Hereditary Keratodermas In Pakistan: A Distinct Genetic Landscape Shaped By Consanguinity

Abstract

Hereditary keratodermas are a heterogeneous group of epidermal differentiation disorders. They range from mild focal thickening to more severe diffuse or syndromic forms that could have systemic complications. In Pakistan, with more than 50% consanguinity, the inheritance patterns of keratoderma are influenced by population structure, leading to a high burden of autosomal recessive founder variants. This review is based on molecular studies of Pakistani families of last five years. We found 8 reports of Pakistani families, 5 South -Asian comparative studies and 29 international sequencing cohorts. The predominant types were autosomal-dominant (AD) across the world, which is mainly caused by mutations in the keratin genes (KRT1, KRT9, KRT16), but in Pakistan, the pedigrees were dominated by autosomal-recessive (AR) or a combination of the two types (SLURP1, DSG1, DSP, COL20A1, and LOR). Long homozygosity tracts were formed through consanguinity, making it easy to identify variants. In newer cohorts, comprehensive sequencing has yielded a diagnostic result of over 70.  Clinically, diffuse non-syndromic PPK is most frequently reported, though syndromic forms with cardiac, dental, or hair involvement are also prevalent. To convert these findings into better clinical management, new, stronger dermatogenetic infrastructure, databases of curated variants, and national family registries are needed.