Case of Muckle–Wells syndrome with obesity

Abstract

Dear Editor, Muckle– Wells syndrome (MWS) is one of the cryopyrinassociated periodic syndromes (CAPS), an autosomal dominant autoinflammatory disease characterized by genetic mutations in NODlike receptor family pyrin domain containing 3 (NLRP3) and increased interleukin1β (IL1β) levels. Urticarial rash, recurrent fever, arthralgia, and fatigue are major clinical features of MWS. Sensorineural hearing loss and renal amyloidosis can occur in the course of the disease.1,2 Here, we demonstrate a case of MWS whose prominent clinical symptoms occurred with bodyweight gain. A 14yearold Japanese boy presented with a 10year history of untreated repeated asymptomatic erythema on his face, trunk, and limbs with heel pain. Of note, recurrent fever had occurred with his bodyweight gain 5 years before visiting our department (Figure S1). His mother and grandmother had a history of similar repeated erythema and hearing impairment. His grandmother had also obesity and diabetes. Physical examination revealed wheallike erythema or papules on his trunk and limbs (Figure 1a,b). His weight was 71.3 kg and height 160.5 cm. Body mass index was 27.6 kg/m2. Abnormal laboratory results were as follows: white blood cells, 129 × 102/μL; blood platelets, 52.5 × 104/μL; erythrocyte sedimentation rate (1 h), 41 mm; Creactive protein, 1.29 mg/dL; serum amyloid A (SAA), 82.9 μg/mL; and triglycerides, 158 mg/dL. The following laboratory results were within normal limits: creatinine, 0.60 mg/dL; and hemoglobin A1c, 5.8%. Histological examination of a tissue specimen biopsied from the erythema showed perivascular and periadnexal infiltration of inflammatory cells, mainly lymphocytes and neutrophils in the dermis (Figure 1c,d). Otorhinolaryngological hearing test showed a mildly elevated threshold in the midto high frequencies in his left ear. Obtaining informed consent from the patient, a hybridization capturebased nextgeneration sequencing was performed by using the patient’s genomic DNA purified from peripheral blood cells,3 and the c.1043C>T (p.Thr348Met) mutation was identified in NLRP3.4 MWS was diagnosed, and IL1β blockade therapy with canakinumab (150 mg every 8 weeks) had been started. The laboratory data concerning inflammatory reaction and SAA levels was improved after 4 months (Figure 1e). The frequency of fever was reduced, heel pain had completely disappeared, and erythema was observed only in the limited area on his back and abdomen. His bodyweight was increased from 71.3 to 77.1 kg, presumably due to leaving his sports team. The pathophysiological roles of NLRP3 mutation and IL1β have been considerably identified, and IL1β blockade therapy is now clinically utilized for the patients with CAPS. Although the activation of the NLRP3 signaling pathway has been implicated in the pathogenesis of various diseases including atherosclerosis, diabetes, and obesity,5 these diseases are not reported as comorbidities of CAPS. In our patient, recurrent fever had occurred with his bodyweight gain, suggesting that obesityassociated inflammation might increase the serum IL1β levels by activating the NLRP3 signaling pathway together with the gainoffunction in NLRP3 mutation. Since the effects of canakinumab were limited, losing weight may be necessary in our patient. However, since clinical data from CAPS