Melkersson–Rosenthal syndrome: a case report of a rare disease with overlapping features
Melkersson–Rosenthal syndrome (MRS) is a rare, neuro-mucocutaneous disease which presents as orofacial swelling, facial palsy and fissured tongue. These symptoms may occur simultaneously or, more frequently, with a oligosymptomatic or monosymptomatic pattern. Swelling, that is the most common initial finding, may mimic hereditary or acquired angioedema, a disorder caused by histamine or bradykinin-mediated plasma-leakage affecting subcutaneous and/or submucosal tissue. The differential diagnosis of MRS includes also chronic inflammatory and infective diseases characterized by granulomatous infiltration, as well as rosacea, contact dermatitis, allergic reactions and Bell’s palsy.
A 71-year old, non-allergic female patient with no familial and personal history of angioedema presented, a few days after a possible herpes simplex or varicella-zoster virus infection, with monolateral facial paraesthesia and lower lip edema. After temporary remission of symptoms on oral steroids and antihistamines, she showed swelling recurrence refractory to valaciclovir therapy and a subsequent course of antihistamines. The clinical picture and a previous history of non-Hodgkin lymphoma prompted us to rule out an acquired form of paraneoplastic, C1-inhibitor (C1-INH) deficiency: C1q and both antigen and functional C1-INH tested normal, whilst we found low plasma levels of C3 and C4 possibly related to the parallel detection of antiphospholipid antibodies. Thus, we hypothesized a non-histaminergic, idiopathic form of angioedema and planned further therapy with tranexamic acid and the leukotriene receptor antagonist montelukast. Treatment failure with both drugs finally suggested a Melkersson–Rosenthal syndrome, which was confirmed by histologic findings of non caseating granulomas on lip biopsy.
Melkersson–Rosenthal syndrome may occur with rather non-specific symptoms and overlap with alternative conditions, including recurrent angioedema. No specific biomarkers for MRS exist and clinical diagnosis is often of exclusion. The finding of complement or immune alterations, as in our patient, may be further confounding and justify the need for skin or mucosal biopsy to establish a correct diagnosis and prescribe targeted therapy.
KeywordsAngioedema Cheilitis granulomatosa C1-inhibitor Complement Melkersson–Rosenthal syndrome Miescher syndrome Lip edema
Miescher’s cheilitis granulomatosa
Melkersson–Rosenthal syndrome (MRS) is a rare, neuro-mucocutaneous disease of unknown etiology. Age at onset varies from early childhood to late adulthood and diagnosis is based mainly on clinical detection of a triad of symptoms, such as oro-facial swelling, relapsing facial palsy and fissured tongue [1, 2, 3, 4]. However, oligosymptomatic or monosymptomatic forms of this syndrome outnumber those with the classic triad, which is found in around one-fourth or less of patients [1, 2, 3]. Recurrent lip swelling, also termed Miescher’s syndrome or Miescher’s cheilitis granulomatosa (MCG), is the most common monosymptomatic presentation of MRS and histologic features include lymphomonocytic infiltration, non-caseating epithelioid cell granulomas, multinucleate Langerhans-type giant cells and fibrosis [2, 5].
Infectious conditions, including orofacial herpes, may precede the onset of MRS. Painless swelling, which is usually intermittent and fluctuant at the beginning, may become constant and the differential diagnosis of this sub-type of oro-facial granulomatosis includes angioedema (AE), contact dermatitis, Crohn’s disease, sarcoidosis, foreign body reaction and chronic, granulomatous infections. Diagnostic delay may be relevant, and in some cases histopathological examination of a lip biopsy is essential to diagnosis [1, 2, 3].
