Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature.

BACKGROUND: Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. METHODS: A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. RESULTS: Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. CONCLUSIONS: OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.

Queilitis granulomatosa, a propósito de dos casos / Granulomatous cheilitis, regarding two cases

La queilitis granulomatosa es una entidad granulomatosa no infecciosa, poco frecuente, que se presenta como un aumento de volumen persistente de la región orofacial. El estudio histológico, junto con la exclusión de otras patologías granulomatosas son necesarios para su diagnóstico, especialmente cuando no se presenta con la triada clásica del Síndrome de Merkelsson Rosenthal. Presentamos dos casos de queilitis granulomatosa y una revisión de la literatura disponible.

Granulomatous cheilitis is a rare, non-infectious, granulomatous entity that presents as a persistent swelling of the orofacial region. Histological study together with the exclusion of other granulomatous diseases are necessary for the diagnosis, especially when the presentation is not the classic triad of Merkelsson Rosenthal Syndrome. We present two cases of granulomatous cheilitis and a review of the available literature.

Melkersson⁻Rosenthal Syndrome in Childhood: Report of Three Paediatric Cases and a Review of the Literature.

Melkersson-Rosenthal syndrome (MRS) in children is a rare condition, clinically characterised by a triad of synchronous or metachronous symptoms: recurrent peripheral facial palsy, relapsing orofacial oedema, and a fissured tongue; the most recent review published on the topic has reported 30 published patients. The aetiology of this disease is still unclear. However, genetic factors, as well as alterations in immune functions, infections, and allergic reactions have been postulated. We report three children suffering from MRS and perform a literature review of paediatric cases. Taking into account that clinical and laboratoristical criteria for the diagnosis of MRS are lacking, this syndrome is probably underestimated, and we suggest increasing awareness of such a rare syndrome. Close multidisciplinary follow-up of these children with a team composed by paediatricians, neurologists, neuro-ophthalmologists, dermatologists, and otolaryngologists is crucial to guarantee exhaustive management and treatment success, while minimising relapses.

Idiopathic macrocheilia.

A 13-year-boy presented with painless swelling of upper and lower lips accompanied with gingival enlargement. The aetiology for these symptoms included vast pathological varieties but none of them could fit in. Clinical features were similar to orofacial graulomatosis but histopathological examination revealed chronic non-specific infection. Therefore, the final diagnosis was made as idiopathic macrocheilia through exclusion criteria. Management with intralesional triamcinolone acetonide 40 mg, twice a week for 3 weeks, resulted in significant remission in lip swelling without recurrence after a 6-month follow-up.

A Systematic Review of the Literature of the Three Related Disease Entities Cheilitis Granulomatosa, Orofacial Granulomatosis and Melkersson - Rosenthal Syndrome.

BACKGROUND AND OBJECTIVE: Melkersson Rosenthal syndrome (MRS) is a rare disorder of unknown etiology and comprises the triad: orofacial edema, recurrent facial paralysis and lingua plicata. In the current literature confusing heterogeneity exists, mixing together the historically grown terms cheilitis granulomatosa or granulomatous cheilitis, Melkersson Rosenthal syndrome and the umbrella term Orofacial Granulomatosis (OFG). METHODS: We provide a systematic review comprising all three disease entities of orofacial granulomatosis using the computerized database "Pubmed Medline" entering the keywords "orofacial granulomatosis" (141 references), "Melkersson-Rosenthal syndrome" (207 references), "granulomatous cheilitis" or "cheilitis granulomatosa" (102 references) back to 1956. Full-text journals and case studies were included, and data synthesis was performed individually. RESULTS: Etiology remains unclear for all three disease entities. Etiological relatedness to chronic inflammatory bowel disease is under discussion and effectiveness was found for different treatments, e.g. local triamcinolone injections, antibiotics, surgical interventions, TNF alpha blockers or exclusive enteral nutrition. No randomized controlled trial concerning the therapy of orofacial granulomatosis was found. As a consequence, the therapeutic conclusion is drawn mainly from small case series, thus limiting the evidence of therapeutic interventions. CONCLUSION: OFG with the sub-entities MRS and cheilitis granulomatosa is an etiological obscure disease process with various possible therapeutic interventions potentially alleviating the disease course but to broaden treatment knowledge further study in randomized controlled trials is needed.

CLINICAL CHARACTERISTICS AND TREATMENT OF MELKERSSON-ROSENTHAL SYNDROME--OVERVIEW OF SIX PATIENTS.

