604. 18. Peitersen E. Bell’s palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl 2002;549:4 –30. 19. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med 1996;124:27–30. 20. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193–210.
ORIGINAL RESEARCH— OTOLOGY AND NEUROTOLOGY
Melkersson-Rosenthal syndrome Mervi Kanerva, MD, Kirsi Moilanen, MSc, Susanna Virolainen, MD, PhD, Antti Vaheri, MD, PhD, and Anne Pitkäranta, MD, PhD, Helsinki, Finland OBJECTIVES: To study characteristics of MelkerssonRosenthal syndrome (MRS) patients with facial palsy (FP) and differences in patients treated at the Departments of Otorhinolaryngology and Dermatology. METHODS: Clinical picture of MRS was studied from patient charts at two departments. Patients with FP received a questionnaire and were examined. Tissue biopsies were searched for nonnecrotizing granulomatous infiltrations typical of MRS and blood DNA for UNC-93B1 gene mutations predisposing to herpesvirus infection. RESULTS: At the Department of Otorhinolaryngology, all 18 MRS patients had FP, 9 the triad form. Two patients revealed non-necrotizing granulomatous infiltrations during acute edema episodes; another two had association with uveitis. Edema was rarely persistent and did not dominate the clinical picture. No UNC-93B1 mutations were found. At the Department of Dermatology, 2 patients had triad MRS and 15 had monosymptomatic granulomatous cheilitis with persistent edema and typical MRS histology. CONCLUSION: The clinical picture of MRS with FP differed from the current knowledge of edema-dominated MRS. More studies focusing on MRS with FP would broaden our understanding of the syndrome. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
M
elkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology, undefined incidence, and inconsistent classification. MRS is classically defined as a triad of recurrent orofacial edema, recurrent peripheral facial palsy (FP), and fissured tongue (lingua plicata, LP).1 All three symptoms are present in a minority of patients. When two symptoms appear, the form is oligosymptomatic,1,2 and many investigators consider cheilitis granulomatosa (CG), an intermittent labial or orofacial edema, as a monosymptomatic MRS form.1,3 This interpretation results from histopathological biopsy findings of edematous tissues in CG and in some other MRS patients being identical, ie, showing non-necrotizing lymphoepitheloid granulomas.1,3 Some investigators suggest that these two are separate diseases because the majority of CG patients never present with other MRS symptoms.4 Most MRS studies are conducted at departments of der-
matology or oral and plastic surgery and comprise patients with monosymptomatic CG or oligosymptomatic forms of MRS in which the leading clinical symptom is edema. Few publications present more than one or two patients with the triad MRS form.1,3,5,6 Studies on patients with FP and fissured tongue without facial edema are very rare and some investigators do not include these patients in MRS at all.7 MRS patients with FP and without problematic edema have, in general, received little attention. In conducting the study at the Department of Otorhinolaryngology (depORL), we assumed that most MRS patients would have a history of FP. Previous studies have shown that the predominant manifestation and the most important diagnostic feature of MRS is facial edema1,3,5,6; however, this finding may lack relevance for our patients, and we hypothesized that it might stem from the bias of different specialties. Edema is also supposed to affect almost all patients and to progress and become persistent over time.1,3 We hypothesized that in our MRS patients with FP, progression of the disease would not be observed. This view was based on the fact that such patients seldom need follow-up in our department. We also searched patient charts at the Department of Dermatology (depDerma) to determine whether MRS patients treated in these two departments would vary in their forms of MRS. The etiology of MRS is unknown and herpesviruses have been suggested in MRS as well as in Bell’s palsy.8 We sought possible susceptibility to herpes simplex virus-1 (HSV-1) infections by determining autosomal recessive single-gene mutations leading to intracellular UNC-93B protein deficiency. Such a deficiency impairs cellular interferon antiviral responses to HSV-1 but does not compromise immunity to other pathogens.9
