Journal Article

IL2RG-related immunodeficiencies: from SCID to atypical presentations

Spoulou, Vana, Marinakis, Nikolaos, Notarangelo, Luigi D., Briassouli, Efrossini

2026

Overview

The interleukin-2 receptor gamma chain gene ( ) encodes for the common γ chain (γ ) protein, that is a shared signaling component of multiple interleukin receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and plays a pivotal role in lymphocyte development, homeostasis, and function. Mutations in cause X-linked severe combined immunodeficiency (X-SCID) and a broad spectrum of related phenotypes ranging from typical SCID to leaky or atypical presentations, sometimes mimicking common variable immunodeficiency or immune dysregulation syndromes. Over the last decade (2015-2025), advances in molecular diagnostics, next-generation sequencing, and functional immunology have expanded the known mutational spectrum and refined genotype-phenotype correlations. 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. 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 -related spectrum has refined long-term follow-up protocols. Multidisciplinary care, integrating infectious disease, immunology, and genetics expertise, has become essential for optimizing patient outcomes. 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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / atypical X-CID / Autoimmunity / Cells / Clinical trials / Common variable immunodeficiency / Cytokines / Diagnosis / Diarrhea / Disease progression / Failure to thrive / Family medical history / Gene therapy / Genotype & phenotype / Genotypes / Homeostasis / Humans / IL2RG / Immune reconstitution / Immune response / Immune system / Immunology / Infectious diseases / Insertional mutagenesis / Interleukin 2 / Interleukin Receptor Common gamma Subunit - genetics / Interleukin Receptor Common gamma Subunit - immunology / Interleukin Receptor Common gamma Subunit - metabolism / Kinases / leaky SCID / Lymphocytes / Malignancy / maternal T-cell engraftment / Medical screening / Mutation / Newborn babies / Next-generation sequencing / Phenotypes / Proteins / Review / Severe combined immunodeficiency / Severe Combined Immunodeficiency - diagnosis / Severe Combined Immunodeficiency - genetics / Severe Combined Immunodeficiency - immunology / Severe Combined Immunodeficiency - therapy / Signal Transduction / somatic reversion / Stem cell transplantation / Toxicity / Viral infections / X-Linked Combined Immunodeficiency Diseases - diagnosis / X-Linked Combined Immunodeficiency Diseases - genetics / X-Linked Combined Immunodeficiency Diseases - immunology / X-Linked Combined Immunodeficiency Diseases - therapy / X-SCID