A recent study published in Genes & Diseases explores the clinical implications of loss-of-function mutations in IKBKG/NEMO, a key regulator in the NF-κB signaling pathway. These mutations are linked to a range of rare and often severe genetic disorders, including Incontinentia Pigmenti (IP), Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), Immunodeficiency (ID), and NEMO Deleted Exon 5 Autoinflammatory Syndrome (NDAS). The research aims to provide a comprehensive review of the diverse clinical manifestations associated with mutations in the IKBKG gene, highlighting the genotype-phenotype correlation that has remained elusive due to the variability in IKBKG mutations.

The study systematically reviewed data from 144 articles encompassing 564 patients affected by IKBKG mutations, revealing that 78.0% of cases presented as Incontinentia Pigmenti (IP), predominantly affecting females. In contrast, EDA-ID, ID, and NDAS were more prevalent among males, with 100% of affected patients being male. The most frequent clinical presentations included skin abnormalities (89.5% of IP cases), dental anomalies (68.5% in EDA-ID), and infections (100% in both EDA-ID and ID). The study also identified specific mutations linked to more severe clinical outcomes, such as E390RfsX5, which can cause both IP and EDA-ID, and H413R, associated with extensive immune system involvement.

Patients with EDA-ID were often affected by hypogammaglobulinemia, with nearly half presenting low levels of IgG and some exhibiting hyper-IgM syndrome. The primary pathogens associated with these infections included Mycobacterium and Streptococcus, highlighting the increased vulnerability of individuals with these mutations to severe infections. The study also emphasized that certain mutations, particularly in the zinc finger (ZF) domain, lead to severe and life-threatening conditions, suggesting a critical role of this domain in the regulation of immune responses.

One of the major challenges identified is the heterogeneity of clinical manifestations, even among patients with the same mutation, indicating that additional factors may influence disease severity. The study also noted that the diagnosis of IKBKG-related conditions often occurs in early childhood, but genetic testing can sometimes be delayed, complicating timely management.

The findings underline the importance of early genetic screening for IKBKG mutations in patients presenting with recurrent infections, ectodermal dysplasia, or unexplained inflammatory symptoms. Furthermore, the study suggests that integrating central nervous system (CNS) abnormalities into the diagnostic criteria for IP could improve early detection, as these manifestations are more prevalent than previously recognized.

Given the complexity and variability of clinical presentations, this research advocates for a more personalized approach to diagnosing and managing IKBKG-related disorders. Future studies are encouraged to focus on targeted therapies that can modulate the NF-κB pathway and address the diverse immunological challenges posed by these genetic mutations.

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Jin Wang, Kexin Shen, Hongxia Lou, Lina Zhou, Yunfei An, Xiaodong Zhao, Yuan Ding, Clinical relevance of loss-of-function mutations of NEMO/IKBKG, Genes & Diseases, 2025, 101531, https://doi.org/10.1016/j.gendis.2025.101531