A boy aged 5 years and 2 months presented with recurrent high fever for 18 days, accompanied by a mild cough, abdominal pain, diarrhea and hematochezia. Although he was actively treated with intravenous antibiotics and immunoglobin, his fever was persistent. He was the first child in his family. A single episode of mild pneumonia had occurred when he was 4 months old and he received intravenous antibiotics for several days. There was no history of recurrent respiratory infection or eczema. No history of prolonged umbilical stump as well. He did not have chickenpox and was not vaccinated against this. On physical examination, he had moderate malnutrition, multiple ulcers in the oral cavity and on the surface of the tongue, and no lymphadenopathy or hepatosplenomegaly. Laboratory examinations revealed obvious elevation of inflammatory markers; the white blood cell count was 19.44 x 109/L, of which neutrophils accounted for 66.4%; the C-reactive protein (CRP) level was 17.34 mg/L; the erythrocyte sedimentation rate (ESR) was 73 mm/h; and the serum procalcitonin level was 0.412 ng/ml. In addition, the patient had moderate anemia, with a hemoglobin level of 84 g/L, and his serum albumin level was decreased, at 27.4 g/L. Serum antibodies against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were negative, and a T-SPOT TB test was negative. Number of CD19+ B lymphocytes was reduced, accounting for 16.45% (reference range (r.r): 18.5-28.0%) of lymphocytes; CD3+ T lymphocytes accounted for 54.1% (r.r: 56.0-68.0%) of lymphocytes, CD4+ T lymphocytes accounted for 31.45% (r.r: 29.0-40.0%), and CD8+ T lymphocytes accounted for 18.35% (r.r: 19.0-25.0%). The ratio of CD4+ to CD8+ T cells was normal, 1.71 (r.r: 1.1-2.0/1). Abdominal computed tomography scan showed irregular wall thickness, enhancement of the ascending colon and terminal ileum wall, and enlargement of the abdominal lymph nodes (Figure 1A). Intestinal ultrasound showed that the walls of the terminal ileum and colon were thickened. The inflammation affected the vermiform appendix. Colonoscopy was performed, and multiple ulcers in the terminal ileum and colon were detected. The area of the largest ulcer was approximately 3 cm x 4 cm. The ulcers had sharp margins, and most had no exudate or edema; these lesions were mainly located in the ascending colon and cecum. There were also scattered ulcers located in the rectum ( Figure 1B). Histological study of a mucosal biopsy indicated segmental chronic active inflammation of the colon and terminal ileum, cryptitis and crypt abscess were observed at the colon; additionally, several noncaseating granulomas was observed in the ileum and descending colon (Figure 1C). Microbial metagenomic next-generation sequencing (mNGS) of the intestinal biopsy did not reveal any opportunistic pathogens. The patient was diagnosed with VEOIBD and was treated with 2 mg/kg intravenous methylprednisolone twice a day. His fever subsided on the second day of the intravenous methylprednisolone regimen. Then, he was switched to oral prednisone, which was gradually tapered down within 3 months. Repeated colonoscopy showed that the intestinal inflammation was remarkably improved. Only small ulcers in the terminal ileum were observed, and the ulcers located in the colon had healed, leaving a scattering of small inflammatory polyps (Figure 1D). Capsule endoscopy confirmed terminal ileal ulcers. The patient took oral mercaptopurine for 4 months. Although he had a wild-type genotype for thiopurine methyltransferase (TPMT) and NUDT15, he experienced recurrent neutropenia. He was switched to methotrexate (MTX) due to neutropenia, and he had severe sepsis when he was on MTX. He presented with high fever, chill, delirium and shock, accompanied with remarkably elevated CRP and procalcitonin levels. He was treated with vasoactive drug and intravenous antibiotics in the intensive care unit for 1 week. Because of nonspecific intestinal colitis and early onset of disease, he was suspected to have monogenic IBD. The repeated immune work of the peripheral blood was showed in Supplementary Table S1. The number and percentage of memory B cells, central CD8+ T cells, Th1 cells and NK cells were obviously reduced.