A novel heterozygous frameshift mutation in the KRT6A gene responsible for an uncommon phenotype of pachyonychia congenita: One case report and review of literature

Abstract

Pachyonychia congenita is an uncommon autosomal dominant skin disorder characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and cutaneous cysts. And fissured tongue is rarely reported in patients with pachyonychia congenita. The disease is primarily associated with mutations in five keratin genes, namely KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Herein we report a 9-year-old Chinese girl who has thickened nails, keratinized plaques, and fissured tongue since birth. To investigate the underlying genetic cause, whole-exome sequencing and Sanger sequencing were performed in this patient and her family members. We identified a candidate variant c.1460-2_1460del (p.S487Lfs*21) in the KRT6A gene (NM_005554.4) by whole-exome sequencing. Sanger sequencing revealed the absence of the mutation in both parents, indicating that it is a de novo variant. Thus, the novel heterozygous frameshift mutation c.1460-2_1460del (p.S487Lfs*21) within exon 9 of KRT6A was identified as the genetic cause of the patient. Our study identified a rare de novo heterozygous frameshift mutation in the KRT6A gene in a patient with pachyonychia congenita presenting fissured tongue. Our findings expand the KRT6A gene mutation spectrum of Pachyonychia congenita, and will contribute to the future genetic counseling and gene therapy for this disease.

Keywords: Fissured tongue; Genodermatosis; KRT6A; Keratin; Pachyonychia congenita.

Fig. 1

Family Pedigree. Pedigree was constructed for the 7-member family with PC. Squares and circles indicate males and females, respectively. Arrow indicates the proband.

Fig. 2

Clinical Phenotype of the Proband with PC. (a, b) The nail grooves of the fingernails and toenails were partly thickened and raised in a wedge shape, and the surface of the nails was rough, opaque, and dirty brown. (c) The skin on the stressed part of the sole had become keratinized, thickened, darkened, and cracked. (d) The patient exhibited fissured tongue, oral leukokeratosis, and keratotic plaques in the corners of mouth. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Mutant sequence in the KRT6A gene. (a) Sanger sequencing showed the heterozygous c.1460–2_1460del variant in the patient. (b) The patient's parents showed wild-type sequences.

Fig. 4

The domain structure and the location of reported mutations of K6a protein. The α-helical rod domain has four domains, the 1A, 1B, 2A, 2B, each domain consists of seven repeat sequences. These domains are connected by linkers, L1, L12, L2. The rod domain is flanked by variable domains V1 and V2. The ‘stutter’ sequence is marked by S. The H1 and H2 sub-domains are present in type II keratins. KRT6A mutation sites source: IPCRR (www.pachyonychia.org).