IKBKG – Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal disorder predominantly affecting females and typically lethal in hemizygous males. The condition is characterized by four sequential cutaneous stages—vesicular, verrucous, hyperpigmented, and atrophic—and may include dental, ocular, neurological, skeletal, and hair abnormalities. IP is caused by loss-of-function variants in IKBKG (encoding NF-κB essential modulator, NEMO), a key regulator of NF-κB signaling. Clinically, patients present with characteristic Blaschko-linear skin lesions often in the neonatal period, with extracutaneous manifestations in up to 30% of cases.

Genetic evidence supporting a definitive gene–disease relationship includes the identification of a recurrent de novo deletion of exons 4–10 in IKBKG accounting for 90% of >350 unrelated IP patients and over 277 distinct small indels, nonsense, splice-site, and missense variants disrupting NEMO function ([PMID:11590134]). Segregation studies in multiplex families demonstrate X-linked dominant inheritance with affected daughters inheriting the deletion and skewed X-inactivation favoring the wild-type allele in carriers ([PMID:11590134]). Case reports of mother-daughter pairs and multiple sibships further confirm co-segregation of pathogenic variants with the IP phenotype.

The variant spectrum comprises large recurrent deletions (exons 4–10) and 21 reported private indels and point mutations causing frameshifts with premature truncation or hypomorphic NEMO alleles. A representative pathogenic allele is c.924C>G (p.Tyr308Ter), a nonsense mutation that abolishes NEMO’s ability to support both K63-linked and linear polyubiquitination necessary for NF-κB activation ([PMID:30913450]). This variant exemplifies the loss-of-function mechanism underpinning IP.

X-linked dominant inheritance is uniformly observed; obligate carrier females often show skewed X-inactivation, while rare surviving XY males exhibit mosaicism or Klinefelter karyotypes. Segregation data include at least 1 affected relative (daughter) in a described family, confirming familial transmission and variable expressivity.

Functional assays in patient cells and model systems demonstrate that truncating and hypomorphic IKBKG variants impair IKK complex assembly, abolish stimulus-induced NF-κB activation, and sensitize cells to apoptosis. Mutations in the C-terminal CC2-LZ and zinc-finger domains disrupt polyubiquitin binding, revealing a dominant role for NEMO in both pro-survival and inflammatory signaling pathways. Rescue experiments with wild-type NEMO restore NF-κB activity, substantiating pathogenicity.

In summary, the IKBKG–incontinentia pigmenti association meets criteria for a definitive ClinGen classification. Genetic testing for the common exon 4–10 deletion and targeted sequencing of IKBKG reliably confirms diagnosis. Functional studies elucidate a clear loss-of-function mechanism via NF-κB pathway disruption. Key take-home: IKBKG genetic analysis and NF-κB functional assessment are essential for accurate diagnosis and genetic counseling of IP patients.

References

• Human Molecular Genetics • 2001 • A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. [PMID:11590134]
• Indian Journal of Pathology & Microbiology • 2010 • Incontinentia pigmenti. [PMID:20551538]

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