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KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies

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.

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Fig. 1: Pedigrees.
Fig. 2: Phenotypes of patients.

Data availability

Data will be made available upon request.

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Acknowledgements

We are grateful to families for their collaboration. We acknowledge the contribution of Dr. Muhammad Jamal Ullah to clinical evaluation of participants. Adult patients and guardians of minor patients gave written informed consent to publication of the relevant case details.

Funding

Supported by the Istanbul Technical University Research Fund (TGA-2021-42537) and URF-QAU, Pakistan (DAS-1071).

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Authors

Contributions

Conceptualization: AT and SM; Formal analysis: MK and GN; Funding acquisition: AT and SM; Investigation: MK, MN, GN, RMKS, TM, ZH, SM, and AT; Project administration: AT and SM; Supervision: AT and SM; Validation: MK and GN; Visualization: MK, MN, GN, and RMKS; Writing - Original Draft Preparation: AT, SM, MK, and GN; Writing - Review and Editing: AT and SM.

Corresponding authors

Correspondence to Sajid Malik or Aslıhan Tolun.

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The authors declare no competing interests.

Ethical approval

The procedures followed were in accordance with the ethical standards of the Ethical Review Committee of Quaid-i-Azam University (review no DAS-1070) and the Istanbul Technical University Human Research Ethical Review Board (MB62/2019).

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Koprulu, M., Naeem, M., Nalbant, G. et al. KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01128-4

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