Infant with diffuse large B-cell lymphoma identified postmortem with homozygous founder Slavic RAG1 variant: a case report and literature review

Abstract

Background and aims: There is an increased risk of lymphomas in inborn errors of immunity (IEI); however, germline genetic testing is rarely used in oncological patients, even in those with early onset of cancer. Our study focuses on a child with a recombination-activating gene 1 (RAG1) deficiency who was identified through a screening program for Slavic founder genetic variants among patients who died with malignancy at an early age in Belarus.

Results: We identified one homozygous founder RAG1 variant out of 24 available DNA samples from 71 patients who developed lymphoma aged <3 years from the Belarusian cancer registry between 1986 and 2023. Our patient had an episode of pneumonia at 3 months of age and was hospitalized for respiratory distress, candida-positive lung disease, and lymphadenopathy at 14 months of age. The diagnosis of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) was established. The patient had a normal lymphocyte count that decreased over time. One month after chemotherapy initiation, the patient died due to sepsis and multiple organ failure without a genetic diagnosis. In a retrospective analysis, T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) were undetectable in peripheral blood.

Conclusions: A targeted screening program designed to detect a Slavic founder variant in the RAG1 gene among children revealed a 14-month-old Belarusian male infant with low TREC levels who died of EBV-driven DLBCL and complications of chemotherapy including infections. This case highlights how patients with IEI and recurrent infections may develop serious non-infectious complications, such as fatal malignancy. It also emphasizes the importance of early identification, such as newborn screening for severe combined immune deficiency. Earlier diagnosis of RAG deficiency could have prompted hematopoietic stem cell transplant well before the DLBCL occurrence. This likely would impact the onset and/or management strategies for the cancer.

Keywords: RAG deficiency; case report; infant; lymphoma; malignancy in SCID.

Figure 1

(A) Distribution map of Western and Eastern Slavic families with the RAG1 p.K86VfsX33 variant in Slavic countries; the Vistula river basin is overlaid on the map of Poland. The blue line is the Vistula River basin and its largest tributaries (Bug, Narev, San, Wieprz, Pilica, and Muchowiec), the geographic area coincides with the region of the largest concentration of families where patients with p.K86VfsX33 homozygous variants were born. The birthplace of the patients was indicated by the location of the circles; homozygous p.K86VfsTer33 variant is represented by red circles; heterozygous p.K86VfsTer33 variant is half red/half gray; and other variants are gray. (B) Pedigree of the proband; the mother and father are carriers; deceased (line through). Timeline summarizing main turning point of patient's clinical history. Chest radiograph at the age of 3 months: pneumonia; liver biopsy at the age of 1 year 2 months: lymphoma with angiodestructive type of growth. (C) Liver biopsy: solid shut of lymphoma cells, some of them resemble Reed–Sternberg cells and electropherograms of Sanger sequencing of RAG1 p.K86VfsX33 variant from lymphoma tissue. (D) Bone marrow smear: dissociation of neutrophil maturation cells and electropherograms of Sanger sequencing of RAG1 p.K86VfsX33 variant in the bone marrow.