Muckle-wells syndrome Q84.89

Muckle and Wells, 1962

• Recurrent urticarial exanthema.
• Fever attacks with joint and muscle pain, general weakness.
• Progressive sensorineural hearing loss.
• Optional: Secondary systemic amyloidosis of the kidney.

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 humid-cold weather and weather changes
• Fever attacks with joint and muscle pain (polyarthralgia) since childhood
• General feeling of weakness and discomfort
• Optional: Progressive sensorineural hearing loss
• Optional: renal amyloidosis.

cold urticaria; hereditary periodic fever syndromes; chronic recurrent urticaria; secondary systemic amyloidosis; Alport syndrome; Ohlsson syndrome; Schnitzler syndrome.

Recent studies have shown 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: Therapy trials are described with cyclophosphamide (e.g. endoxan) 100 mg/day in combination with methylprednisolone (e.g. Urbason) 40 mg/day (reduction according to clinic), with DADPS (e.g. Dapson Fatol) initial 100 mg/day and with colchicine (e.g. Colchicum dispersed).

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. At J Med gene 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) Urticarial 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-family syndrome. Quart J Med 31: 235-248