Objective To analyze the clinical features and gene phenotype of sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) due to TRNT1 mutation in two siblings from non-consanguineous parents. Methods The clinical data of the siblings with SIFD that were diagnosed in the department of allergy, immunology and rheumatology of Guangzhou Women and Children's Medical Center were collected. Then we detected the whole genome sequencing analysis with the peripheral blood samples of the patients and their parent. We summarize the clinical characteristics and gene analysis of 55 patients with SIFD that were concluded from the PubMed, China national knowledge internet and Wanfang databases. Results The proband was a 15-year-old girl, she presented with recurrent fever and elevated inflammatory markers since she was 8 months of age. After 1 year-old of age, she gradually developed swelling and arthralgia of the right knee, flexion deformity of arthritis, bilateral cataract, developmental delay and growth retardation. She can't talk with others, can't walk by herself and had no menstruation until now. The proband's sibling brother was 7 years old, presented with hypoimmunoglobulinemia and normal B cell counts at 3 months, which showed low immunoglobulin A but with normal immunoglobulin G and M and normal B cell counts at 2 years old. Diarrhea appeared at 4 months of age. He was hospitalized with fever, bronchopneumonia and diarrhea at 8 months of age. Since then, he was prone to recurrent fever and diarrhea. At 19 months, he developed arthritis of both knees and presented bilateral cataract at the age of 2 years. Irregular infusion of immunoglobulin was performed, swelling and pain of the knee gradually improved and the frequency of fever decreased. Now, he still presents with developmental delay and growth retardation. He can talk with people by 3-7 words short sentences, but the pronunciation is not clear. He can understand and carry out the orders of his parent. He can walk alone but with poor stability. Whole genome sequencing of the blood revealed biallelic TRNT1 heterozygous mutations, c.1056+1G>A/c.1246A>G (p.K416E). A total of 55 cases were reported in the literatures, including 21 males and 30 females, and 4 cases were not mentioned in the references. The clinical manifestations presented with repeated fever, different levels of sideroblastic anemia and immunologic abnormalities, arthritis, growth retardation, hearing abnormalities, cataracts, repeated infections, skin rashes and so on. Intravenous infusion of immunoglobulin and tumor necrosis factor-α antagonists, hematopoietic stem cell transplantation and positive symptomatic treatments may improve the prognosis. Conclusions SIFD caused by TRNT1 gene mutation is an autosomal recessive inherited disease with diverse clinical manifestations. Genetic testing of TRNT1 gene mutationis is the basis of clinical diagnosis. Clinicians should recognize the complex disease, early diagnosis and intervention can improve the quality of life for patients.