IL2RG-Related Immunodeficiencies: From SCID to Atypical Presentations

Efrossini Briassouli^1*Nikolaos Marinakis²Vana Spoulou³Luigi D. Notarangelo⁴

• ¹Geniko Nosokomeio Paidon Athenon Panagioti & Aglaias Kyriakou, Athens, Greece
• ²Laboratory of Medical Genetics, National and Kapodistrian University of Athens, St. Sophia’s Children’s Hospital, Athens, Greece
• ³First Department of Paediatrics & Immunobiology & Vaccinology Research Lab, National and Kapodistrian University of Athens, “Agia Sophia” Children’s Hospital of Athens,, Athens, Greece
• ⁴⁴ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, United States

Pathogenic variants in the IL2RG gene – encoding the common gamma chain (γc) shared by multiple interleukin receptors – cause a spectrum of X-linked immunodeficiencies. The classic and most severe phenotype is X-linked severe combined immunodeficiency (X-SCID), characterized by profoundly impaired T-cell and NK-cell development with dysfunctional B cells (1). Affected infants with X-SCID typically succumb to infections in the first year of life if untreated (2). Over the past years, newborn screening, high-throughput sequencing and curated variant databases have broadened this view, revealing numerous hypomorphic and atypical IL2RG variants. These give rise to "leaky" phenotypes and overlapping clinical pictures, including combined immunodeficiency, X-linked lymphoproliferative disease–like syndromes and even common variable immunodeficiency (CVID). Finally, in some cases the clinical and immunological phenotype has been modified by somatic reversion. In this review, we synthesize current knowledge on IL2RG biology and γc cytokine signaling, and link molecular mechanisms to the evolving clinical spectrum—from classical X-SCID with maternal T-cell engraftment to leaky and CVID-like disease. We summarize genotype–phenotype correlations, diagnostic and functional approaches, and current curative strategies, including hematopoietic stem cell transplantation (HSCT) and gene therapy. Our goal is to provide an up-to-date, clinically oriented reference for immunologists and clinicians involved in the diagnosis and management of IL2RG-related immunodeficiencies.