Melkersson-rosenthal syndrome G51.2

Chronic, systemic, granulomatous inflammation with the classic symptom triad: Cheilitis granulomatosa, facial paresis, lingua plicata. The full picture of the syndrome is rare, more frequent are differently pronounced minus variants. That of E. Melkersson and C. Rosenthal is now increasingly referred to under the broader term"orofacial granulomatosis" and more generally defined as "recurrent uni- or bilateral orofacial swelling with cranial nerve dysfunction or paresis".

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. Discussed are:

• Constitutional anomaly, hereditary or acquired disorder of the autonomic defense system, inflammatory, possibly infectious-allergic reactions to various antigens.
• A familial occurrence is reported in around 30% of patients (Feng et al. 2014/Mansour M et al. 2019). An autosomal dominant inheritance is being discussed. It is possible that the responsible gene is located on chromosome 9p11.

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

The fully developed syndrome is only observed in a minority of patients in larger collectives. Monosymptomatic and oligosymptomatic cases are the rule (>80%); they are also mainly found as indicative initial manifestations.

Typical is a variable course of symptoms with circumscribed facial swelling, mostly lip swelling (initially recurrent, later persistent, usually unilateral) and facial nerve palsy. The changes are functionally and cosmetically disturbing for the patient, and sometimes painful.

• Circumscribed facial swelling:
  • Cheilitis granulomatosa (by far the most common partial manifestation of Melkersson-Rosenthal syndrome).
  • Other partial manifestations described include circumscribed swelling of the cheeks, eyelids, forehead, palate, gingiva, 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): Mostly unilateral, in 25% of cases bilateral, always of the peripheral type.
• Lingua plicata in 54% of cases (normal population 13%). Assignment to the cardinal symptoms has been abandoned in recent years and now only has an indicator function. Note: May occur in co-occurrence with exfoliatio areata linguae.

• Associations with monogenic migraine (familial hemiplegic migraine/FHM/Azzarà A et al. 2023) and MRS have been described. Of note is the finding in one affected family, one sister of whom had recurrent facial paralysis with associated symptoms of Melkersson-Rosenthal syndrome. A c.3521C>G missense heterozygous variant in the SCN1A gene was identified. In addition to familial hemiplegic migraine (FHM), variants in the SCN1A gene can cause a whole spectrum of early-onset epileptic encephalopathies. It is possible that the mutation in the SCN1A gene indicates an overlap between MRS and FHM (Azzarà A et al. 2023).

• Minorsymptoms: Due to their frequent and constant occurrence, they play an important role in diagnostics. They are found with decreasing frequency:
  • Crohn's disease (6.8%)
  • Migraine headaches (5.7% -Hazey MA et al. 2009)
  • Paresthesias in the swelling area
  • Disorders of tear secretion
  • redness
  • itching
  • Nausea/nausea
  • Secretion disorders of the salivary glands or nasal mucosa
  • dizziness
  • Tingling
  • Facial sweating
  • Acroparesthesia
  • Feeling of heat
  • globus sensation in the throat
  • acoustic 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.

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.

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

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