Melkersson Rosenthal Syndrome: Symptoms, Types, Causes and Treatment

Melkersson-Rosenthal Syndrome (MRS) is a rare, chronic neuro-mucocutaneous disorder that often poses significant challenges in diagnosis and management. Its presentation is highly variable, and many patients may never develop the full spectrum of classic symptoms, making awareness and understanding of this condition essential for both patients and clinicians. This article explores the key symptoms, subtypes, causes, and current treatment approaches for MRS, with a focus on evidence-based insights from clinical research.

Symptoms of Melkersson Rosenthal Syndrome

Melkersson-Rosenthal Syndrome is best known for its "classic triad" of symptoms. However, most patients do not exhibit all three features at once, and many present with just one or two. Early recognition and understanding of the diverse ways MRS can manifest are crucial for timely diagnosis and effective care.

Symptom	Description	Frequency	Source(s)
Orofacial Edema	Swelling of lips and/or face	Most common (all cases in some series)	1 3 7 8 14
Facial Paralysis	Recurrent, usually unilateral facial palsy	~19–47%	1 3 5 8 9
Fissured Tongue	Grooved or plicated appearance	~47–50%	1 3 5 8
Other Sites	Edema/Granulomas in eyelids, palate, gingiva	Rare	6 8 15

Table 1: Key Symptoms of Melkersson-Rosenthal Syndrome

The Classic Triad

The hallmark symptoms of MRS are:

• Orofacial Edema: This is the most frequent and often the initial sign. Swelling most commonly affects the lips (cheilitis granulomatosa), but may extend to the cheeks, eyelids, or other facial areas. The swelling is typically non-pitting and can be recurrent or persistent 1 3 7 8 14.
• Facial Nerve Palsy: Usually presents as a sudden, recurrent weakness of one side of the face (lower motor neuron palsy). Episodes may be mistaken for Bell’s palsy, but recurrences and coexistence with swelling should raise suspicion for MRS 1 3 5 8 9.
• Fissured (Plicated) Tongue (Lingua Plicata): Characterized by grooves or furrows on the dorsal surface of the tongue. This sign is less likely to cause symptoms but is an important diagnostic clue, present in about half of patients 1 3 8.

Oligosymptomatic and Monosymptomatic Forms

Most patients do not develop all three features at once. Many have only one or two symptoms, which can make diagnosis challenging:

• Cheilitis Granulomatosa (Miescher’s cheilitis): Chronic lip swelling without other features is considered a monosymptomatic form 7 8.
• Atypical Presentations: In rare cases, swelling or granulomatous inflammation may affect the eyelids (blepharitis), palate (palatitis), or gums (gingivitis) 6 8 15.

Progression and Course

• Chronic and Progressive: The disease tends to be chronic, with periods of exacerbation and remission. Symptoms may persist for years; the median time to diagnosis can be several years after onset 3 14.
• Pediatric Cases: Children can be affected, though MRS is rare in this group. In pediatric patients, the triad may develop over time, and recurrent edema or facial palsy should prompt consideration of the syndrome 2 9 12.

Types of Melkersson Rosenthal Syndrome

Understanding the spectrum of MRS is vital, as the condition can range from full-blown classical triad to isolated symptoms. Recent literature has also suggested clinical classifications based on the predominant site of involvement.

Type/Pattern	Key Features	Prevalence	Source(s)
Classical	Triad: Edema, facial palsy, fissured tongue	~13–25%	1 3 5 8
Oligosymptomatic	Any two of the triad	~25–50%+	1 3 8
Monosymptomatic	Isolated symptom (usually lip swelling)	Most common	7 8 14
Perioral-type	Lesions confined to lips/face	Typical	6
Periocular-type	Lesions confined to eyelids/orbital fat	Rare	6 15

Table 2: Clinical Types of Melkersson-Rosenthal Syndrome

Classical and Incomplete Forms

• Classical (Complete Triad): Only a minority of patients—between 10% and 25%—develop all three classic features at some point in their disease course. The triad may not appear simultaneously and can evolve over years 1 3 8.
• Oligosymptomatic: Far more common are patients with just two components, such as lip swelling and facial palsy, or facial swelling and fissured tongue 1 3 8.

Monosymptomatic Forms

• Miescher’s Cheilitis Granulomatosa: Persistent lip swelling alone is the most frequent monosymptomatic form and may remain the only manifestation for years or indefinitely 7 8 14.
• Other Isolated Manifestations: Rarely, isolated fissured tongue or recurrent facial nerve palsy may be the sole presenting symptom 1 3 8.

Site-Based Clinical Types

• Perioral (Type 1): Classic, affecting lips and adjacent perioral tissues 6.
• Periocular (Type 2): Swelling and granulomatous involvement of eyelids or orbital fat. This is rare and may lead to fibrosis if untreated 6 15.

Rare and Overlapping Variants

• Other Mucosal Sites: Granulomatous inflammation may rarely involve the gingiva (gingivitis), palate (palatitis), or even the eyelids (blepharitis) 8 15.
• Association with Systemic Disease: Overlap with conditions like Crohn’s disease or sarcoidosis has been reported, and comorbidities may impact presentation 3 8 11.

Causes of Melkersson Rosenthal Syndrome

Despite decades of research, the exact cause of Melkersson-Rosenthal Syndrome remains elusive. A combination of genetic, immunological, and possibly environmental factors is thought to play a role.

