SPINK5 Variants Drive Clinical Variability in Netherton Syndrome Through Th2/Th17 Skewing and Influence Therapeutic...

Area of Science:

• Genetics and Immunology
• Dermatology
• Rare Diseases

Background:

• Netherton syndrome (NS) is a rare genetic disorder caused by SPINK5 gene mutations, leading to LEKTI protein deficiency.
• Current classification as a hyper-IgE syndrome is challenged by NS manifestations, with limited genotype-phenotype data and inconsistent pediatric biologic therapy outcomes.

Purpose of the Study:

• Investigate clinical and immunological features of NS.
• Analyze genotype-phenotype correlations and pediatric outcomes of systemic and biologic therapies.
• Clarify the role of skin barrier defects in NS immune dysregulation.

Main Methods:

• Retrospective-prospective study of eight NS patients.
• Analysis of clinical, immunological, and treatment data.
• Categorization of SPINK5 variants based on LEKTI protein fragments (FR1-FR5).

Main Results:

• Four FR1-related SPINK5 variants linked to severe NS phenotypes; two FR5-related variants associated with milder disease.
• Skin barrier disruption correlated with immune activation (Th2/Th17 skewing), increased PD-1, and altered T cell populations.
• Secukinumab effective for scaling, dupilumab for pruritus in erythroderma; dupilumab and infliximab showed temporary efficacy; immunoglobulin therapy supported growth.

Conclusions:

• NS involves indirect immune dysregulation secondary to a defective skin barrier.
• Therapeutic strategies should address skin barrier repair and broader immune modulation beyond single targets.
• Further research needed on genotype-phenotype correlations and optimizing pediatric NS management.