METHODS A computer search of patient records for MRS (diagnosis code G51.2 according to the international statistical classification of diseases and related health problems, ICD) was performed from January 1, 1996 to June 30, 2007 at depDerma and depORL. LP was defined according to Axell10
Received October 18, 2007; revised November 6, 2007; accepted November 14, 2007.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2007.11.015
Kanerva et al
Melkersson-Rosenthal syndrome
Table 1 Additional episodic symptoms in 17 patients responding to the Melkersson-Rosenthal syndrome study questionnaire Additional symptoms Migraine Headaches other than migraine Tinnitus Sudden deafness Dizziness Dry mouth Contractions or weaknesses of facial muscle Facial dysesthesia or pain Dysphagia Excessive facial sweating Facial anhidrosis Dry eyes Disturbances of vision Excessive tearing
Number of patients (%) 8 10 6 1 10 7 5
(47) (59) (35) (6) (59) (41) (29)
6 (35) 5 (29) 1 (6) 0 5 (29) 5 (29) 4 (24)
as the dorsum or margins of the tongue being crossed by one or several grooves, estimated to be at least 2 mm deep over a minimum total length of 15 mm. If there was any doubt in patient charts about the LP, severity was considered moderate and not recorded as real LP. Patients with a history of FP received a questionnaire by mail. They were asked about the time of onset, side, and number of FPs; about the location, duration, frequency, and persistence of facial edema; and about the existence of edemas in other body parts. They were asked whether any relatives had FP, edemas, or fissured tongue and were questioned about additional symptoms (Table 1). They were asked about allergies, any other diseases, medications, and gastrointestinal symptoms. Finally, they were invited to a clinical examination. If the patient had LP, the tongue was photographed (Fig 1). Facial function was assessed by the House-Brackmann11 and Sunnybrook12 facial grading systems. A tissue sample (lip, cheek, or tongue) was taken with a 4-mm biopsy punch (in cheek and lip from inside the mouth deep to the underlying muscle) for possible granulomatous infiltration diagnosis. The samples were fixed in formalin. Paraffin-embedded samples were then cut and stained with hematoxylin-eosin and periodic acid-Schiff. The slides were examined by a dermatopathologist. A blood sample was drawn for genetic testing from 13 patients. The samples were stored at ⫺20°C until further use. Genomic DNA was isolated using QiaAmp DNA blood mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Mutation (c.1034del4 and c.781G⬎A) locations in chromosome 11q13 for gene UNC93B1 were amplified in two distinct reactions with specific primers using AmpliTaq Gold polymerase enzyme (Applied Biosystems, Foster City, CA). Polymerase chain reaction
247 products were purified by QIAquick Gel Extraction Kit (Qiagen) and sequenced. The study protocol was approved by the Helsinki University Central Hospital Ethics Committee. All patients taking part by questionnaire or examinations gave their written informed consent. The funding source had only a financial role in the study.
RESULTS The study comprised 35 patients; the computer search yielded 26 patients and an additional 9 patients were found by the authors or with help from colleagues. There were 23 women and 12 men. In depDerma, all 17 patients had labial or facial edema as their most frequent or persistent symptom (Table 2). Samples from edematous tissues, taken for diagnostic purposes, had shown lymphocyte clusters surrounding small vessels in 3 patients and non-necrotizing granulomatous infiltrations typical of MRS in 14 patients. Two of these patients with granulomas also had FP and LP (Table 3, patients 1 and 2), hence a complete triad form of MRS. The remaining 15 patients had CG as a monosymptomatic form of MRS. One of the CG patients had Crohn’s disease. All 18 patients in depORL had FP (Tables 2 and 3, patients 3–20). A full triad of symptoms could be seen in nine patients (Table 3, patients 3, 5–12). Five patients had FP with edema (Table 3, patients 4, 13–16), one had FPs with LP (Table 3, patient 17), and one had an episode of FP with LP and several additional symptoms (Table 3, patient 18) (Table 1). One patient had had FP four times and recurring tears and blisters of the mucous membranes of the mouth (Table 3, patient 19). Herpes infection or MRS was
Figure 1
Plicated tongue.
