Abstract
We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma, folliculitis, alopecia, sparse eyebrows, dental anomalies and variable acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters on soles and/or arms, rough sparse hair on scalp and keratosis pilaris. By exome sequencing we detected homozygous KRT17 c.281G>A (p.(Arg94His)) in affected individuals, and linkage mapping indicated a single locus. Heterozygous variants in KRT17 cause PC2 (PC-K17) with main characteristics of pachyonychia, subungual keratosis, palmoplantar keratoderma, hyperhidrosis, oral leukokeratosis and epidermal cysts, or steatocystoma multiplex, both with dominant inheritance. The causative variant has been reported in heterozygous state in a family afflicted with severe steatocystoma multiplex and in a sporadic PC2 case, and thus we also define a third phenotype related to the variant. Both exome sequencing and linkage mapping demonstrated recessive inheritance whereas Sanger sequencing indicated heterozygosity for the causal variant, reiterating caution for simple targeted sequencing for genetic testing. Testing parents for variants found in sibs could uncover recessive inheritance also in other KRT genes.