Melkersson-rosenthal syndrome G51.2

Melkersson, 1928; Rosenthal, 1931

Chronic, systemic, granulomatous neurocutaneous (intestinal) inflammation with the classic triad of symptoms: cheilitis granulomatosa, facial nerve palsy, and lingua plicata. The full clinical picture of the syndrome is rare; variants with varying degrees of severity are more common. The clinical picture first described by E. Melkersson and C. Rosenthal is now increasingly classified under the broader term“orofacial granulomatosis” and is more generally defined as: “recurrent unilateral or bilateral orofacial swelling with cranial nerve dysfunction or palsy.” 

The incidence of Melkersson-Rosenthal syndrome (MRS) in adults is reported to be 1:1250 (Ziem et al. 2000). In children, the full-blown MRS is rare.

Unknown. Possible causes include:

• Constitutional abnormalities, hereditary or acquired disorders of the innate immune system, inflammatory reactions, and possibly infection-related allergic reactions to various antigens. 

• To date, no generally established causative genetic defect for Melkersson-Rosenthal syndrome (MRS) is known. Familial cases (Feng et al. 2014/Mansour M et al. 2019) suggest, in some instances, an autosomal dominant pattern of inheritance with variable expressivity. The following genetic variants are under discussion:    

  • SLC27A1 (FATP1): The heterozygous missense variant c.68C>G; p.Pro23Arg was described in a Chinese family. The gene encodes the fatty acid transporter FATP1. Functional studies revealed reduced protein levels and impaired uptake of long-chain fatty acids. This finding is considered a candidate finding, not a generally confirmed cause of MRS. No putatively pathogenic SLC27A1 variants were found in 14 other unrelated affected individuals (Pei Y et al. 2019).

  • Chromosomal region 9p11:A de novo translocation t(9;21)(p11;p11) was describedinone patient. This led to the hypothesis of a disease locus on 9p11. A responsible gene has not been identified. The occasional statement that “MRS is caused by identified mutations on 9p11” is therefore not a proven finding.

    SCN1A:An association has been postulated on several occasions (Azzarà A et al. 2023—see above).

The average age at first manifestation is 14.1 years (Feng et al 2014).

The fully developed syndrome is observed in only a minority of patients in larger cohorts. Mono- and oligosymptomatic cases are the norm (>80%); they are also frequently found as indicative initial manifestations.

A typical course of symptoms includes localized facial swelling, usually of the lips (initially recurrent, later persistent, usually unilateral), and facial nerve palsy. These changes are functionally and cosmetically distressing for the patient and, in some cases, painful.

• Localized facial swelling:
  • Granulomatous cheilitis (by far the most common partial manifestation of Melkersson-Rosenthal syndrome). 
  • Other manifestations include localized swelling ofthe cheeks, eyelids, forehead, palate, gums, tongue(see also macroprosopitis), buttocks, and anogenital region (see below Granulomatous lymphangitis of the scrotum and penis)
• Facial nerve palsy (in 19.4% of cases): Usually unilateral, bilateral in 25% of cases, always of the peripheral type.
• Lingua plicata in 54% of cases (13% in the general population). Classification as a cardinal symptom has been abandoned in recent years; it now serves only as an indicator. Note: May occur in combination with exfoliatio areata linguae.

• Associations with monogenic migraine (familial hemiplegic migraine/FHM/Azzarà A et al. 2023) and MRS have been described. Noteworthy is the finding in an affected family in which one sister presented with recurrent facial paralysis associated with symptoms of Melkersson-Rosenthal syndrome. A c.3521C>G missense heterozygous variant in the SCN1A gene was identified. Variants in the SCN1A gene can cause not only familial hemiplegic migraine (FHM) but also a whole spectrum of early-onset epileptic encephalopathies. The mutation in the SCN1A gene may indicate an overlap between MRS and FHM (Azzarà A et al. 2023). 

• Minor symptoms: Due to their frequent and consistent occurrence, they play an important role in diagnosis. The following are found in descending order of frequency:
  • Crohn’s disease (6.8%) and ulcerative colitis: An evaluation of long-term outcomes (median follow-up time from symptom onset was 30 years!) in patients with Melkersson-Rosenthal syndrome revealed the following regarding inflammatory bowel disease (IBD) (Haaramo A et al. 2019): 11.1% of patients developed IBD during this period; one patient with granulomatous cheilitis developed Crohn’s disease, and two patients with fully developed Melkersson-Rosenthal syndrome developed ulcerative colitis. Other patients reported unspecified gastrointestinal symptoms (calprotectin in stool: n/a)
  • Migraine-like headaches (5.7%—Hazey MA et al. 2009)
  • Paresthesias in the swollen area
  • Disorders of tear secretion
  • Redness
  • Itching
  • Nausea/vomiting
  • Secretory disorders of the salivary glands or nasal mucosa
  • Dizziness
  • Tingling
  • Facial sweating
  • Acroparesthesia
  • Feeling of heat
  • Lump in the throat
  • Auditory sensations.
  • Systemic lupus erythematosus (2.3%)

Erysipelas recidivans: Characteristic history with the early erysipelas tetrad (fever, redness, painful swelling, acute lymphadenopathy). Laboratory: signs of inflammation.

Herpes simplex recidivans: Typical interval-like course with signs of evident herpes simplex on the skin.

Furuncle of the upper lip: Acute course with circumscribed dolent swelling. The tip of the abscess is often purulent.

Macrocheilia of other cause: No variable course. Mostly evident underlying diseases such as exfoliative cheilitides etc.

Facial paresis of other cause: not combined with other partial symptoms of Melkersson-Rosenthal syndrome.

The treatment is difficult and often unsuccessful.

