History and prospects of Nagashima-type palmoplantar keratosis, the most common palmoplantar keratoderma in east Asian populations

Nagashima-type palmoplantar keratosis (NPPK) has been shown to represent a form of autosomal recessive palmoplantar keratosis due to biallelic pathological variants of SERPINB7, which encodes a serine protease inhibitor expressed in the epidermis. Approximately 10 years have elapsed since NPPK was demonstrated to be an independent genetic disease, and the most prevalent palmoplantar keratoderma (PPK) in East Asian countries due to a high prevalence of founder mutations in SERPINB7. Since then, it has become evident that biallelic pathological variants of SERPINA12, which encodes a serine protease inhibitor expressed in the epidermis, can also manifest symptoms analogous to those of NPPK. Furthermore, a pathological variant of SERPINB7 was identified as a risk factor for the development of atopic dermatitis in a genome-wide association study (GWAS) of atopic dermatitis, indicating that the frequent co-occurrence of NPPK and atopic dermatitis is not a mere coincidence. Despite the documentation of NPPK cases in Japan since the 1970s, there have been no reports of individuals with similar symptoms from other regions, including Europe and the USA. Consequently, the existence and independence of the disease remained uncertain until its genetic cause was identified. The disease's independence was established through the accumulation of data on affected individuals, including the provision of accurate descriptions of their symptoms, which enabled the identification of the genetic cause. This review presents a comprehensive overview of the history and prospects of NPPK with a particular focus on the history of the process of establishing NPPK as an independent disease.