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▼ Description

Muckle-Wells syndrome (MWS) is characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis (Dode et al., 2002).

See also familial cold-induced autoinflammatory syndrome-1 (FCAS1, CAPS1; 120100), an allelic disorder with overlapping clinical features.

▼ Clinical Features

Muckle and Wells (1962) described a family in which urticaria, progressive perceptive deafness, and amyloidosis were combined in a dominantly inherited syndrome. Five generations were affected. Autopsy in 2 patients showed absent organ of Corti, atrophy of the cochlear nerve, and amyloid infiltration of the kidneys. Black (1969) described affected persons in 3 generations of a family and emphasized limb pains as a feature.

Berthelot et al. (1994) reported a 4-generation family in which 7 persons showed various signs of the syndrome associated with bipolar aphthosis (buccal and genital thrush) in 5 and cystinuria in 1; 2 other relatives had ichthyosis. No signs of amyloidosis were detected.

Throssell et al. (1996) reported a 3-generation family in which 3 sisters had episodic urticaria, polyarthralgia, and periodic abdominal pain. All 3 had microscopic hematuria but no evidence of renal amyloidosis. Microscopic hematuria was found also in their mother and in the daughter of one of them. None of the patients had evidence of deafness.

Gerbig et al. (1998) described a 21-year-old woman and her father, both suffering from MWS, in whom elevated serum levels of IL6 (147620) could be documented during the flare-ups of urticaria. The symptoms and the elevation of IL6 showed a circadian pattern in the daughter. Her urticaria predominantly affected the trunk and limbs, was nonpruritic, and seemed to follow an 'internal clock' beginning in the early afternoon, culminating in the late evening, and then fading away during the night. It was often associated with fever, chills, rigors, malaise, and aches and pains in the limbs, symptoms that were usually most prominent on Mondays. During the morning there were absolutely no symptoms. The patient could define no triggering factors apart from fatigue and hot, sunny weather. At the age of 7, an audiogram showed mild sensorineural deafness, but the parents refused further investigations because the father, suffering from identical symptoms and showing a constantly elevated erythrocyte sedimentation rate, otherwise felt completely healthy.

Gerbig et al. (1998) stated that about 100 cases of the urticaria-deafness-amyloidosis syndrome had been reported since the description of the syndrome in 9 members of a Derbyshire family by Muckle and Wells (1962). They suggested that some of the sporadic cases in particular had probably been confounded with other disorders, particularly CINCA (chronic infantile neurologic, cutaneous, and articular) syndrome (607115; Prieur et al., 1987). They pointed to the sporadic case of Linke et al. (1983) as a probable instance of the latter condition.

Lieberman et al. (1998) described the histopathologic features of the skin lesions in a sporadic case of MWS. The patient, a 54-year-old man, had had an asymptomatic, evanescent eruption since the age of 2 months, often accompanied by chills, arthralgias, and, later in the course, aching lower extremities. His childhood was complicated by persistent lymphadenopathy, hepatosplenomegaly, papilledema, anemia, 'gouty' arthritis, and an elevated sedimentation rate without an apparent cause. At age 19, perceptive hearing loss required bilateral hearing aids and was attributed to a course of antibiotics for a kidney infection. In his twenties and thirties, he had several episodes of culture-negative, eosinophilic meningitis with coma or seizures. This was partially responsive to corticosteroids and, therefore, presumed to be due to central nervous system vasculitis. Brain biopsy demonstrated chronic meningitis with vascular astroglial reaction without vasculitis. In his thirties and forties, he had recurrent abdominal pain, profuse diarrhea, and nephrotic syndrome requiring peritoneal dialysis. Rectal and renal biopsy specimens showed amyloid deposits. At age 50, he underwent bilateral corneal transplants for calcific band keratopathy. At age 54, despite antiinflammatory therapy including prednisone, azathioprine, and cyclosporine, his condition progressively deteriorated and he died during a hypotensive episode. Family history was negative for findings consistent with MWS. The diagnosis of MWS was not made until shortly before the patient's death.

▼ Mapping

Using a genomewide search strategy in 3 families, Cuisset et al. (1999) identified the locus for MWS at chromosome 1q44. The results indicated that the gene is located within a 13.9-cM region between markers D1S2811 and D1S2882, with a maximum 2-point lod score of 4.66 (recombination fraction of 0.00) at D1S2836 when full penetrance was assumed.

▼ Molecular Genetics

In a family with Muckle-Wells syndrome, Hoffman et al. (2001) found a mutation in the NLRP3 gene (606416.0004). Hoffman et al. (2001) also found mutations in the NLRP3 gene causing familial cold autoinflammatory syndrome (120100), thus demonstrating that these 2 disorders are allelic.

▼ Animal Model

By analyzing the immune responses of mice carrying an R258W mutation in the Nlrp3 gene, which is equivalent to the R260W mutation (606416.0005) associated with Muckle-Wells syndrome and FCAS1 (120100) in humans, Meng et al. (2009) found that antigen-presenting cells from mutant mice produced massive amounts of Il1b upon stimulation with microbial components in the absence of ATP, most likely due to a diminished inflammasome activation threshold allowing a response to a small amount of agonist. The mutant mice exhibited skin inflammation characterized by neutrophil infiltration and an Il1b-dependent Th17 (603149) dominant cytokine response. Meng et al. (2009) concluded that the R258W mutation mimics human Muckle-Wells syndrome and leads to inflammasome hyperactivation and Th17 cell-dominant immunopathology.

Tags: 1q44