Phenotype Compatible with Late-Onset, Nonclassical Combined Immunodeficiency (CDI)

Inborn errors of immunity (IEIs) with cytopenias and immunodysregulation can mimic hematological malignancies, making timely diagnosis difficult. The identification of mutations associated with inborn errors of immunity allows for clarification of their nature. Case Presentation: A 16-year-old female (Cajamarca, Peru) with a history of multiple early maternal deaths. Since the age of 13, she has presented with recurrent respiratory and gastrointestinal infections, with a partial response to antimicrobials. She presented with persistent fever, epistaxis, lymphadenopathy, polyserositis, hepatosplenomegaly, and chronic diarrhea. Blood tests showed persistent pancytopenia with marked lymphopenia, microcytosis, schistocytes, and dacryocytes in peripheral blood smears. Bone marrow aspirate and biopsy revealed mild dysplastic changes, without leukemic clonality; a second study ruled out myelodysplasia. Immune competence study showed severe hypogammaglobulinemia with vaccine failure (hepatitis B and pneumococcus).

Flow cytometry (PIDOT) showed profound B and T lymphopenia, with natural killer (NK) cells at the lower limit. Genetic testing using a panel of inborn errors of immunity (Invitae, 2025) identified four heterozygous variants of uncertain significance (VUS) in the genes RTEL1, POLD2, and TMEM173, involved in telomere maintenance, DNA repair, and type I interferon activation, respectively.

The triad of B-T-NK lymphopenia, mild bone marrow dysplasia, and vaccine failure suggests combined immunodeficiency with hematopoietic compromise. Variants in POLD2 (DNA replication and repair) and TMEM173 (SAVI-like interferonopathy) could explain the cytopenia, inflammation, and polyserositis. Functional studies (polymerase deficiencies or repair defects, interferon score) and family genetic evaluation are required to confirm the diagnosis and to consider hematopoietic transplantation as a possible definitive treatment.