Molecular Evidence for KRT6A-Associated Pachyonychia Congenita Tarda with Onset at Age 53

Pachyonychia congenita tarda (PCT) is a rare late-onset variant of pachyonychia congenita (PC), with its nosological status remaining controversial due to limited molecular confirmation in adult-onset cases. We report a 57-year-old Chinese woman who presented with a four-year history of progressive, painful thickening of all 20 nails, accompanied by mild palmoplantar keratoderma. Repeated mycological examinations were negative, and no clinical improvement was observed after prolonged antifungal therapy. Familial segregation analysis could not be performed because biological samples from relatives were unavailable, and the patient reported no known affected relatives. Whole-exome sequencing (WES), followed by Sanger confirmation, identified a heterozygous missense variant in KRT6A (c.661C>A, p.Leu221Ile), predicted to be pathogenic. Notably, the mutation is located outside the highly conserved helix boundary motifs (HBM), in contrast to classic PC-associated variants that typically present in early childhood. The patient's phenotype was relatively mild and characterized by isolated late-onset nail dystrophy. To our knowledge, this case represents the latest reported onset of PCT, occurring at 53 years of age, and provides molecular evidence supporting PCT as a distinct clinical entity rather than a misdiagnosis of other keratinization disorders. We further propose that mutations outside HBM regions, combined with conservative amino acid substitutions, may preserve partial keratin function and delay disease manifestation until later in life. In conclusion, PCT should be considered in the differential diagnosis of treatment-resistant onychomycosis, particularly in older adults, and WES may serve as a valuable tool for accurate diagnosis.