Ectodermal dysplasia/skin fragility syndrome (EDSFS) (MIM604536) is a newly described autosomal recessive disorder characterized by skin fragility and blistering, palmoplantar keratoderma, abnormal hair growth, nail dystrophy, and occasionally defective sweating. It results from mutations in the PKP1 gene encoding plakophilin 1 (PKP1), which is an important component of stratifying epithelial desmosomes and a nuclear component of many cell types. Our study was performed to further characterize the histopathology of EDSFS in different cutaneous sites with a special emphasis on the hypotrichosis and keratoderma. A total of 4 biopsies were obtained from 2 EDSFS female patients, aged 9 days to 4 years. The biopsies were taken from the blistering skin of the leg and trunk, the hyperkeratotic skin of the sole, and the hypotrichotic scalp. The observed histopathologic features included: widened intercellular spaces, suprabasal intraepidermal clefts and blisters with acantholytic keratinocytes, detachments of the upper epidermal layers due to disadhesion, varying degrees of dyskeratosis that were much more pronounced in the plantar hyperkeratotic skin, and increased number of catagen-telogen hair follicles. The electron-microscopic observations attributed the disadhesion and acantholysis to reduced numbers of small hypoplastic desmosomes, and the dyskeratosis to the detachment of intracellular keratin filaments from the desmosomes with perinuclear condensation, which might also underlie the plantar keratoderma. The hair follicle findings suggest disturbance in the hair cycle, which might be attributed to disturbed nuclear PKP1 function or result from aberrant desmosomal signaling.