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Muckle-Wells syndrome (MWS) is an intermediate form of cryopyrin-associated periodic syndrome (CAPS; see this term) and is characterized by recurrent fever (with malaise and chills), recurrent urticaria-like skin rash, sensorineural deafness, general signs of inflammation (eye redness, headaches, arthralgia/myalgia) and potentially life-threatening secondary amyloidosis (AA type).
ORPHA:575Classification level: Disorder
The prevalence of MWS is unknown. However a French survey through genetic laboratories has reported 135 cases and estimated CAPS prevalence at 1/360,000.
MWS onset is variable but patients usually present within the first few years of life with recurrent peak of fever (max of 39-40°C, starting generally in the evening (circadian pattern) and lasting a few hours, with a variable recurrence during a week. Intense general malaise and chills occur at the same time and lead to severe disability. Non-pruriginous urticarial rash (diffuse, erythematous, edematous plaques on a background of generalized, faintly erythematous patches) is a key feature of CAPS and is generally present with marked intensification during acute episodes. Progressive, high frequency, sensorineural deafness due at least in part to chronic inflammation of the cochlea begins in childhood (generally after the age of 10 years) resulting in complete deafness. Myalgia, arthralgias and distal edema are very common. With age, patients develop eythematous band over the hands as well as digital clubbing. Additional features include severe chronic fatigue, recurrent headaches, cognitive impairment, ocular involvement (conjunctivitis, uveitis, episcleritis), oral aphthosis, lymphadenopathy, thoracic and abdominal pain. Cold, fatigue, stress, or exercise are universal triggers of acute inflammation however acute attacks may appear unprovoked. Secondary amyloidosisis (see this term), revealed by persistent proteinuria, is a prominent feature affecting 25% of patients and can result in chronic renal insufficiency. Severe MWS cases, (MWS/CINCA) may display chronic meningitis, papillar edema with progressive optic atrophy. Failure to thrive and male sterility are common.
MWS is due to dominant mutation in the NLRP3 (1q44) gene which encodes cryopyrin. This defect results in the gain of function of cryopyrin that ultimately leads to the increased secretion of the proinflammatory cytokine interleukin (IL)-1 beta and and dysregulated inflammation. Mutations in this gene may also cause two additional phenotypes of CAPS: familial cold urticaria (FCAS) and CINCA syndrome (see these terms), Patients carrying identical amino acid substitution may present with distinctly different clinical subtypes, suggesting that additional genetic and/or environmental modifying factors are important in disease expression. Somatic NLRP3 mosaicism could explain 30-60% of patients with negative conventional genetic testing. Some patients with a classical phenotype of MWS, FCAS or CINCA syndrome may not have mutations in NLRP3.
Transmission is autosomal dominant with variable expression within a family and from one family to another.
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