248
Otolaryngology–Head and Neck Surgery, Vol 138, No 2, February 2008 revealed non-necrotizing granulomatous infiltration. Another patient (Table 3, patient 4) had had edemas recurring in the right cheek for a year. Again, a tissue sample taken during an acute edema episode demonstrated non-necrotizing granulomas consisting of histiocytic cells and small lymphocytes. Samples taken without acute edema from six other patients (Table 3) displayed no specific findings. UNC-93B1 gene mutations (13 patients, Table 3) were not found. Ten of the 14 patients with multiple FPs (Table 3) had them on both sides of the face. The median time between episodes was 6.5 (range 1–50) years. Eight of the 14 patients examined received a reduced grade in facial grading (Table 4). In the FP group, three triad patients had constant facial edema and patient 1 (Table 3) had had cheiloplasty of the upper and lower lip. In other MRS FP patients, edema was not the dominating feature of the syndrome; it appeared seldom, and it was mostly moderate in nature. The first symptom of the syndrome in the FP group was FP in 12 patients, edema in 3 patients, and FP and edema simultaneously in 5 patients. In the CG group, 12 of the 15 patients had developed persistent edema. The most common site in both groups was the upper lip, but both lips, cheeks, and tongue were also common. Other sites included the neck, eyelids, larynx, and vulva; patient 1 (Table 3) had biopsyconfirmed vulvitis granulomatosa. Two triad MRS patients were siblings (Table 3, patients 8 and 9). To their knowledge, no one else in the family had any of the symptoms. One triad patient (Table 3, patient 7) had a father with FP, a mother with facial edemas, and four siblings with LP. She was also a symptomless carrier of a gene mutation in chromosome 10q24 for infantile onset spinocerebellar ataxia, which is a severe autosomal recessively inherited neurodegenerative disorder. One triad patient had a brother with FP (Table 3, patient 3), another triad
Table 2 Frequency of symptoms in 35 Melkersson-Rosenthal syndrome patients in two specialty departments Otorhinolaryngology Dermatology (n ⫽ 17) (n ⫽ 18) Number of patients Number of patients (%) (%)
Symptom Facial palsy Triad of symptoms* Edema Lingua plicata (LP) LP or moderately plicated tongue
18 (100) 9 (50)
2 (12) 2 (12)
16 (89) 11 (61)
17 (100) 2 (12)
12 (67)
5 (29)
*Facial palsy, lingua plicata, and edema
suspected. One patient had recurrent edema of the cheek and weakness of the marginal branch of the facial nerve (Table 3, patient 20). The median age was 47 (range 19 –75) years: 45.5 years for the FP group and 47 years for the CG group. The median age at symptom onset was 21.5 years and 34 years, respectively. The difference was not statistically significant (Mann-Whitney U test, P ⫽ 0.26). Of the 20 patients with FP receiving the questionnaire, 17 replied and 14 were able to attend the clinical examination. Patients 1 and 2 (Table 3) had previously had a tissue sample showing typical granuloma-infiltrating edematous tissue. For several years, patient 3 (Table 3) had in the upper lip short episodes of edema, which gradually became more persistent. Tissue biopsies had been taken without specific findings but biopsies taken during an acute edema episode
Table 3 Melkersson-Rosenthal syndrome (MRS) patients (n ⴝ 20) with facial palsy (FP) Patients 1
2
3
4
5
6
7
F 50 22 1 ● ● ● ● ⫺ ⫹
F 37 10 2 ● ● ● ● ⫺ ⫹
M 59 39 1 ● ● ● ●
F 47 12 1 ⫺ ● ● ● ⫺ ⫹
M 36 24 2 ● ● ● ● ⫺ ⫺
M 39 21 2 ● ● ● ● ⫺ ⫺
F 60 23 3 ● ● ● ● ⫺ ⫺
MRS Gender Age Age at onset Number of FP Lingua plicata Facial edema Questionnaire Examination Mutations* Histology ⫹/⫺
⫹
8 9 Proven M 41 31 1 ● ● ● ● ⫺ ⫺
F 40 21 2 ● ● ● ● ⫺
10
11
12
13
14
15
F 36 21 2 ● ● ●
F 74 48 3 ● ●
F 34 15 4 ● ●
F 48 13 4 ⫺ ● ● ● ⫺
F 54 47 2 ⫺ ● ●
M 36 20 3 ⫺ x1 ● ● ⫺ ⫺
16 17 18 19 20 Probable Possible F 47 43 2 j x1 ● ● ⫺
M 72 20 3 ● ⫺ ●
M 44 44 1 ● ⫺
F 59 12 4 ⫺ j ● ● ⫺
F 67 67 1 ⫺ ● ● ● ⫺ ⫺
Patients 1 and 2 from the Department of Dermatology; Patients 3–20 from the Department of Otorhinolaryngology F, female; M, male; ●, yes; j, mild symptom; ⫺, no *Leading to UNC-93B protein deficiency: ⫺, mutations not found; Histology: ⫹, non-necrotizing granulomas; ⫺, atypical finding
Kanerva et al
Melkersson-Rosenthal syndrome
249
Table 4 House-Brackmann (H-BFGS) and Sunnybrook (SFGS) facial grading system results in 14 Melkersson-Rosenthal syndrome patients with facial palsy (FP) Patients (numbers according to Table 3) 1
2
3
4
5
6
7
8
9
13
15
16
19
20
FP* 1 2 1 1 2 2 3 1 2 4 3 2 4 1 H-BFGS† 1 2 1 1 2 2-3 2 1 1 2 2 2 3-4 1 100/100 97/100 100/100 100/100 79/95 100/70 97/97 100/100 100/100 85/85 93/98 100/91 49/85 100/100 SFGS‡ right/ left *Number of episodes †Grade 1– 6: 1 ⫽ full function, 6 ⫽ total paralysis ‡Grade 0 –100: 100 ⫽ full function, 0 ⫽ total paralysis
