Although deleterious mutations in interleukin-10 and its receptor molecules cause severe infantile-onset inflammatory bowel disease, there are no reports of mutations affecting this signaling pathway in Japanese patients. Here we report a novel exonic mutation in the IL10RA gene that caused unique splicing aberrations in a Japanese patient with infantile-onset of inflammatory bowel disease in association with immune thrombocytopenic purpura and a transient clinical syndrome mimicking juvenile myelomonocytic leukemia. A Japanese boy, who was the first child of non-consanguineous healthy parents, developed bloody diarrhea, perianal fistula, and folliculitis in early infancy and was diagnosed with inflammatory bowel disease. He also developed immune thrombocytopenic purpura and transient features mimicking juvenile myelomonocytic leukemia. The patient failed to respond to various treatments, including elemental diet, salazosulfapyridine, metronidazole, corticosteroid, infliximab, and adalimumab. We identified a novel mutation (c.537G > A, p.T179T) in exon 4 of the IL10RA gene causing unique splicing aberrations and resulting in lack of signaling through the interleukin-10 receptor. At 21 months of age, the patient underwent allogeneic hematopoietic stem cell transplantation and achieved clinical remission. We describe a novel exonic mutation in the IL10RA gene resulting in infantile-onset inflammatory bowel disease. This mutation might also be involved in his early-onset hematologic disorders. Physicians should be familiar with the clinical phenotype of IL-10 signaling defects in order to enable prompt diagnosis at an early age and referral for allogeneic hematopoietic stem cell transplantation.

Background and Aim: Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long‐term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy.Methods: We retrospectively and prospectively examined children under 10 years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan.Results: Twenty‐four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1 month after initiation of treatment and usually remained under 50 U/L from 1 to 8 years of treatment. Twenty four‐hour urinary copper decreased significantly at 6 months and usually remained under 75 μg/day and between 1 and 3 μg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6 years old who received 50 mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1 month after initiation of treatment, as did γ‐glutamyltransferase and 24‐h urinary copper at 6 months.Conclusions: To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50 U/L when normalization is difficult) and 24‐h urinary copper excretion between 1 and 3 μg/kg/day and under 75 μg/day is a reasonable goal. An initial dose of 50 mg/day is appropriate for patients under 6 years old.

Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNFα to apoptosis of the bile duct epithelium in the presence of IFNγ. Here, we investigate if TNFα signaling regulates pathogenic mechanisms of biliary atresia. First, we quantified the expression of TNFA and its receptors TNFR1 and TNFR2 in human livers and found an increased expression of the receptors at the time of diagnosis. In mechanistic experiments using a neonatal mouse model of rhesus rotavirus–induced (RRV-induced) biliary atresia, the expression of the ligand and both receptors increased 6- to 8-fold in hepatic DCs and NK lymphocytes above controls. The activation of tissue NK cells by RRV-primed DCs was independent of TNFα-TNFR signaling. Once activated, the expression of TNFα by NK cells induced lysis of 55% ± 2% of bile duct epithelial cells, which was completely prevented by blocking TNFα or TNFR2, but not TNFR1. More notably, antibody-mediated or genetic disruption of TNFα-TNFR2 signaling in vivo decreased apoptosis and epithelial injury; suppressed the infiltration of livers by T cells, DCs, and NK cells; prevented extrahepatic bile duct obstruction; and promoted long-term survival. These findings point to a key role for the TNFα/TNFR2 axis on pathogenesis of experimental biliary atresia and identify new therapeutic targets to suppress the disease phenotype.