INTRODUCTION: Melkersson-Rosenthal syndrome is a rare disease of unknown etiology. Histopathologically, it presents as granulomatous cheilitis. From laboratory aspect, it is a nonspecific, differential diagnostically and therapeutically complex condition. CASE REPORT: This is a report of six cases treated at the Department of Allergology and Immunology of the Clinical Center of Serbia, who had presented with the referral diagnosis of recurring or persistent lip edema, and who were diagnosed with Melkersson-Rosenthal syndrome upon detailed evaluation. Three patients had complete triad of symptoms, two had the oligosymptomatic form and one manifested the monosymptomatic form of the disease. Histopathological findings of the oral mucosa specimens verified the presence of non-necrotic epithelioid granulomas in all patients. The patients were treated with the H1 and H2 antihistamines, corticosteroids, followed by anabolic drugs and antibiotics, resulting in transient and unfavorable effects. CONCLUSION: In differential diagnosis, Melkersson-Rosenthal syndrome diagnosis primarily refers to conditions of angioneurotic edema and hereditary angioedema, as well as granulomatous diseases such as sarcoidosis, tuberculosis and Chron's disease. It is necessary to follow-up these patients in view of monitoring the effects of the therapy and possible development of systemic granulomatous diseases.

Melkersson-Rosenthal syndrome: a retrospective study of 44 patients.

CONCLUSION: When patients with recurrent facial paralysis are encountered, otolaryngologists should check for fissured tongue, and question those patients about orofacial edema, minor symptoms, and family history. Histologic evidence is not necessary for the diagnosis of Melkersson-Rosenthal syndrome (MRS), while coronary high-resolution CT (HRCT) reconstruction of temporal bone and food allergen detection may be beneficial. Prophylactic decompression of the facial nerve for patients with appropriate electrophysiological indication may prevent further facial palsy attacks. OBJECTIVES: The objective of this study was to analyze the clinical features of a group of patients with MRS with major complaints of facial palsy treated at the Department of Otorhinolaryngology, and to comment on MRS from the perspective of otolaryngologists. METHODS: A retrospective review of patient database for the last 6 years in the Department of Otorhinolaryngology in Beijing Shijitan Hospital was performed to find patients diagnosed with MRS. RESULTS: A total of 44 MRS patients were included in this study. The mean age at onset was 14.1 years. A total of 13 (29.5%) patients had family history, 17 (38.6%) revealed broadened fallopian canal on coronary HRCT reconstruction of temporal bone, and 20/23 (87.0%) patients showed positive results in food allergen detection. Thirty-one patients accepted subtotal facial nerve decompression and only one patient had facial palsy recurrence on the same side as the operation.

Melkersson-Rosenthal syndrome: a review of seven patients.

Melkersson-Rosenthal syndrome (MRS) is a rare disorder consisting of a triad of persistent or recurrent orofacial edema, relapsing facial paralysis and fissured tongue. It is difficult to diagnose and treat. A retrospective review of our MRS patients was performed. The medical files, and treatment, radiologic and histopathologic records of these patients were reviewed. The study group consisted of seven male MRS patients. In four patients, the three classical manifestations were present simultaneously. Neuroimaging examinations found facial soft-tissue thickening and swelling in two patients. The indicators of the disease in our patients were as follows: two had family histories, two had elevated levels of protein in the cerebrospinal fluid, one had an increased immunoglobulin G level in the blood and one had reactive arthritis. All patients responded to systemic corticosteroid treatment. We discuss the genetic, infectious and immunologic factors in the etiology of MRS. Neuroimaging examinations were useful in determining the diagnosis and in determining whether the initial treatment of MRS should be with systemic corticosteroids.

Granulomatous cheilitis of Miescher: the diagnostic proof for a Melkersson-Rosenthal syndrome.

BACKGROUND: The Melkersson-Rosenthal syndrome (MRS) is a very rare clinical entity and its classical form is being characterized by the following triad: facial nerve palsy, swelling of the lips and fissured tongue. However, the monosymptomatic form is more common and the typical manifestation is facial edema and/or enlargement of the lips. CASE REPORT: We report a case of monosymptomatic MRS with a positive biopsy of granulomatous cheilitis. CONCLUSIONS: In the daily practice as a pediatrician, it is not usual to diagnose a patient as having MRS. We consider that this is partly because of misdiagnosis. We therefore believe that this case report will supply additional information, in the scope of recurrent facial paralysis and orofacial edema in both children and adults.

Melkersson-Rosenthal syndrome: lymphoscintigraphy-documented impairment and restoration of facial lymphatic drainage in the course of disease.

Melkersson-Rosenthal syndrome (MRS) is an idiopathic, rare disorder manifested by facial swelling, congenital plicated tongue and recurrent peripheral facial nerve palsy. Labial involvement alone is referred to as cheilitis granulomatosa. Differential diagnosis of MRS includes allergic angioedema, bacterial, viral or filarial infections as well as autoimmunological inflammation in the course of systemic lupus erythematosus, dermatomyositis, and others. We present 4 patients who experienced periodically painless edema of the face and/or lips. Lesions were diagnosed as recurrent Quincke's edema and were treated with antihistamine agents and glucocorticoids without improvement. In all four cases of MRS, we were able to document impaired lymphatic drainage from the swollen area using lymphoscintigraphy. We also documented in follow-up lymphoscintigraphy a restoration of lymphatic flow in three of the four patients with MRS and these results corresponded with clinical improvement. We have demonstrated that lymphatic pathology plays an important role in pathophysiology of chronic facial swelling in patients with Melkersson-Rosenthal syndrome.