patient had a sister and a grandfather with LP (Table 3, patient 2), and one patient had an uncle with FP (Table 3, patient 16). Two triad MRS patients had recurring acute anterior uveitis (Table 3, patients 1 and 5). Patient 5 had anterior uveitis unilaterally three times, and he had laser treatment for small retinal ablation in the same eye preceding the first attack. Patient 1 had bilateral uveitis that recurred in one eye. Examinations did not reveal sarcoidosis or diseases other than MRS. Both patients were HLA-B27 negative. Table 1 lists additional episodic (ie, inconsistent) symptoms inquired about in the questionnaire and the number of patients affected by them. Five patients had gastrointestinal symptoms, two with specific diagnosis: diverticulitis (Table 3, patient 7) and ulcerous colitis (Table 3, patient 15).
DISCUSSION Symptoms of MRS patients treated in the two departments varied greatly according to the specialty: FP was always present in the patient history in depORL, while edema was seen in depDerma patients. These findings support our hypothesis that the existing knowledge regarding MRS is influenced by most studies being from the departments of dermatology and oral or plastic surgery, which treat MRS patients troubled by edema. Most of our patients in depORL had never visited a doctor because of edema. This study has several shortcomings. In depORL, the computer search yielded only MRS patients with a specific diagnosis code. More patients might have been found under the diagnosis of FP, but with over 300 FP diagnoses a year, we were unable to examine most of the charts. Thus, the actual number of MRS patients is likely greater than that presented here. The same shortcomings apply to depDerma. Only patients with positive histology were coded under MRS (as is correct with monosymptomatic CG), and thus, we missed all suspected MRS patients. The classification
may also have influenced the MRS forms found in depDerma. Two triad MRS patients in our study had acute uveitis. To our knowledge, only one report exists of uveitis in association with triad MRS.13 One of our two patients had an eye operation as a predisposing factor to uveitis, but the longstanding nature of the disease and recurrences after two years suggest additional etiological factors. These findings might be associated with immunologic or autoimmune disturbances, which are considered potential etiological factors in MRS.2 MRS affects all age groups.1 In our study, the median age at onset was 24 years, which is close to previous findings of 25 to 40 years.3,5,14 Our female:male ratio was 2:1, in accordance with previous studies,5,14 while equal presentation3 or male predominance6 have also been reported. Edema was the most common initial symptom in our study as it is in the literature.3,5,6,14 However, MRS patients with FP had FP as the most common initial symptom, as also described previously.1 The most common site of edema was the upper lip, then both lips, cheeks, and tongue, in accordance with earlier reports.3,5,6,14 FP has most commonly been estimated to appear in 20% to 30%3-5,14,15 of all MRS cases, but reviews with 50%16 or 90%17 existences have also been published. The triad form is found in up to 20% of all MRS cases.3-6 In our study, combining the patients of both departments, FP was present in 57% and the triad form in 31% of all cases. Zimmer et al14 postulated that FP episodes in MRS are initially short, later lasting longer or becoming permanent. That was not the case with most of our patients, although more than half had residual symptoms from FP. LP can be found on average in 6% of the general population, with an increasing prevalence with age.10 About half of the patients have had LP in previous studies,3,5,6,14 compared to about one third in our study. The rarity of the disease makes assumptions about incidence difficult. Hornstein15 estimated an incidence of 80 in
250
Otolaryngology–Head and Neck Surgery, Vol 138, No 2, February 2008
100,000 per year, with MRS FP patients accounting for 25%. In a 25-year prospective study of peripheral FP etiology,18 the incidence of MRS with FP was 0.36 in 100,000 per year, corresponding to total incidence of 0.7 to 1.8 in 100,000 per year if FP is evident in 20% to 50% of all cases. The incidence of idiopathic peripheral FP (Bell’s palsy) is 20 to 30 in 100,000 per year18 worldwide, and in this respect the incidence of MRS with FP in Hornstein15 (20/100,000/ year) may be excessive. In our retrospective material, the annual incidence of MRS with FP was 0.2 in 100,000 per year and of all cases 0.3 in 100,000 per year. We probably missed undiagnosed patients, and only biopsy-proven cases of MRS from the depDerma were