NFKBIA – Ectodermal Dysplasia with Immunodeficiency

Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is an autosomal dominant syndrome caused by gain-of-function variants in NFKBIA, encoding the NF-κB inhibitor IκBα. Affected individuals present with hypohidrosis, sparse hair, dental anomalies, and combined immunodeficiency often leading to severe infections or non-infectious inflammation, with occasional hematopoietic stem cell transplantation (HSCT) to restore immune function.

Heterozygous GOF mutations cluster in the N-terminal degron region of IκBα, preventing phosphorylation, ubiquitination, and degradation. Fourteen unrelated probands (13 de novo, one inherited from a mosaic parent) have been reported, demonstrating consistent AD inheritance and functional impairment ([PMID:28597146]). Segregation in the mosaic parent further supports pathogenicity.

The variant spectrum includes eight missense changes affecting Ser32 or Ser36 (e.g., c.107C>A (p.Ser36Tyr) [PMID:23864385]) and three upstream nonsense or frameshift mutations (e.g., c.40G>T (p.Glu14Ter) [PMID:35005117], c.32G>A (p.Trp11Ter) [PMID:17931563]). Additional novel variants, such as c.94A>T (p.Ser32Cys) [PMID:36292785], c.91G>A (p.Asp31Asn) [PMID:32222431], and c.110T>A (p.Met37Lys) [PMID:23708964], expand the mutational landscape yet converge on the same pathogenic mechanism.

Functional assays in patient fibroblasts and transfected cell lines show abolished IκBα degradation, impaired NF-κB nuclear translocation, and reduced cytokine responses (TNF, IL-1, TLR agonists) consistent across models ([PMID:28597146]; [PMID:17931563]). HSCT corrects the immune defect but not the ectodermal phenotype, underscoring tissue-specific requirements for NF-κB activity.

No study has refuted this association, and all evidence is concordant. The clear genotype–phenotype correlation and successful functional rescue by HSCT support a Strong gene–disease validity classification.

Key Take-home: Heterozygous NFKBIA GOF variants cause AD EDA-ID via impaired IκBα degradation; genetic testing informs prognosis and HSCT decisions.

References

• Journal of clinical immunology • 2017 • Human IκBα Gain of Function: a Severe and Syndromic Immunodefic PMID:28597146
• Journal of clinical immunology • 2013 • Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel NFKBIA mutation, p.Ser36Tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation PMID:23864385
• Genes & diseases • 2022 • A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response PMID:35005117
• The Journal of allergy and clinical immunology • 2007 • Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency PMID:17931563
• Genes • 2022 • A Novel De Novo NFKBIA Missense Mutation Associated to Ectodermal Dysplasia with Dysgammaglobulinemia PMID:36292785
• Journal of clinical immunology • 2013 • A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy PMID:23708964
• European journal of medical genetics • 2020 • Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing PMID:32222431

Evidence Based Scoring (AI generated)