A 19-year-old Chinese Han man presented with skin rash and joint contracture. Red papules had developed on his back only 1 month after birth. The rash gradually spread to his trunk and upper and lower limbs. He had no familial history of autoinflammatory diseases. At age 3, he had arthritis with symmetric periarticular swelling of wrists, knees, and ankles, and developed progressive deformity at proximal interphalangeal joints. At age 5, he was diagnosed with hypertension. In the local hospital, laboratory tests showed an erythrocyte sedimentation rate (ESR) of 27 mm/h (normal range: 0-15 mm/h), C reactive protein (CRP) of 36.5 mg/L (normal range: 0-8 mg/L), serum IgG of 18 g/L (normal range: 5.53-13.07 g/L), and IgA of 5.04 g/L (normal range: 0.33-1.08 g/L). Magnetic resonance (MR) angiography showed stenosis and thickening of the wall of the abdominal aortic at the level of the renal artery (Figure 2A) and mild hepatosplenomegaly. Skin biopsy revealed non-caseating granulomas in the superficial dermis, multinucleated giant cells, scattered lymphocytes, and infiltration of a few eosinophils. Special staining of the skin tissue, including with acid-fast staining, periodic acid-Schiff staining, and hexamine silver staining, was negative. He was still undiagnosed, and his blood pressure was well controlled with amlodipine. He was intermittently treated with diclofenac sodium for arthralgia. Eye redness had often occurred before age 10, but the cause was unknown. At age 18, he suffered from hematemesis and melena. A complete blood count found that hemoglobin (Hb) was 64 g/L (normal range: 130-175 g/L), and the platelet (PLT) count was 96 x 109/L (normal range: 125-350 x 109/L). The liver function test showed that serum albumin (ALB) was 32.7 g/L (normal range: 40-55 g/L), alkaline phosphatase (ALP) was 145 U/L (normal range: 45-125 U/L), gamma-glutamine transferase (GGT) was 148 U/L (normal range: 10-60 U/L), total bilirubin (TBIL) was 25.56 mumol/L (normal range: 3-22 mumol/L), and direct bilirubin was 12.39 mumol/L (DBIL) (normal range: 0-8 mumol/L). Hepatitis serologies for hepatitis B and C, ceruloplasmin, and autoimmune liver disease-related autoantibodies were negative. Abdominal computed tomography (CT) showed liver cirrhosis, splenomegaly, portal hypertension, and ascites (Figure 2B). Gastroscopy revealed esophageal and gastric varicose veins (F3 varices, gastroesophageal varices type 1) and portal hypertensive gastropathy. MR imaging showed joint effusion with extensive synovial thickening and bone destruction of the distal femur and proximal tibia in the left knee (Figure 2C). A liver biopsy revealed cirrhosis and hepatic granulomas (Figure 2D). He was given red-blood-cell transfusion and endoscopic injection sclerotherapy for esophageal varices and was transferred to our hospital.
On physical examination, he appeared with camptodactyly (Figures 3A,B) and boggy swelling of both wrists and knees. Ichthyosiform rashes on the whole body (Figures 3C,D) and splenomegaly were noted. Further whole exome sequencing by Next-Generation Sequencing identified a de novo pathogenic heterozygous variant of the NOD2 gene (NM_022162, Exon4), c.1000C>T, p.R334W. He was diagnosed with BS and treated with subcutaneous adalimumab, 40 mg once every 2 weeks. The rash and joint symptoms improved, but he had repeated gastrointestinal bleeding. He received a transjugular intrahepatic portosystemic shunt (TIPS) combined with balloon-occluded retrograde transvenous obliteration thereafter. At 1-year follow-up, the rash and arthritis had relapsed. Adalimumab was discontinued, and canakinumab was given subcutaneously 150 mg every 8 weeks. At the last follow-up, his symptoms had become stable. Laboratory tests showed the following results: Hb: 82 g/L, WBC: 2.01 x 109/L, PLT: 63 x 109/L, ALB: 30.9 g/L, GGT: 75 U/L, ALP: 186 U/L, TBIL: 50.63 mumol/L, DBIL: 30.88 mumol/L, IgG: 21.9 g/L, and PT: 14.1 s. Blood ammonia, CRP, and ESR were all normal.