included. The etiology of MRS remains unsolved. The relation of the monosymptomatic CG form with sarcoidosis and Crohn’s disease has particularly been studied because of the common finding of non-necrotizing granulomas1,4; no definite association exists. One patient in depDerma had had Crohn’s disease for over 10 years, after which she developed CG. One of the FP patients had ulcerative colitis. We did not find similar cases in the literature. MRS with FP resembles Bell’s palsy in which herpesviruses are considered possible etiologic factors.19 Such an etiology is also suggested for MRS with FP.8 MRS is sometimes associated with herpes infection–type blisters at the beginning of edema.3,8,15 We searched for mutations that would predispose the patient to HSV-1 infection, but to no avail. Casrouge et al9 found these mutations in two otherwise healthy children with HSV-1 encephalitis. None of our patients had serious infections recorded in their patient histories. Hornstein et al suggested diagnostic criteria for MRS in their work in 19875 and in an adjusted version in 1997.2 In the 1987 version, complete form is not a synonym for triad form; LP was not necessary for a diagnosis of complete form, and one episode of edema combined with FP was sufficient with a typical biopsy finding. In the 1997 version of the complete form, LP is included and recurrent edema with typical histology is required, whereas recurrence of FP is not necessary. Typical MRS histology shows lymphoepitheloid granuloma infiltrations, which might also be replaced by small lymphoplasmocytic clusters or mononuclear infiltrates surrounding small vessels.2 Edema has previously been shown to be the most common feature in MRS, affecting almost all patients and eventually becoming persistent.1,3,5,6 This could also be seen in depDerma patients in our study, but not in depORL MRS patients. All patients from depDerma with persistent edema had typical biopsy findings. Negative histological findings in typical clinical MRS are common,14 and repeated biopsies in persistent edema cases are recommended.3 One of our patients had slight persistent edema in the upper lip with unspecific previous biopsy results. New biopsies were taken during an acute edema episode, revealing typical MRS histology. Some
investigators have suspected the need for persistent edema and advanced disease before granulomatous infiltrations develop.1 Another patient had nonpersistent edema symptoms for only a year with non-necrotizing granulomatous infiltrations found during an acute edema episode. These two patient findings suggest that taking biopsies during the acute edema phase is beneficial. Most MRS patients with FP in our study had mild edema symptoms or edema attacks were far apart. Thus, emphasizing the importance of edema episodes in MRS diagnostics might underestimate the prevalence and forms of MRS in patients treated in otorhinolaryngology departments. As major signs of MRS, Hornstein2 included palsies of other cranial nerves apart from the facial nerve. One triad patient in our study had experienced sudden deafness. Additional criteria suggested for MRS by Hornstein2 include minor signs of unilateral or bilateral sensory, motor neuron, or autonomous disturbances. These symptoms have been found in 80% of the patients2,5 and have been considered as additions to the diagnosis in incomplete, oligosymptomatic forms of the disease.2 Of the patients answering the questionnaire in our study, all but one reported at least one additional symptom (Table 1). Migraine was very common in our patients (47%), as reported previously (41%).5 In two other MRS studies,1,16 by contrast, the prevalence of migraine did not exceed the figure of 10(-20)% in the general population.20
CONCLUSION The clinical picture of MRS varied according to the department specialty where the patient was treated. MRS apparently could be divided into two separate forms according to the aggressiveness of the edema. Moreover, patients with monosymptomatic CG differed from the other MRS patients as though it were a distinct, separate disease. Our findings support taking tissue biopsies during acute edema episodes to reveal non-necrotizing granulomatous infiltrations. UNC93B1 gene mutations predisposing to HSV-1 infections could not be found. Even though the etiology of MRS is unknown and treatments (not discussed here) are often unsatisfactory, it is a relief to the patient to have MRS diagnosed and the odd separate symptoms explained. We suspect MRS is more frequent than diagnosed in cases of nondominating edema. More studies, especially from departments of otorhinolaryngology, could clarify the clinical picture and the incidence of different forms of MRS, providing us with a better understanding of this mystery.
