TLR7-associated primary pure red cell aplasia in a boy with multigenic modifiers
DOI:
https://doi.org/10.15574/SP.2025.6(150).94103Keywords:
pure red cell aplasia, hemizygous TLR7 mutation (p.His1038Tyr), primary immune dysregulation, hypogammaglobulinemia, childrenAbstract
Primary pure red cell aplasia (PRCA) in infants is a rare condition characterized by isolated suppression of erythropoiesis in the bone marrow. In children, it most commonly has a viral or autoimmune origin; however, isolated cases are associated with primary genetically determined immune dysregulation. TLR7 mutations have infrequently been described as a key factor in the development of PRCA in early childhood. Expanded genetic analysis enables the detection of causative and concurrent variants, as well as mosaic structural chromosomal abnormalities that may modify the clinical phenotype and immune dysregulation.
Aim - to describe a clinical case of PRCA in a boy with a hemizygous TLR7 mutation, accompanying genetic modifiers, and immune dysregulation, including disproportion of lymphocyte subpopulations and marked hypogammaglobulinemia.
Clinical case. At 9 months of age, the boy first diagnosed with transfusion-dependent anemia accompanied by a severe decrease in reticulocytes, hepatosplenomegaly, and a strongly positive direct Coombs test without evidence of hemolysis. Bone marrow examination revealed a marked reduction of the erythroid lineage while overall cellularity was preserved. Lymphocyte analysis revealed normal total counts but a mild disproportion, with increased B cells and decreased T cells, while the CD4/CD8 ratio remained normal. Hypogammaglobulinemia detected without infectious manifestations, along with elevated liver enzymes. Genetic testing identified a hemizygous TLR7 mutation (p.His1038Tyr), concomitant heterozygous variants in SPTA1, TTC7A, HFE, FANCF, FANCM, as well as mosaic deletions in 9p23-p21.1 and 7p14.1-р14.1. The peripheral blood smear demonstrated ovalocytes, correlating with the SPTA1 variant. Treatment with prednisolone, intravenous immunoglobulin, deferasirox led to a positive clinical and laboratory response.
Conclusions. The TLR7-mutated gene is a principal driver of PRCA, while accompanying genetic variants and mosaic deletions contribute to a polygenic, modified phenotype, influencing disease severity, erythrocyte morphology, and immune dysregulation, including disproportion of lymphocyte subpopulations and marked hypogammaglobulinemia. These findings emphasize the importance of comprehensive genetic and immunological evaluation in children with rare forms of PRCA.
The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies.
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