Factor	Description	Evidence/Notes	Source(s)
Genetics	HLA associations, familial clustering	Predisposing and protective alleles found	9 11
Immune Dysregulation	Granulomatous inflammation, noncaseating granulomas	Biopsy findings, immune alterations	3 7 10 14
Infections	HSV, COVID-19, other triggers	Case reports, associations	4 10 12
Allergic/Atopic	Hypersensitivity to food additives, atopy	Some associations	7 3
Unknown/Idiopathic	No trigger identified in most cases	Diagnosis of exclusion	1 3 10

Table 3: Suspected Causes and Risk Factors for MRS

Genetic Predisposition

• HLA Associations: Studies have found increased frequency of certain HLA alleles (such as HLA A02, DRB111, DQB1*03) in patients, suggesting a genetic susceptibility. Other alleles appear protective 11.
• Familial Tendency: Rare familial cases support a genetic component, though most cases are sporadic 9 11.

Immune System and Granulomatous Inflammation

• Biopsy Findings: The presence of noncaseating granulomas in affected tissues (especially lips) is a diagnostic hallmark. These lesions resemble those seen in other granulomatous diseases, implicating immune system dysregulation 3 7 10 14.
• Autoimmunity/Altered Immunity: Some patients have altered complement levels or associated autoimmune conditions, though no single immune marker is diagnostic 10.

Infectious and Environmental Triggers

• Infectious Agents: Viral infections (notably HSV and, in rare cases, COVID-19) have been implicated as possible triggers for onset or exacerbation 4 10 12.
• Allergy/Atopy: Hypersensitivity reactions to foods or additives and personal/family history of atopic disease are more common in some series, suggesting an environmental component 7 3.

Idiopathic and Multifactorial Nature

• Diagnosis of Exclusion: In most patients, no clear cause is identified. MRS is often diagnosed after ruling out other causes of facial swelling and nerve palsy (e.g., angioedema, sarcoidosis, neoplasm) 1 3 10.
• Potential Triggers: Trauma, dental procedures, and stress have been reported as potential precipitating factors in isolated cases, but evidence is limited 3 10.

Treatment of Melkersson Rosenthal Syndrome

Treatment of MRS is challenging, as no single therapy is universally effective or curative. Management requires a tailored, multidisciplinary approach, focusing on symptom control and prevention of complications.

Therapy Type	Examples/Approach	Efficacy/Notes	Source(s)
Corticosteroids	Oral, intralesional, topical	Most common, variable response	3 5 7 8 12 15 16
Immunosuppressives	Thalidomide, dapsone, methotrexate, azathioprine	Used for resistant cases	3 8 14
Antibiotics	Tetracyclines, minocycline, metronidazole	Anti-inflammatory effects	3 7 8 16
Clofazimine	Anti-inflammatory, granuloma clearance	Effective in some cases	13 14
Surgery	Cheiloplasty, excision for chronic edema	For persistent, deforming lesions	15 16
Symptomatic	NSAIDs, acyclovir, antihistamines	Supportive, limited effect	3 10 12
Multidisciplinary	Neurologist, dermatologist, ENT, dentist	Essential for management	5 9 12

Table 4: Treatment Modalities for Melkersson-Rosenthal Syndrome

Medical Therapy

• Corticosteroids: These are the mainstay for acute edema and facial palsy. They can be administered orally, intralesionally, or topically. Responses are variable; some patients achieve remission, while others relapse after cessation 3 5 7 8 12 15 16.
• Immunosuppressive Agents: Thalidomide, dapsone, methotrexate, and azathioprine have been used for refractory or chronic cases, with mixed results. Careful monitoring for side effects is necessary 3 8 14.
• Antibiotics with Anti-inflammatory Action: Tetracyclines (e.g., minocycline, doxycycline) and metronidazole may reduce inflammation and granuloma formation 3 7 8 16.
• Clofazimine: This anti-inflammatory agent can induce clearance of granulomas and reduce swelling in moderate cases, with some reports of complete remission 13 14.

Surgical and Supportive Management

• Surgical Interventions: Reserved for persistent, disfiguring lip or eyelid edema unresponsive to medical therapy. Procedures include cheiloplasty or excision and reconstruction, often with good outcomes 15 16.
• Other Symptomatic Treatments: NSAIDs, antihistamines, antivirals (e.g., acyclovir) may be tried, especially if an infectious or allergic trigger is suspected, but are usually of limited benefit 3 10 12.

Multidisciplinary and Individualized Care

• Team Approach: Management should involve neurologists, dermatologists, otolaryngologists, dentists, and—particularly in children—pediatric specialists. This strategy optimizes symptom control and minimizes long-term sequelae 5 9 12.
• Monitoring and Recurrence: Relapses are common, and long-term follow-up is recommended. Individualized plans are essential due to the unpredictable nature of the disease 3 5 9.

Conclusion

Melkersson-Rosenthal Syndrome is a rare, complex disorder with highly variable manifestations and no single cause or cure. Awareness of its diverse symptoms, forms, and potential triggers is essential for timely diagnosis and effective, patient-centered management.

Key points:

• MRS typically presents with orofacial edema, recurrent facial palsy, and fissured tongue, but most patients have only one or two features.
• The syndrome includes classical, oligosymptomatic, and monosymptomatic forms, and can rarely involve atypical sites like the eyelids or gums.
• Causes remain unclear, but genetic predisposition, immune dysregulation, infections, and environmental triggers are implicated.
• Treatment is individualized and includes corticosteroids, immunosuppressive drugs, anti-inflammatory antibiotics, and, for persistent cases, surgery.
• A multidisciplinary approach is crucial to reduce relapses and prevent complications.

Awareness and early intervention can significantly improve quality of life for individuals affected by Melkersson-Rosenthal Syndrome.