GJB2 – Keratitis-Ichthyosis-Deafness (KID) Syndrome

Keratitis-ichthyosis-deafness (KID) syndrome (MONDO:0018781) is a rare autosomal dominant ectodermal dysplasia characterized by progressive vascularizing keratitis, ichthyosiform erythrokeratoderma, and neurosensory hearing loss. Heterozygous missense mutations in GJB2 (HGNC:4284) encoding connexin-26 have been implicated as the primary genetic etiology. Screening for GJB2 variants is essential in patients presenting with congenital sensorineural hearing loss and disorders of cornification.

In a landmark study of 10 unrelated KID patients, seven distinct GJB2 missense mutations affecting conserved residues in the amino-terminus or first extracellular loop were identified, including the recurrent c.148G>A (p.Asp50Asn) in six sporadic cases and one multigenerational family (PMID:11912510). This cohort provided evidence of autosomal dominant inheritance and segregation of GJB2 variants with disease in a pedigree, yielding a total of 11 probands with KID syndrome ([PMID:11912510]).

An independent report described a Swedish patient with KID syndrome harboring the same p.Asp50Asn variant, further supporting recurrence and phenotypic consistency ([PMID:17106596]). Together, these case series fulfill the threshold for strong genetic evidence under ClinGen guidelines.

Functional assays in paired Xenopus oocytes and HeLa/N2A cells have demonstrated that KID-associated Cx26 mutants (e.g., p.Ser17Cys, p.Gly12Arg, p.Ile30Asn, p.Asp50Tyr) are incapable of forming functional gap junction plaques, exhibit aberrant hemichannel opening, and disrupt intercellular ion homeostasis ([PMID:11912510]; [PMID:26831144]). These dominant-negative effects on gap junction intercellular communication are concordant with human disease manifestations.

The pathogenic mechanism for GJB2-related KID syndrome is dominant-negative loss of connexin-26 function, leading to impaired gap junctional coupling in epidermal and cochlear epithelia. No substantive conflicting evidence has been reported for GJB2 in KID syndrome, although genetic heterogeneity exists (e.g., GJB6 mutations).

Key Take-home: Autosomal dominant GJB2 missense variants, notably c.148G>A (p.Asp50Asn), are a well‐established cause of KID syndrome, supporting their inclusion in diagnostic gene panels for ectodermal dysplasias with hearing loss.

References

• American Journal of Human Genetics • 2002 • Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. PMID:11912510
• Acta dermato-venereologica • 2006 • Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin. PMID:17106596
• Biochemical and biophysical research communications • 2010 • Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss. PMID:20307501
• BMC cell biology • 2016 • Altered cellular localization and hemichannel activities of KID syndrome associated connexin26 I30N and D50Y mutations. PMID:26831144

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