ACKNOWLEDGMENTS We thank Kaija Haukka, IT coordinator; Heli Hyry, MD, PhD; and Juhani Rinne, MD, PhD at the Department of Dermatology for assisting with data collection; and Eija Nenye and Leena Juvonen, medical laboratory tech-
Kanerva et al
Melkersson-Rosenthal syndrome
nologists at the research laboratory of the Department of Otorhinolaryngology, for their help with patient samples.
AUTHOR INFORMATION From the Department of Otorhinolaryngology, Helsinki University Central Hospital (M. Kanerva and A. Pitkäranta); and the Departments of Virology (K. Moilanen and A. Vaheri) and Pathology (S. Virolainen), Haartman Institute, University of Helsinki. Corresponding author: Mervi Kanerva, MD, Department of Otorhinolaryngology, Helsinki University Central Hospital, POB 220, FIN-00029 HUS, Helsinki, Finland. E-mail address: [email protected]. “Melkersson-Rosenthal syndrome and UNC-93B protein” was presented as a research forum poster at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Washington, DC, September 16-19, 2007.
AUTHOR CONTRIBUTIONS Mervi Kanerva, study design and conduct, data collection, main writer; Kirsi Moilanen, gene analysis, writer; Susanna Virolainen, tissue histology analysis, writer; Antti Vaheri, study design, gene analysis and supervision, manuscript preparation; Anne Pitkäranta, study design and supervision, manuscript preparation.
FINANCIAL DISCLOSURE This study was supported in part by a grant from the Helsinki University Central Hospital Research Fund.
REFERENCES 1. Greene RM, Rogers RS 3rd. Melkersson-Rosenthal syndrome: a review of 36 patients. J Am Acad Dermatol 1989;21:1263–70. 2. Hornstein OP. Melkersson-Rosenthal syndrome—a challenge for dermatologists to participate in the field of oral medicine. J Dermatol 1997;24:281–96.
251 3. Worsaae N, Christensen KC, Schiodt M, et al. Melkersson-Rosenthal syndrome and cheilitis granulomatosa. A clinicopathological study of thirty-three patients with special reference to their oral lesions. Oral Surg Oral Med Oral Pathol 1982;54:404 –13. 4. van der Waal RI, Schulten EA, van der Meij EH, et al. Cheilitis granulomatosa: overview of 13 patients with long-term follow-up— results of management. Int J Dermatol 2002;41:225–9. 5. Hornstein OP, Stosiek N, Schonberger A, et al. Classification and scope of clinical variations of Melkersson-Rosenthal syndrome. Z Hautkr 1987;62:1453– 66. 6. Rintala A, Alhopuro S, Ritsila V, et al. Cheilitis granulomatosa—the Melkersson-Rosenthal syndrome. Scand J Plast Reconstr Surg 1973; 7:130 – 6. 7. Mair IW, de Graaf AS. Peripheral facial palsy in sub-arctic Norway. Acta Otolaryngol 1974;77:119 –25. 8. Ziem PE, Pfrommer C, Goerdt S, et al. Melkersson-Rosenthal syndrome in childhood: a challenge in differential diagnosis and treatment. Br J Dermatol 2000;143:860 –3. 9. Casrouge A, Zhang SY, Eidenschenk C, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 2006;314:308 – 12. 10. Axell T. A prevalence study of oral mucosal lesions in an adult Swedish population. Odontol Revy 1976;27:1–103. 11. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg 1985;93:146 –7. 12. Ross BG, Fradet G, Nedzelski JM. Development of a sensitive clinical facial grading system. Otolaryngol Head Neck Surg 1996;114:380 – 6. 13. Ates O, Yoruk O. Unilateral anterior uveitis in Melkersson-Rosenthal syndrome: a case report. J Int Med Res 2006;34:428 –32. 14. Zimmer WM, Rogers RS 3rd, Reeve CM, et al. Orofacial manifestations of Melkersson-Rosenthal syndrome. A study of 42 patients and review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 1992;74:610 –9. 15. Hornstein OP. Melkersson-Rosenthal syndrome. A neuro-muco-cutaneous disease of complex origin. Curr Probl Dermatol 1973;5:117–56. 16. Vistnes LM, Kernahan DA. The Melkersson-Rosenthal syndrome. Plast Reconstr Surg 1971;48:126 –32. 17. Alexander RW, James RB. Melkersson-Rosenthal syndrome: review of literature and report of case. J Oral Surg 1972;30:599 – 604. 18. Peitersen E. Bell’s palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl 2002;549:4 –30. 19. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med 1996;124:27–30. 20. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193–210.