Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1

We report a 2-year-old boy with an unusual autosomal recessively inherited skin disease comprising trauma-induced skin fragility and congenital ectode rmal dysplasia affecting hair, nails and sweat glands. Skin biopsy showed w idening of intercellular spaces between keratinocytes and ultrastructural f indings of small, poorly formed desmosomes with reduced connections to the keratin filament cytoskeleton, Immunohistochemical analysis revealed a comp lete absence of staining for the accessory desmosomal plaque protein plakop hilin 1 (PKP1; band 6 protein). The affected individual was a compound hete rozygote for null mutations on both alleles of the PKP1 gene. Both mutation s occurred within the amino terminus of PKP1, the domain which normally bin ds the cytoskeletal keratin filament network to the cell membrane. Apart fr om its localization within desmosomal plaques, PKP1 may also be present wit hin the cytoplasm and nucleus and has putative roles in signal transduction and regulation of gene activity. The clinicopathological observations in t his patient demonstrate the relevance of PKP1 to desmosome formation, cutan eous cell-cell adhesion and epidermal development and demonstrate the speci fic manifestations of human functional knockout mutations in this gene.