Melkersson–Rosenthal syndrome is a rare, neuro-mucocutaneous syndrome with an estimated incidence of 0.08% in the general population . Onset of this disease is more frequent in young adults, between the second and the third decades of life . The complete pattern of MRS, in which orofacial granulomatosis is accompanied by facial palsy and plicated tongue, may present in 8% to 25% of cases . Some authors found oligosymptomatic forms in 50%, while the combination of orofacial swelling and facial palsy was seen in 22% by Chan et al. . Elias et al., in a retrospective study found that facial edema was always present, with isolated lip involvement in 74% of cases and with only 13% of patients showing the full triad of symptoms of MRS . Recurrent lip swellings presenting as a monosymptomatic, clinical variant of MRS and with identical histological features, is also known as Miescher’s cheilitis granulomatosa [2, 5]. The differential diagnosis of MRS includes a broad spectrum of heterogeneous conditions, mainly represented by other granulomatous disorders such as foreign body reaction, sarcoidosis, Crohn’s disease, Wegener’s vasculitis, amyloidosis and a wide variety of infections; Bell’s palsy, orofacial herpes, rosacea, contact dermatitis and allergic reactions should also be considered [1, 3, 4, 5]. Furthermore, when facial or lip swelling is the monosymptomatic presentation of MRS, usually intermittent upon onset as in this case report, it can strongly mimic angioedema [5, 10].
Recurrence of edema with no apparent trigger, lack of efficacy of antihistamine prophylaxis and a previous history of non-Hodgkin lymphoma prompted us to investigate the possibility of AE due to C1-INH deficiency in our patient [6, 7, 8, 9, 10, 11]. Laboratory analyses did not confirm this hypothesis, nor treatment failure of both tranexamic acid and montelukast supported an alternative diagnosis of idiopathic AE [7, 8, 10, 13]. Thus, we pointed to Melkersson–Rosenthal syndrome and planned lip biopsy, which was performed on the mucosal side (Fig. 2) to avoid undesirable scarring and skin retraction.
Although MRS can be frequently diagnosed by clinical criteria with no need for further investigation [16, 17], the lack of specific biomarkers , the unusual age of onset in our patient, the positive anamnesis for lymphoproliferative disease, and the finding of complement consumption and autoimmune condition justified in this case an invasive approach. The histopathological examination, showing non caseating granulomas (Fig. 3), allowed to establish the correct diagnosis of MRS, probably triggered by a recent viral infection characterized by facial blistering, reassure the patient and prescribe targeted therapy. One month of oral steroid resulted in remission of lip swelling, that since then is treated by a few-days, on-demand regimen of prednisone when patient perceives a cosmetically disturbing relapse of edema.
It is well known, on the other hand, that there is no definitive therapy for MRS and recurrences are frequent [1, 5]. The proposed treatments include non-steroidal anti-inflammatory drugs, antihistamines, lymecycline and methotrexate, with systemic and/or intralesional corticosteroids usually considered as initial choices [4, 5]. Finally, a surgical approach has been suggested only for those patients with oro-facial swelling refractory to steroid therapy and/or who present a significant face deformation .
Melkersson–Rosenthal syndrome is a rare disorder which may present as a classic triad of orofacial swelling, facial palsy and fissured tongue or, more frequently, with oligo/mono-symptomatic features. Differential diagnosis with other granulomatous diseases and angioedema must be considered, as symptoms and signs usually overlap. In selected cases, such as in this case-report of unusual presentation and with evidence of complement and immune system activation, skin or mucosal biopsy may be crucial to diagnosis.
MC evaluated the patient on admission at ER and coordinated further diagnostic and therapeutic approaches; RS participated in clinical management; RB carried out laboratory testing; SS and SG ruled out alternative causes of oral diseases, performed lip biopsy and provided the photos; AA and MF processed and examined histologic sample, leading to final diagnosis. All authors (MC, SG, AA, MF, RB, RS, SS) participated in interpretation of data and drafting of the manuscript. All authors read and approved the final manuscript.
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The patient gave written informed consent for participation in this case report, which has been approved by the Ethical Commitee of the General Hospital-University of Padova (Italy).
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