Background Epidermolysis bullosa simplex (EBS) is a rare genodermatosis 
resulting from multiple gene mutations, including KRT5 and KRT14. The clinical 
expression of the mechanobullous skin fragility disease has not been fully 
explained by the genotype. Case Description An 11-day-old Japanese newborn 
infant was hospitalized because of herpetiform skin blistering on the feet, 
which expanded systemically after birth. There was no evidence of virus 
infection. The biopsied skin lesion showed a blister on the lamina densa without 
keratin clumps, indicating a diagnosis of EBS-generalized intermediate. We 
punctured the blisters to remove the contents daily, which led to no 
exacerbation or infection. The genetic study determined that the patient carried 
double substitutions of KRT5 c.1424A > G (p.E475G) and KRT14 c.1237G > A 
(p.A413T). The asymptomatic mother and sister carried the KRT14 substitution, 
but the healthy father had no substitution of the KRT gene. Conclusion This is 
the first report of EBS-generalized intermediate in a newborn with de novo KRT5 
gene mutation and KRT14 gene polymorphism, and no familial history of 
epidermolysis. Neonatal blistering due to EBS requires optimal skin management 
after excluding infectious and immunobullous diseases.