Diffuse large B-cell lymphoma in 1-year male with founder Slavic RAG1 mutation: case report

Lymphomas in RAG1 deficiency are extremely rare, especially in early childhood. Only a few cases of lymphoma in RAG1 deficiency have been previously described in the literature. Sanger sequencing of Slavic founders mutation (RAG1-c.256_257del, p.Lys86ValfsTer33, IL7Rα - c.132C>G, p.Ser44Arg, NBN1 -c.657_661del5, p.Lys219AsnfsTer16 genes) in DNA of died children with malignancy in early age in Belarus. We report a case of 14 month-old boy affected by diffuse large B-cell lymphoma diagnosed with RAG1 deficiency. A male patient of Belarus origin was born full-term from non-consanguineous parents. He had a history of recurrent pneumonia since 3 months of age. The patient was hospitalized in 14 month-old with subfebrile fever, wet cough, lymphadenopathy and cyanosis of the nasolabial triangle. Chest x-ray showed bilateral polysegmental pneumonia. Microbiological analysis of sputum found Candida. Ultrasound examination showed hepato-(+3 cm)-spleno- (+3 cm)-megaly and lymphadenopathy of multiple groups of lymph nodes (cervical, inguinal and axillary). Lymph-node, liver, and intestines biopsies were suggestive of EBV-positive Diffuse Large B-cell lymphoma, NOS. He had progressive leukopenia (from 3100 cells/µl to 200 cells/µl). Lymphopenia (400 cells/µl), decreased T-cells (300 cells/µl) and elevated activated T-cells (41%) were detected. B-cell percentage was in normal ranges (33%), but absolute number was slightly decreased (160 cells/µl). TRECs – 0 per 1 million leukocytes, KRECs – 0 per 1 million leukocytes. According to the clinical and immunological phenotype, combined immunodeficiency was suspected. The patient died (age 15 m) one month after the start of the chemotherapy cycle due to sepsis and multiple organ failure without genetic diagnosis. His material was studied post-mortem due to the lymphoma at early age and place of birth (Brest, Western Belarus). Targeted Sanger sequencing revealed a homozygous deletion in RAG1 gene (NM_000448.3) c.256_257del (p.Lys86ValfsTer33). We described a rare case of EBV-positive diffuse large B-cell lymphoma NOS in a patient with homozygous founder Slavic mutation in the RAG1 gene.