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

Abstract

Background: Netherton syndrome (NS) is a rare genetic disorder resulting from biallelic mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI). Although currently classified as a hyper-IgE syndrome, several manifestations contradict this categorization. Data on genotype-phenotype correlations remain limited, and pediatric outcomes of biologic therapies are inconsistent.

Objective: This study investigated the clinical, immunological features, genotype-phenotype correlations, and pediatric outcomes of various systemic and biologic therapies in detail.

Methods: Clinical, immunological, and treatment data from 8 patients were collected in a mixed retrospective-prospective design. Variants were categorized based on the affected bioreactive fragments (FR1-FR5) of the LEKTI protein.

Results: Among 6 SPINK5 variants, including 2 novel ones, 4 FR1-related variants were linked to severe phenotypes, whereas 2 FR5-related variants were associated with milder disease. The onset of skin features was significantly earlier in patients with allergic manifestations than in those without. Although no intrinsic developmental defects in T or B cells were identified, skin barrier disruption was associated with immune activation and skewing toward Th2/Th17 responses. Notably, increased programmed cell death protein-1 expression, expansion of CD4⁺IL-17⁺ T cells, and reduced frequencies of IFN-γ-producing CD4⁺ T cells correlated with clinical disease severity. In scaly erythroderma, secukinumab was most effective for scaling, whereas dupilumab was more effective for pruritus. The efficacy of dupilumab and infliximab was temporary, with rebound skin lesions observed during follow-up. Immunoglobulin therapy supported growth but revealed variable skin benefits.

Conclusion: The described findings support the concept of indirect immune dysregulation in NS due to a defective skin barrier, emphasizing the need for therapies that extend beyond single cytokine or receptor blockade.

Keywords: Biological therapy; Genotype-phenotype correlation; Immunophenotype; Netherton syndrome; SPINK5.