Severe combined immunodeficiency due to DCLRE1C deficiency

Severe combined immunodeficiency due to DCLRE1C deficiency (also known as Artemis-SCID or radiosensitive SCID) is a rare, life-threatening primary immunodeficiency caused by mutations in the DCLRE1C gene, which encodes the Artemis protein. Artemis plays a critical role in V(D)J recombination, the process by which immune cells (T and B lymphocytes) rearrange their antigen receptor genes to generate a diverse immune repertoire. It is also involved in DNA double-strand break repair through the non-homologous end joining (NHEJ) pathway. Loss of Artemis function results in a complete absence of both functional T cells and B cells (T-B-NK+ SCID phenotype), leaving affected infants profoundly vulnerable to severe, recurrent, and life-threatening infections. Infants with Artemis-SCID typically present within the first months of life with failure to thrive, chronic diarrhea, recurrent pneumonia, persistent oral thrush (candidiasis), and severe bacterial, viral, and fungal infections. Because the Artemis protein is also involved in general DNA repair, affected individuals exhibit increased sensitivity to ionizing radiation and alkylating agents, which is a distinguishing feature from other forms of SCID. This radiosensitivity has important implications for treatment, particularly regarding conditioning regimens used before hematopoietic stem cell transplantation (HSCT). The primary curative treatment is HSCT, ideally from an HLA-matched sibling donor, though outcomes with alternative donors have improved. However, the radiosensitivity of these patients necessitates modified, reduced-intensity conditioning protocols to minimize toxicity. Without treatment, the disease is fatal in early childhood. Gene therapy approaches are under active investigation as a potential alternative treatment. Supportive care includes infection prophylaxis with antimicrobials, immunoglobulin replacement therapy, and strict isolation precautions. Newborn screening programs using the TREC (T-cell receptor excision circle) assay can identify affected infants before the onset of severe infections, enabling earlier intervention and improved outcomes. This condition is particularly prevalent in certain populations, including Athabascan-speaking Native Americans, due to founder mutations.

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