KRT17 – Pachyonychia Congenita Type 2

Pachyonychia congenita type 2 (PC-2) is an autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma and multiple pilosebaceous cysts. Germline mutations in keratin 17 disrupt intermediate filament assembly, leading to the PC-2 phenotype.

Initial linkage in a single family identified a novel heterozygous missense variant c.263T>C (p.Met88Thr) (PMID:10571744). Subsequent reports described three additional alleles within the 1A domain—c.281_295del (p.Arg94_Tyr98del), c.281G>C (p.Arg94Pro) and c.284T>A (p.Leu95Gln)—in unrelated patients (PMID:11348474). A large Chinese pedigree with delayed-onset PC-2 revealed c.325A>G (p.Asn109Asp) segregating in 19 affected members (PMID:15102078). Another six-generation kindred carrying c.274A>G (p.Asn92Ser) exhibited 15 affected individuals with a consistent phenotype (PMID:19107515).

Collectively, six probands across four unrelated families and segregation in 32 additional affected relatives support a strong gene–disease association. All pathogenic variants cluster within the conserved 1A coiled-coil domain, consistent with a dominant-negative mechanism disrupting keratin filament networks.

Direct functional assays of PC-2–associated KRT17 variants are lacking, limiting mechanistic evidence to structural modeling and predicted impacts on filament assembly.

No conflicting data have been reported. Additional high-throughput and cellular studies exist but exceed the scope of this clinical summary.

Key Take-home: Heterozygous missense and small in-frame deletion mutations in KRT17’s 1A domain cause autosomal dominant PC-2; KRT17 genetic testing is essential for diagnosis, prognosis and family counseling.

References

• The Journal of investigative dermatology • 1999 • Mutation report: identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. PMID:10571744
• The Journal of investigative dermatology • 2001 • Novel keratin 17 mutations in pachyonychia congenita type 2. PMID:11348474
• The Journal of investigative dermatology • 2004 • A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2. PMID:15102078
• European journal of pediatrics • 2009 • Pachyonychia congenita type 2, N92S mutation of keratin 17 gene: clinical features, mutation analysis and pathological view. PMID:19107515

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