Melkersson-Rosenthal syndrome in an allergic patient successfully treated with fresh frozen plasma

ABSTRACT

Melkersson-Rosenthal syndrome (MRS) is a rare and often challenging condition of unknown etiology, typically defined by a clinical triad of peripheral facial nerve palsy, recurrent orofacial edema, and fissured tongue. Its variable presentation and overlap with allergic reactions, mast cell-mediated disorders, and drug hypersensitivity reactions can delay diagnosis and appropriate management. We report the case of a 43-year-old man with a personal long-standing history of recurrent hemifacial and lip swelling associated with facial nerve palsy and a plicated tongue, fulfilling the complete clinical triad of MRS. Extensive laboratory, immunological, infectious, and allergological investigations ruled out alternative diagnoses, including hereditary angioedema and drug hypersensitivity. Histopathological examination of a lip biopsy did not reveal granulomatous inflammation. The disease was refractory to multiple standard therapies, including antihistamines, corticosteroids, epinephrine, antibiotics, and immunomodulatory agents. Administration of fresh frozen plasma at a dose of 10 ml/kg resulted in a rapid and marked clinical improvement within 6 hours. This case highlights a rare complete presentation of MRS and underscores the challenges in diagnosis and management. The favorable response to fresh frozen plasma suggests a potential therapeutic option in refractory cases; however, further studies are required to clarify its role and mechanism of action in Melkersson-Rosenthal syndrome.

INTRODUCTION

Melkersson-Rosenthal syndrome (MRS) is a rare and diagnostically challenging disorder of unknown etiology. It is predominantly a clinical diagnosis based on the presence of a characteristic triad of facial nerve palsy, recurrent or persistent orofacial edema, and fissured (plicated) tongue. These symptoms may occur either synchronously or metachronously.

Clinical diagnostic patterns are: the complete form with the presence of all three components of the triad, the oligosymptomatic form with two of the features and the monosymptomatic form usually with recurrent or persistent lip or facial edema which is clinically identical to orofacial granulomatosis [1,2]. Because the complete triad occurs in only 8-25% of cases, most diagnoses rely on partial clinical presentations.

Histopathological findings play a supportive but non-mandatory role in diagnosis. Lip biopsy may show non-caseating granulomas, perivascular lymphocytic infiltration, edema and fibrosis. The last two clinical patterns need the evidence of granulomatous cheilitis on biopsy to support the diagnosis.

Given the limited therapy options for MRS and the frequent occurrence of treatment-refractory cases, reporting novel therapeutic approaches is of particular importance. In this context, the rapid response observed following fresh frozen plasma (FFP) administration in our case, highlights a potential new treatment avenue and suggests the involvement of alternative pathophysiological mechanisms warranting further investigation.

CASE PRESENTATION

We describe the case of a 43-year-old male whose symptoms began approximately 30 years prior (around age 14) with peripheral facial paralysis, representing the first manifestation of MRS. Subsequently, he developed recurrent episodes of lip and right hemifacial edema, occurring 2-3 times per week, each lasting 48-72 hours, without urticaria. Over time, these episodes persisted and progressively worsened. After approximately 23 years of recurrent episodes, the edema evolved into permanent angioedema (Figure 1) with intermittent exacerbations, some occurring spontaneously and at least one temporally associated with amoxicillin-clavulanic acid administration for a respiratory infection. During the disease course, the patient was also noted to have a plicated (fissured) tongue, completing the full clinical triad of MRS. He did not develop angioedema involving the extremities, trunk, airways, or abdominal organs. Past medical history included mild persistent allergic rhinitis sensitized to dust mites and Blattella germanica, autoimmune thyroiditis, hepatomegaly with serous cysts, and left C2 costal arch ecchondroma. He had never received angiotensin converting enzyme (ACE) inhibitor treatment. The patient's family history is negative for MRS symptoms.

Fig. 1.

Persistent facial angioedema before treatment.

Laboratory investigations showed elevated thyroid peroxidase antibodies and the ACE level was 23.08 U/L (near the lower limit of the 20-70 U/L range).

Extensive diagnostic workup excluded other causes, including hereditary angioedema (HAE) (two assays of C1 esterase inhibitor protein levels and functional activity, and C4 complement during an angioedema attack, C1q, and total hemolytic complement were normal), other autoimmune diseases (including anti-double-stranded DNA, cytoplasmic antineutrophil cytoplasmic, perinuclear anti-neutrophil cytoplasmic, anti-transglutaminase antibodies), infections (including Human immunodeficiency virus, Cytomegalovirus, Epstein–Barr virus, Toxoplasma spp., Herpes simplex virus types 1 and 2, hepatitis B and C viruses, bacteriological examination of pharyngeal swabs and nasal secretions, and Helicobacter pylori), sarcoidosis, and malignancy, while allergy testing identified sensitization to mites and Blattella germanica (German cockroach). Furthermore, skin prick and intradermal testing were performed, followed by an oral graded challenge test with amoxicillin-clavulanic acid, given the temporal association between antibiotic administration and the exacerbation of angioedema; all tests were negative.

A lip biopsy performed during an acute episode of edema revealed no granulomas, showing instead nonspecific changes like ectatic vessels, edema, and focal fibrosis.

Over the years, the disease proved refractory to multiple treatments, including antihistamines, corticosteroids, epinephrine, antibiotics, vitamins, hydroxychloroquine, and clofazimine.

Finally, considering potential immunological mechanisms, administration of FFP resulted in a rapid and marked clinical improvement within 6 hours (Figure 2), representing a significant therapeutic breakthrough in this case. Since 2023, the patient has been receiving maintenance therapy with FFP at a dose of 10 ml/kg every 6 to 8 weeks upon the recurrence of edema, with a favorable clinical course.