Obstructive sleep apnea in a patient with the Melkersson-Rosenthal syndrome.

INTRODUCTION: Melkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology. It is characterized by the triad of macrocheilitis, peripheral facial palsy, and lingua plicata. CASE REPORT: A 48-year-old nonobese man with a diagnosis of MRS and marked macroglossia was evaluated because of clinically suspected obstructive sleep apnea (OSA). Established causes of OSA such as anatomic abnormalities of the upper airways or the facial skeleton were not present in this patient. Furthermore, hypothyroidism and acromegaly were excluded as underlying diseases. Polysomnography revealed moderate-to-severe OSA. As the swelling of the tongue had been unresponsive to immunosuppressive pharmacotherapy and surgery did not seem to be a reasonable therapeutic option, the patient was finally treated by continuous positive airway pressure therapy. DISCUSSION: To the best of our knowledge, this is the first report of OSA occurring in a patient with MRS.

Melkersson-Rosenthal syndrome and acquired C1 inhibitor deficiency.

BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare disease whose full-blown form is characterized by orofacial swelling, facial palsy and lingua plicata. OBJECTIVE: To investigate the complement system as well as its role in patients with MRS. METHODS: Seven patients presenting at this hospital between November 2002 and May 2003 and meeting the diagnostic criteria according to Hornstein were evaluated retrospectively. The investigations included clinical signs, an analysis of the complement system including levels of CH50, C3, C4, C1 inhibitor (INH) functions and C1-INH antigen detection. RESULTS: Two female patients showed isolated low levels of functional C1-INH as determined by duplicate tests. Both patients took estrogen-progestin contraceptives. CONCLUSION: Since deficiency in plasma protease C1-INH is known to lead to recurrent angioedema, we hypothesize that low levels of functional C1-INH may have contributed to the orofacial swelling in the 2 patients.

Case of cheilitis granulomatosa associated with apical periodontitis.

The etiology of cheilitis granulomatosa is unknown. In some cases, rapid improvement and/or complete elimination of swelling of the lips after dental treatment has been reported. Here, we describe another case of improvement following dental treatment. A 57-year-old woman had developed asymptomatic swelling of the lower lip 2 months previously. Histological examination revealed non-caseous giant cell granulomas. Neither facial nerve palsy nor fissuring of the tongue was present. Patch testing for metal allergy revealed only mild irritation to zinc ion. Although topical corticosteroid ointment and oral tranilast for 4 months were ineffective, rapid and remarkable improvement of the swelling was noted soon after treatment of two lesions of apical periodontitis. Thorough examination for foci of infection is necessary when treating a patient with cheilitis granulomatosa.

[Melkersson-Rosenthal syndrome--diagnostic and therapeutic problems]. / Zespól Melkerssona-Rosenthala - problemy diagnostyczne i lecznicze.

It is very difficult to differentiate Melkersson-Rosenthal syndrom and macrochelitis granulomatosa. Two neurologists: Ernt Melkersson and Curt Rosenthal in 1928 and 1931 described classical symptoms of this syndrom: recurring facial paralysis, swelling of the face and lips and the development of folds and furrows in the tongue. In 1945 Miescher described a few cases of primary interstitial inflammation of the lips and gave them the name macrochelitis granulomatosa. Some patients had paralysis of the facial nerve, others folds of the tongue. In the present study the etiopatho-genesis, diagnostic and therapeutic problems are presented.

Melkersson-Rosenthal syndrome in the periocular area: a review of the literature and case report.

A triad of facial palsy, facial edema, and furrowed tongue characterizes Melkersson-Rosenthal syndrome, a rare, noncaseating granulomatous disease of unknown cause. Although most reported cases of Melkersson-Rosenthal syndrome involve swelling of the perioral area, the authors present a case of Melkersson-Rosenthal syndrome involving the periocular area. Because of its rarity, the syndrome is usually ignored and misdiagnosed; however, the syndrome should not only be considered in the classic perioral presentation but also in the rare periocular form, which may be confused with orbital tumors and orbital pseudotumors. Biopsies should be performed routinely in all patients who present with eyelid edema of unknown etiology. The physician and surgeon who see patients with head and neck pathology should be familiar with Melkersson-Rosenthal syndrome, and with the possibility of its presentation in the orbit and periocular region.

Síndrome de Melkersson-Rosenthal: relato de um caso clínico completo / Melkersson-Rosenthal Syndrome: a complete case report

O presente trabalho visa relatar um caso clínico completo de um paciente de 24 anos de idade, feoderma, portador da Síndrome de Melkersson-Rosenthal, atendido no Setor de Cirurgia Buco-maxilo-facial do Hospital Universitário Pedro Ernesto. Atríade clássica desta síndrome, constituída de granulomatose orofacial, paralisia facial (Paralisia de Bell) e língua fissurada, é rara e pode ser observada no presente caso. Este artigo visa também atentar para outras possíveis manifestaçöes orofaciais da síndrome, além de ressaltar os parâmetros para o correto diagnóstico e seus possíveis tratamentos