The use of glucocorticoids intralesionally usually shows only temporary success and can be useful at the beginning of a relapse. This is done by intradermal injection of triamcinolone acetonide crystal suspension (e.g. Volon A diluted 1:1 with local anesthetics such as scandicain) once a month.

To date, there are no approved therapies for this disease. Unfortunately, there is a lack of reliable study results due to the rarity of the disease.

• Improvements can be achieved with clofazimine (e.g. Lamprene). Early use in particular improves the chances of success, initially 100 mg/day p.o. for 10 days, then alternating 100 mg 3-4 times/week for 6 months, repeated after a 3-month break if necessary. If unsuccessful, dosage can be doubled.
• Alternative (better therapeutic modality): Fumaric acid ester (e.g. Fumaderm®) in the usual dosage. There are own personal experiences about this therapy approach as well as some published casuistics (G. Hauck 2017). Remark: This therapy has to be planned over a period of >12 months!
• Alternative: Permanent intake of non-steroidal anti-inflammatory drugs like ibuprofen (e.g. Ibuprofen Heumann 400-800 mg/day).
• Alternative: Systemic glucocorticoids are often recommended, but in our experience show only moderate success. Prednisolone (e.g. Decortin H) initially 40-60 mg/day p.o. for 2-4 weeks, followed by slow dose reduction.
• Alternative: Omalizumab (Nettis E et al. 2018).
• Other procedures: Multiple therapeutic modalities with chloroquine, diuretics, DADPS, acetylsalicylic acid, nicotinic acid amide, and others have been described with equivocal success.

In the stage of persistent swellings, the operative reduction of the lip (lip reduction plastic surgery) is often the only possibility to achieve a permanent improvement.

Thrustworthy, chronic, years-long, possibly life-long course. Quoad vitam good, quoad sanationem bad. Spontaneous remission possible.

1. Azzarà A et al. (2023) Melkersson-Rosenthal Syndrome and Migraine: A New Phenotype Associated with SCN1A Variants? Genes (Basel) 14:1482.
2. Elias MK et al. (2013) Melkersson-Rosenthal syndrome: a retrospective study of cases with biopsy. J Neurol 260:138–143
3. Feng S et al. (2014) Melkersson-Rosenthal syndrome: a retrospective study of 44 patients. Acta Otolaryngol 134:977–981
4. Galdiero MR et al. (2021) Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature. Allergy 76:2189–2200.
5. Haaramo A et al. (2019) A 30-year follow-up study of patients with Melkersson-Rosenthal syndrome shows an association with inflammatory bowel disease. Ann Med 51:149–155.
6. Hazey MA et al. (2009) Melkersson-Rosenthal syndrome with migraine-like headaches treated with minocycline: a case report and review of the literature. W V Med J 105:15–17
7. Hauck G (2017) Fumaric acid ester therapy for Melkersson-Rosenthal syndrome. Akt Dermatol 43: 459–460
8. Hornstein OP et al. (1987) Classification and clinical variability of Melkersson-Rosenthal syndrome (MRS). Z Hautkr 62: 1453–1475
9. Lüscher E (1949) Melkersson-Rosenthal syndrome. Schweiz Med Wochenschr 79: 1-3
10. Mansour M et al. (2019) Melkersson-Rosenthal syndrome: A report on a Tunisian family and a review of the literature. Clin Neurol Neurosurg 185:105457.
11. Melkersson E (1928) A case of recurrent facial paralysis associated with angioneurotic edema. *Hygiea*, Stockholm 90: 737–741
12. Miescher G (1956) Granulomatous cheilitis and paresis without facial nerve palsy in the presence of a lingua scrotalis. *Dermatologica* 112: 536
13. Neuhofer J, Fritsch P (1984) Cheilitis granulomatosa (Melkersson-Rosenthal syndrome): Treatment with clofazimine. Hautarzt 35: 459–463
14. Nettis E et al. (2018) A favorable response to omalizumab in a patient with granulomatous cheilitis. J Allergy Clin Immunol Pract 6:1425-1426.
15. Pei Y et al. (2019) Clinical and genetic heterogeneity in Melkersson-Rosenthal syndrome. Eur J Med Genet 62:103536.
16. Rosenthal C (1931) A clinical and hereditary-biological contribution to constitutional pathology. Co-occurrence of recurrent familial facial paralysis, angioneurotic facial edema, and lingua plicata in families with arthritis. Z Gesamte Neurol Psychiat 131: 475–501
17. Stosiek N et al. (1991) Melkersson-Rosenthal syndrome—course analysis of 73 patients (1968–1990). Z Hautkr 66: 18–24
18. Sussman GL et al. (1992) Melkersson-Rosenthal syndrome: clinical, pathologic, and therapeutic considerations. Ann Allergy 69: 187–194
19. Tausch I et al. (1992) Experience with clofazimine therapy for Melkersson-Rosenthal syndrome. Hautarzt 43: 194–198
20. Shapiro M et al. (2003) Melkersson-Rosenthal syndrome in the periocular area: a review of the literature and case report. Ann Plast Surg 50: 644–648
21. van De Scheur MR et al. (2003) Orofacial granulomatosis in a patient with Crohn’s disease. J Am Acad Dermatol 49: 952–954
22. van der Waal RI et al. (2001) Cheilitis granulomatosa. J Eur Acad Dermatol Venereol. 15: 519–523
23. Volz A et al. (2010) Surgical lip reduction in treatment-resistant cheilitis granulomatosa. JDDG 8: 303–305
24. Ziem PE et al. (2000) Melkersson-Rosenthal syndrome in childhood: a challenge in differential diagnosis and treatment. Br J Dermatol 143: 860–863
25. Zimmer WM et al. (1992) Orofacial manifestations of Melkersson-Rosenthal syndrome. A study of 42 patients and a review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 74: 610-619