Fig. 2.

Rapid resolution of the facial angioedema after first FFP infusion.

DISCUSSION

MRS remains a rare and heterogeneous disorder, although it was first mentioned by Melkersson in 1928 and Rosenthal in 1930 [3]. Its etiopathogenesis is unclear, but a genetic predisposition has been postulated, with links to HLA A*02 and DRB1 alleles [4]. FATP1 (fatty acid transport protein 1) mutations have been identified within familial clusters suggesting a hereditary component [5]. Furthermore, MRS has been documented in association with alterations in immune functions such as osteoarthritis [6] or Hashimoto thyroiditis [7] and infections like Mycobacterium tuberculosis [8], and Mycolicibacterium fortuitum [9]. It may also be related to other systemic diseases such as allergic reactions and coeliac disease [10]. Cases with a herpes infection associated with facial edema and with vesicular lesions but polymerase chain reaction negative for the genomic sequences of herpes simplex virus [11] have been described. The correlation between MRS and sarcoidosis was also presented in some cases [12] and a case with a high level of serum angiotensin converting enzyme has been published.

The epidemiology of MRS remains poorly defined. Reported incidence rates vary widely, ranging from approximately 0.2 to 80 cases per 100,000 individuals [13]. This broad variability reflects differences in diagnostic criteria, inclusion of incomplete clinical forms, and the absence of standardized epidemiological studies. Estimates expressed as percentages in some reports are inconsistent and likely reflect methodological limitations rather than true population- based prevalence. Therefore, the true burden of MRS is likely underestimated, particularly because incomplete and oligosymptomatic forms predominate and frequently remain unrecognized.

Our case is notable because, although rare in children [14], he had an adolescent onset and the presence of the complete triad, even though it is uncommon, supports the clinical diagnosis despite the absence of granulomas on biopsy. Histopathological findings, such as non-caseating granulomas, are supportive but not mandatory, as they may be absent in a significant proportion of cases. Consequently, a negative biopsy does not exclude the diagnosis, particularly when typical clinical features are present. Sensitivity of the lip biopsy depends on both site selection and timing because histopathological findings may be missed if sampling is not performed during an acute episode. In some cases, only lymphocytic inflammation around the blood vessels may be present, and frank granulomas may be absent. A defining feature of this case is the long-standing, recurrent angioedema refractory to conventional therapies including antihistamines [15], immunomodulators [1,17,17], corticosteroids [18,19], epinephrine, and antibiotics [20]. This therapeutic resistance raises important questions regarding the underlying pathophysiological mechanism of the edema, particularly whether it may extend beyond classical histamine-mediated or granulomatous inflammatory processes.

The rapid clinical response to FFP in our patient suggests a mechanism involving circulating plasma factors, rather than purely local inflammatory pathways. FFP is not part of the standard MRS management; however, it is an established therapeutic option in bradykinin- mediated angioedema, particularly in hereditary angioedema, acquired C1-inhibitor deficiency and ACE inhibitor-induced angioedema. In these conditions, FFP provides functional C1 esterase inhibitor (C1-INH) and other regulatory proteins that help suppress excessive bradykinin production, thereby reducing vascular permeability and edema.

Although our patient had normal C1-INH levels and other complement tests, effectively excluding classical HAE, several aspects of the clinical presentation raise the possibility of a bradykinin-related or bradykinin-like mechanism including recurrent angioedema with prolonged duration of the episodes (48-72 hours), but without urticaria, lack of response to antihistamines, corticosteroids, and epinephrine and absence of clear trigger in many attacks. These features are more typical of non-histaminergic angioedema, in which bradykinin plays a central role. The efficacy of FFP in this case may therefore reflect: replacement of regulatory proteins involved in the kallikrein- kinin system, modulation of vascular permeability pathways independent of mast cell activation, and correction of a functional or acquired imbalance in protease inhibitors, not detectable by routine complement.

We hypothesize that, in this patient, the disease may involve a functional deficiency or dysregulation of circulating inhibitors, leading to episodic increases in vasoactive mediators such as bradykinin. This could explain the refractoriness to conventional antihistaminic treatments, the rapid response to FFP administration, and the absence of granulomatous inflammation on biopsy. This case expands the therapeutic perspective in MRS, FFP can be considered a rescue therapy, especially when standard treatments fail.

CONCLUSIONS

Melkersson-Rosenthal syndrome with the complete clinical triad remains an uncommon and diagnostically challenging entity. In our case, the most notable observation was rapid clinical improvement following administration of FFP in a patient with longstanding, treatment-refractory disease. The underlying mechanism remains uncertain, and the observed effect may reflect a complex and not yet fully understood interaction between plasma factors and the pathophysiology of the disease. Although parallels can be drawn with the established use of FFP in certain forms of bradykinin-mediated angioedema, it is not possible, based on a single case, to establish a definitive mechanism link or therapeutic indication. Therefore, this report should be considered hypothesis-generating rather than confirmatory. Further research is needed to clarify the role of bradykinin in MRS-associated edema, and to evaluate the efficacy and safety of FFP in larger case series.

Conflict of interest

The authors declare that they have no competing interests.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Ethical approval statement

This study has been approved by the Ethical Committee of the Sf. Spiridon Univeristy Hospital, Iasi (Romania).

Financial support

This research was funded by The Health Programme (PS) 2021- 2017, Policy Objective 4, Priority 3, Project title: ”Support for Enhancing Performance and Innovation in Excellent Medical Doctoral Research”, acronym INNODOC-MED, SMIS code 351058.