Background: Muckle-Wells syndrome (MWS) represents a moderate phenotype of cryopyrinopathies. Sensorineural hearing loss and AA amyloidosis belong to the most severe manifestations of uncontrolled disease. Simultaneous discovery of MWS in four generations of one large kindred has enabled us to document natural evolution of untreated disease and their response to targeted therapy. Methods: A retrospective case study, clinical assessment at the time of diagnosis and 2-year prospective follow-up using standardized disease assessments were combined. Results: Collaborative effort of primary care physicians and pediatric and adult specialists led to identification of 11 individuals with MWS within one family. Presence of p.Ala441Val mutation was confirmed. The mildest phenotype of young children suffering with recurrent rash surprised by normal blood tests and absence of fevers. Young adults all presented with fevers, rash, conjunctivitis, and arthralgia/arthritis with raised inflammatory markers. Two patients aged over 50 years suffered with hearing loss and AA amyloidosis. IL-1 blockade induced disease remission in all individuals while hearing mildly improved or remained stable in affected patients as did renal function in one surviving individual with amyloidosis. Conclusions: We have shown that severity of MWS symptoms gradually increased with age toward distinct generation-specific phenotypes. A uniform trajectory of disease evolution has encouraged us to postpone institution of IL-1 blockade in affected oligosymptomatic children. This report illustrates importance of close interdisciplinary collaboration.

Clinical and Transplant Pathology Centre Institute for Clinical and Experimental Medicine Prague Czechia

Department of Clinical Immunology and Allergology St Anne's University Hospital in Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Nephrology 1st Faculty of Medicine General University Hospital Prague Charles University Prague Czechia

Department of Paediatric Rheumatology University Hospital Brno Brno Czechia

Department of Rheumatology St Anne's University Hospital Brno Brno Czechia

Laboratory for Study of Mitochondrial Disorders 1st Faculty of Medicine General University Hospital Prague Charles University Prague Czechia

Paediatric Rheumatology and Autoinflammatory Diseases Unit Department of Paediatrics and Adolescent Medicine 1st Faculty of Medicine General University Hospital Prague Charles University Prague Czechia

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