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Annular epidermolytic ichthyosis (AEI) is a rare autosomal dominant ichthyosis characterized by recurrent, polycyclic, migratory erythematous and scaly plaques with variable palmoplantar keratoderma. It arises from heterozygous pathogenic variants in keratin genes, predominantly KRT1 and KRT10, disrupting keratin intermediate filament assembly and epidermal integrity.
Two independent de novo missense variants in KRT1 have been reported in patients with AEI: c.1436T>C (p.Ile479Thr) in a 5-year-old girl presenting with cyclic erythematous plaques and palmoplantar keratoderma (PMID:30152556), and c.1349C>A (p.Ala450Asp) in a 3-year-old with Greither-like PPK and recurrent hyperkeratotic plaques with hyperhidrosis (PMID:35202349).
A large Chinese pedigree spanning three generations demonstrated autosomal dominant segregation of c.1436T>C (p.Ile479Thr) in nine affected relatives, confirming co-segregation with AEI phenotype (PMID:32666929).
These variants localize within the conserved helix 2B domain of KRT1, a hotspot for dominant-negative mutations in epidermolytic disorders. The recurrent c.1436T>C change has now been documented in multiple unrelated families, highlighting founder or mutational hotspot effects.
Histopathology of lesional skin shows epidermolysis and granular layer hyperkeratosis consistent with keratin network collapse. In vitro overexpression studies of 2B domain mutants demonstrate keratin aggregate formation and filament network disruption, supporting a dominant-negative mechanism.
Collectively, clinical, genetic, and functional data establish a moderate to strong association between KRT1 missense variants and AEI. Genetic testing for KRT1 enables definitive diagnosis, guides genetic counseling, and informs management of this genodermatosis.
Gene–Disease AssociationModerate11 probands (including two de novo cases and one large pedigree with 9 affected relatives) and segregation consistent with autosomal dominant inheritance Genetic EvidenceModerate11 probands across three independent events, including one multigenerational family; variant clustering in the helix 2B domain Functional EvidenceSupportingHistopathology showing epidermolysis and hyperkeratosis; in vitro keratin aggregate formation demonstrates dominant-negative effects |