Muckle-Wells syndrome:: clinical and histological skin findings compatible with cold air urticaria in a large kindred

Background Muckle-Wells syndrome is a rare familial disease with autosomal dominant inheritance. characterized by cold sensitivity and polyarthralgias since childhood, with possible later development of nerve deafness and renal amyloidosis. The nature of the skin manifestations is. however. not well characterized. Objectives To clarify the nature of cutaneous cold sensitivity in patients with Muckle-Wells syndrome by studying clinical aspects and histological features. Methods Eighteen members of a family with Muckle-Wells syndrome and the recently identified mutation of the CIAS1 gene at focus 260 of chromosome 1q44 were available for study. Examination included a thorough history, physical examination and a battery of laboratory tests. In two brothers. standard cold contact and cold air provocation tests were performed, as were biopsies from normal and lesional skin. Results All affected family members reported an increased sensitivity to cold, dampness or changes in temperature, and most had arthritis and conjunctivitis. Eight had developed hearing loss, four renal involvement. and amyloid deposits were found in three of five patients in whom rectal biopsies were performed. Laboratory tests showed leucocytosis and elevated C-reactive protein, but no serum cold agglutinins and cryoglobulins. Skin eruptions, with weals of 0(.)2-3 cm, lasted from 5 to 24 h and were associated with local itching or pain as well as fever, malaise and chills. On cold provocation of two patients, lesions could be reproduced by cold air, but not by contact with an ice cube or cold water. On histology, there was increased vasodilatation, marked infiltration with neutrophils and monocytes/macrophages. and increased expression of beta2 integrins in lesional vs. normal skin. Numbers of mast cells as well as expression of interleukin-3 and tumour necrosis factor-alpha were unchanged. Conclusions Cold-induced skin lesions in Muckle-Wells syndrome represent typical generalized cold air/wind inflammatory reactions, as also observed in familial cold urticaria. Microscopic features are similar to those observed in other types of urticaria.