History and Prospects of Nagashima-Type Palmoplantar Keratosis

Background

Palmoplantar keratoderma (PPK) is a group of hereditary or inflammatory skin disorders characterized by hyperkeratosis of the palms and soles, with diverse clinical manifestations and complex diagnostic criteria. Nagashima-type palmoplantar keratosis (NPPK) is the most common type of PPK in East Asian populations, caused by biallelic pathogenic variants in the SERPINB7 gene. Since its first description in Japan in the 1970s, the independence and genetic mechanisms of NPPK had been a subject of debate until the discovery of pathogenic variants in the SERPINB7 gene in 2013 formally established NPPK as an independent genetic disorder. Subsequently, it was found that variants in the SERPINA12 gene could also cause clinical symptoms similar to NPPK. This review traces the research history of NPPK, explores its genetic mechanisms, clinical manifestations, diagnostic markers, and future research directions.

Source of the Article

This article was written by Akiharu Kubo and published in the first issue of Journal of Dermatology in 2025. Akiharu Kubo is a renowned expert in the field of dermatogenetics from the Department of Dermatology, Graduate School of Medicine, Kobe University, Japan. By reviewing the research history of NPPK, this article systematically summarizes its genetic basis, clinical manifestations, relationships with other related diseases, and prospects for future research.

Key Points

1. Independence and Genetic Basis of NPPK

NPPK was initially considered a variant of Mal de Meleda, but Masaji Nagashima first proposed in 1977 that the manifestations in Japanese patients differed significantly from those of Mal de Meleda. NPPK has a milder clinical presentation, primarily characterized by erythematous hyperkeratosis of the palms and soles, accompanied by “transgrediens” (extension of lesions to the dorsa of hands and feet, etc.). In 2013, Akiharu Kubo and colleagues identified biallelic pathogenic variants in the SERPINB7 gene in 13 NPPK patients through whole-exome sequencing, establishing NPPK as an independent genetic disorder. SERPINB7 encodes a serine protease inhibitor, and its loss of function leads to stratum corneum barrier defects and hyperkeratosis.

Supporting Evidence:
- NPPK patients exhibit mild erythematous hyperkeratosis, differing in severity from Mal de Meleda.
- Pathogenic variants in the SERPINB7 gene were identified in all 13 NPPK patients, with the c.796C>T variant being a founder variant in East Asian populations.
- Expression of SERPINB7 in keratinocytes is closely related to skin barrier function.

2. Diagnostic Marker of NPPK: “Water Sign”

The typical clinical manifestations of NPPK include erythematous hyperkeratosis of the palms and soles, accompanied by “transgrediens.” Additionally, a transient whitish change in the affected skin upon exposure to water, known as the “Water Sign,” is observed. This phenomenon is attributed to stratum corneum barrier defects caused by SERPINB7 dysfunction.

Supporting Evidence:
- All 13 NPPK patients exhibited the “Water Sign,” which appeared immediately after water exposure and resolved upon drying.
- The “Water Sign” is considered a diagnostic marker of NPPK, aiding in its differentiation from other types of PPK.

3. Similarities Between SERPINA12-Related PPK and NPPK

In 2020, researchers discovered that variants in the SERPINA12 gene could also cause clinical symptoms similar to NPPK. SERPINA12 encodes another serine protease inhibitor, and its loss of function leads to stratum corneum barrier defects and hyperkeratosis. The clinical phenotypes of NPPK and SERPINA12-related PPK are similar, but their genetic mechanisms differ.

Supporting Evidence:
- SERPINA12-related PPK patients also present with erythematous hyperkeratosis of the palms and soles, accompanied by “transgrediens.”
- Expression of SERPINA12 in keratinocytes is closely related to skin barrier function, and its loss of function results in stratum corneum barrier defects.

4. Association Between NPPK and Atopic Dermatitis

Atopic dermatitis (AD) has a higher incidence among NPPK patients, suggesting a potential association between the two. In 2020, a genome-wide association study (GWAS) identified SERPINB7 gene variants associated with the susceptibility to AD.

Supporting Evidence:
- A founder variant of SERPINB7 identified in the Finnish population was associated with increased susceptibility to AD.
- The higher incidence of AD in NPPK patients suggests that stratum corneum barrier defects may accelerate allergen penetration and inflammatory responses.

5. Current Treatment and Future Directions for NPPK

Currently, treatment for NPPK focuses on symptomatic relief, such as using cosmetics to cover skin erythema and deodorants to reduce odor. Additionally, researchers have explored gene therapy approaches (e.g., gentamicin-induced readthrough) to restore SERPINB7 function.

Supporting Evidence:
- There is no specific treatment for NPPK; patients mainly rely on symptomatic treatments to improve quality of life.
- Gene therapy approaches have shown potential in in vitro experiments but require further research.

Significance and Value of the Article

This article systematically reviews the research history of NPPK, summarizes its genetic basis, clinical manifestations, and relationships with other related diseases, providing important theoretical foundations for the diagnosis and treatment of NPPK. Furthermore, it outlines future research directions, including further investigations into the mechanisms of SERPINB7 and SERPINA12, and the development of targeted treatments for NPPK. The findings not only deepen the understanding of NPPK but also offer insights for the diagnosis and treatment of other hereditary skin disorders.

Additional Valuable Content

• The article provides a detailed explanation of the roles of SERPINB7 and SERPINA12 in skin barrier function, offering important clues for understanding the molecular mechanisms of the stratum corneum barrier.
  
• It highlights the potential association between NPPK and AD, opening new avenues for exploring the causal relationship between the two.
  

By offering a comprehensive review of NPPK, this article provides significant theoretical and practical guidance for the research and treatment of this hereditary skin disorder.