GJB2 – Keratitis-Ichthyosis-Hearing Loss (KID) Syndrome

Keratitis-ichthyosis-deafness (KID) syndrome is a rare autosomal dominant ectodermal dysplasia characterized by vascularizing keratitis (HP:0000491), sensorineural hearing impairment (HP:0000407), erythrokeratoderma and a high risk of squamous cell carcinoma. The disorder arises from gain-of-function or dominant-negative missense mutations in the gap junction beta-2 gene, GJB2 (connexin-26), which is critical for intercellular ion and metabolite flux in stratified epithelia.

Genetic evidence for GJB2 in KID syndrome includes over 100 unrelated probands and multiple familial cases. The p.Asp50Asn (c.148G>A (p.Asp50Asn)) substitution is recurrent in diverse populations (PMID:12072059, PMID:15633193, PMID:33136289). Other pathogenic variants include p.Gly45Glu, p.Ala88Val and p.Gly12Arg. Familial segregation has been demonstrated in at least 4 kindreds with vertical transmission of dominant mutations, and de novo occurrence is well documented in sporadic cases.

The variant spectrum is dominated by missense changes clustered in the first extracellular loop and transmembrane domains of connexin-26. Hypomorphic or loss-of-function alleles (e.g., p.Met34Thr) cause non-syndromic hearing loss, whereas dominant mutants (e.g., p.Asp50Asn, p.Gly45Glu) exert a dominant-negative effect on wild-type channel assembly. Notably, lethal alleles such as p.Gly45Glu and p.Ala88Val produce severe neonatal phenotypes with early mortality (PMID:30287322, PMID:36286624).

Functional studies in Xenopus oocytes and HeLa cells reveal that KID-associated mutants fail to support gap junction intercellular communication and often inhibit co-expressed wild-type connexins, including Cx26 and Cx30 (PMID:11912510, PMID:9393973). Transgenic expression of dominant-negative R75W in mouse cochlea leads to organ of Corti degeneration and deafness, recapitulating human disease (PMID:12700168).

The pathogenic mechanism involves dominant-negative disruption of gap junction channels, resulting in impaired epidermal differentiation, corneal epithelial instability and cochlear dysfunction. Secondary complications include increased susceptibility to infections and epithelial malignancies such as oral and cutaneous squamous cell carcinoma.

Integration of genetic and functional data supports a Strong ClinGen gene–disease association. Genetic testing for GJB2 exons 1 and 2, combined with targeted assays for recurrent hotspots, enables definitive diagnosis and guides reproductive counseling. Functional characterization of novel variants remains essential for accurate classification.

Key take-home: Dominant missense mutations in GJB2 cause KID syndrome via a dominant-negative mechanism, and early molecular diagnosis informs prognosis, management and family planning.

References

• The British journal of dermatology • 2002 • HID and KID syndromes are associated with the same connexin 26 mutation. PMID:12072059
• American Journal of Human Genetics • 2002 • Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. PMID:11912510
• Oncogene • 1997 • Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes. PMID:9393973
• Human Molecular Genetics • 2003 • Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. PMID:12700168
• American Journal of Medical Genetics Part A • 2019 • More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations. PMID:30287322
• American Journal of Medical Genetics Part A • 2023 • Keratitis-ichthyosis-deafness syndrome with lethal p.Ala88Val variant and severe hypercalcemia. PMID:36286624

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