Muckle-wells syndrome Q84.89

Muckle and Wells, 1962

Very rare, hereditary, autoinflammatory disorder characterized by:

Recurrent urticarial exanthema, febrile episodes with joint and muscle pain, generalized weakness, progressive sensorineural hearing loss, and facultative renal amyloidosis (AA amyloidosis).

Hereditary disease with autosomal dominant inheritance (mutation inherited with incomplete penetrance of the CIAS1 gene (cold-induced autoinflammatory syndrome 1 gene, NLRP3 gene) located on chromosomal region 1q44. The gene is expressed in peripheral blood leukocytes and encodes cryopyrin. It has the same N-terminal protein domain as pyrin, alterations in which are the cause of Familial Mediterranean Fever.

Mutations in the NALP3/CIAS1/PYPAF1 genes are responsible for 2 other clinical syndromes:

• Familial cold urticaria (FCAS)
• and
• Chronic infantile neuro-dermo-articular syndrome also called CINCA syndrome.

Clinical symptoms are:

• Chronic recurrent urticarial exanthema (rarely: urticarial vasculitis).
• Sensitivity to cold, especially in cold and humid weather and weather changes
• Fever episodes with joint and muscle pain (polyarthralgias) since childhood
• General feeling of weakness and malaise
• Optional: progressive sensorineural hearing loss
• Optional: systemic amyloidosis

Cold urticaria: clear association with exposure to cold.

Hereditary periodic fever syndromes of other genesis (see there).

Chronic recurrent urticaria: no arthritides, no amyloidosis, no vasculitic phenomena

Secondary systemic amyloidosis: no actual differential diagnosis, as systemic concomitant phenomenon in numerous diseases

Alport syndrome: genetically defined; variants in genes encoding collagen type IV. Six genes (COL4A1-COL4A6), corresponding to the six homologous collagen chains (α1-α6) for collagen type IV, are known. The mutations lead to progressive glomerular basement membrane disease. This is combined with sensorineural hearing loss and ocular changes

Schnitzler syndrome: chronic recurrent urticarial exanthema (urticarial vasculitis) associated with recurrent fevers, fatigue, bone pain, arthralgia or arthritides of the large joints, lymphadenopathy, hepato- or splenomegaly, and monoclonal IgM gammopathy (less commonly IgG gammopathy) of uncertain significance ( MGUS). Less commonly, there is concomitant angioedema and bone thickening.

Versch. Studies show good experience with the interleukin-1 receptor antagonist anakinra (100 mg/day s.c. every 2 days), which is approved for rheumatoid arthritis.

Alternative: Immunosuppressive therapy to prevent further amyloid deposition.

Alternative: Cyclophosphamide (e.g. Endoxan) 100 mg/day in combination with methylprednisolone (e.g. Urbason) 40 mg/day (reduction according to clinic),

Alternative: DADPS (e.g., dapsone fatol) initial 100 mg/day.

Alternative: Colchicine (e.g. Colchicum dispert).

History: Already since pre-school age the patient, who is now 45 years old, suffers from recurrent exanthema of the trunk and the lower extremities. Under NSAR she has a slight improvement. More significant clinical effects could be achieved with medium prednisolone doses.

First acute hearing loss at the age of 20. Recurrent arthritis mostly associated with fever, headache and urticarial exanthema. The relapse activity starts 3-4 times a year.

At the age of 30 years high frequency hearing loss was detected.

For 10 years the patient has been taking ibuprofen regularly, almost daily.

Reason for visitation: fever, fatigue and feeling ill, acute painful swelling of the left ankle joint, also of the base joints of the fingers. Simultaneous urticarial exanthema of the trunk and extremities with small spots. Face free.

Laboratory: BSG: 60/111, CRP 65mg/l, neutrophil leukocytosis, lymphopenia, erythrocyturia, discrete serum amyloid A elevation. Discrete ANA, ENA, C3,C4, RF. c-ANCA. p-ANCA.

Human genetic diagnosis: Detection of a mutation of the CIAS1 gene (cold-induced autoinflammatory syndrome 1 gene) located on chromosome region 1q44.

Therapy: IL-1 receptor antagonist (anakinra) at a dose of 100mg/day s.c.

1. Berthelot JM et al (1994) Autosomal dominant muckle-wells syndrome associated with cystinuria, ichthyosis, and aphthosis in a four-generation familiy. Am J Med Gen 53: 72-74
2. Black AK (2001) Unusual urticarias. J Dermatol 28: 632-634.
3. Gerbig AW et al (2001) Muckle-Wells syndrome? J Am Acad Dermatol 44: 875-876.
4. Granel B et al (2003) CIAS1 mutation in a patient with overlap between muckle-wells and chronic infantile neurological cutaneous and articular syndromes. Dermatology 206: 257-259
5. Grassegger A et al (1991) Urticular vasculitis as a syndrome of muckle-wells syndrome? Dermatologist 42: 116-119
6. Hawkins PN et al (2003) Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 348: 2583-2584.
7. Muckle TJ, Wells MV (1962) Urticaria, deafness and amyloidosis: a new heredo-familial syndrome. Quart J Med 31: 235-248