IL2RG-related immunodeficiencies: from SCID to atypical presentations.

Background and significance: The interleukin-2 receptor gamma chain gene ( Recent advances: Recent research has uncovered novel hypomorphic variants, revealed the structural basis of receptor dysfunction, and elucidated the impact of specific mutations on JAK-STAT signaling. Longitudinal natural history studies have improved understanding of disease progression in partial loss-of-function cases, while expanded newborn screening for SCID has facilitated earlier diagnosis. Advances in preclinical and clinical gene therapy have addressed historical challenges such as insertional mutagenesis, with emerging protocols achieving stable multilineage immune reconstitution. Moreover, comparative HSCT outcome analyses have informed donor selection, conditioning strategies, and post-transplant care, particularly in resource-limited settings. Clinical Impact: Improved molecular diagnostics have enabled precision diagnosis in patients with atypical presentations, allowing earlier initiation of curative therapies such as HSCT or gene therapy. Recognition of immune dysregulation, autoimmunity, and malignancy as part of the Future Directions: Ongoing priorities include the expansion of gene therapy trials to cover hypomorphic and late-presenting cases, refinement of reduced-intensity conditioning regimens to minimize toxicity, and development of targeted molecular therapies to modulate downstream signaling in non-transplant candidates. Global initiatives for SCID newborn screening, coupled with collaborative registries, are expected to improve early diagnosis and equitable access to curative interventions.