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Netherton syndrome

Disease Pathophysiology Research Template

2026-02-19
Falcon MONDO:0009735 Model: Edison Scientific Literature 19 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Netherton syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Netherton syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Netherton Syndrome (NS): a 2023–2024–focused molecular/cellular research report

  1. Disease identifiers and current definition

Disease: Netherton syndrome (NS) is a rare, severe Mendelian disorder of epidermal barrier function and immune/allergic dysregulation caused by loss-of-function variants in SPINK5, encoding the serine protease inhibitor LEKTI. In Open Targets, NS is mapped to MONDO_0009735 and is strongly associated with SPINK5. (moltrasio2023nethertonsyndromecaused pages 1-2)

Identifiers - MONDO: MONDO_0009735 (Open Targets disease page; accessed via Open Targets API in this run). - OMIM: #256500 (moltrasio2023nethertonsyndromecaused pages 1-2)

Epidemiology (recently reiterated) - Petrova et al. (2024) states NS affects ~1:200,000 persons worldwide. (petrova2024comparativeanalysesof pages 1-2) - Moltrasio et al. (2023) summarizes incidence estimates around ~1:100,000–1:200,000 and notes prevalence estimates. (moltrasio2023nethertonsyndromecaused pages 1-2)

  1. Core pathophysiology: key concepts and current understanding

2.1 Primary molecular defect: SPINK5/LEKTI deficiency → uncontrolled epidermal proteolysis

Core concept - NS is fundamentally a “protease-inhibitor” disease: SPINK5 loss leads to functional deficiency of LEKTI, which normally restrains epidermal serine protease activity.

Mechanistic chain (barrier and inflammation) - Petrova et al. (2024) describes LEKTI as expressed in differentiated epidermis and normally inhibiting multiple serine proteases including KLK5, KLK6, KLK7, KLK13, and KLK14 (as well as cathepsin G and caspase-14). LEKTI deficiency results in “unrestrained proteolytic activity.” (petrova2024comparativeanalysesof pages 1-2) - Moltrasio et al. (2023) describes that SPINK5 mutations leading to LEKTI dysfunction produce “persistent activation of skin kallikreins (KLK) and increased premature degradation of desmosomal and corneodesmosomal cadherins.” (moltrasio2023nethertonsyndromecaused pages 1-2)

2.2 Barrier breakdown mechanisms

(1) Corneodesmosome/desmosome cleavage → premature detachment of stratum corneum - Petrova et al. (2024) links uncontrolled epidermal proteases to “proteolytic degradation of (corneo)desmosomal cadherins and stratum corneum lipid-processing enzymes,” producing barrier defects and premature detachment. (petrova2024comparativeanalysesof pages 1-2) - Moltrasio et al. (2023) highlights premature degradation of desmosomal/corneodesmosomal cadherins and impaired keratinization/cornification. (moltrasio2023nethertonsyndromecaused pages 1-2, moltrasio2023nethertonsyndromecaused pages 5-7)

(2) Defective stratum corneum processing and keratinization - Petrova et al. (2024) reports enrichment of GO terms related to keratinization and protease activity in NS/Spink5-cKO shared signatures and emphasizes that focusing on “protease activity” improves correlation to human NS, “indicating the key role of protease activity in NS pathogenesis.” (petrova2024comparativeanalysesof pages 6-7)

2.3 Protease-activated inflammatory signaling: PAR2 axis and epithelial “alarmins”

PAR2 as a bridge from proteolysis to inflammation - Petrova et al. (2024) states that unrestrained protease activity promotes inflammation via “proteolytic activation of PAR-2 signaling” and by proteolytic processing of complement C3 and IL-1B. (petrova2024comparativeanalysesof pages 1-2) - Moltrasio et al. (2023) provides a canonical quote connecting kallikrein hyperactivity to Th2 skewing: “unregulated KLK5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in LEKTI-deficient epidermis.” (moltrasio2023nethertonsyndromecaused pages 5-7)

Downstream mediators and epithelial activation - Moltrasio et al. (2023) explicitly lists downstream mediators induced in this cascade, including “thymic stromal lymphopoietin (TSLP), tumor necrosis factor (TNF)-α, interleukin (IL)-8, and intercellular adhesion molecule 1 (ICAM-1).” (moltrasio2023nethertonsyndromecaused pages 1-2)

2.4 Immune dysregulation: mixed Th2 + Th17/IL-17/IL-36 programs

Th17/IL-17/IL-36 signature (psoriasis-like overlap) - Petrova et al. (2024) reports shared NS patient and Spink5 conditional KO signatures with “up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling” and identifies a conserved “KLK/IL-36 signaling axis.” (petrova2024comparativeanalysesof pages 1-2) - Petrova et al. (2024) transcriptomic heatmaps include IL17A, IL17C, IL17F, IL36A, IL36G, IL36RN, IL22, IL23A, IL1A and IL1B as part of the immune/inflammatory response signature. (petrova2024comparativeanalysesof pages 6-7) - Pawlowski et al. (2024) reports that “Both cases demonstrated robust expression of IL-36,” supporting that NS is “at least in part, driven by Th17 inflammation.” (pawlowski2024interleukin36ishighly pages 1-2, pawlowski2024interleukin36ishighly pages 5-6)

Th2/atopic features - Moltrasio et al. (2023) links LEKTI dysfunction with atopy and elevated IgE, and notes potential mechanisms via altered thymic T-cell maturation affecting Th2 responsiveness. (moltrasio2023nethertonsyndromecaused pages 2-5)

  1. Key molecular players (genes/proteins; chemicals; cells; tissues)

3.1 Genes and proteins (HGNC symbols)

Causal gene - SPINK5 (HGNC: serine peptidase inhibitor Kazal type 5); protein: LEKTI. (moltrasio2023nethertonsyndromecaused pages 1-2, petrova2024comparativeanalysesof pages 1-2)

Protease cascade / enzymes - Kallikreins inhibited by LEKTI: KLK5, KLK6, KLK7, KLK13, KLK14. (petrova2024comparativeanalysesof pages 1-2) - Additional proteases referenced: Cathepsin G, Caspase-14. (petrova2024comparativeanalysesof pages 1-2)

Barrier structural targets (proteolysis substrates) - Desmosomal/corneodesmosomal cadherins (e.g., desmoglein 1 [DSG1], desmocollin 1 [DSC1]) are reduced/cleaved in the setting of protease hyperactivity, impairing barrier adhesion. (moltrasio2023nethertonsyndromecaused pages 5-7, kline2024staphylococcusaureusproteases pages 1-2)

Inflammatory and cytokine pathway genes - IL17A/IL17C/IL17F; IL36A/IL36G/IL36RN; IL22; IL23A; IL1A/IL1B. (petrova2024comparativeanalysesof pages 6-7) - TSLP, TNF, IL8 (CXCL8), ICAM1. (moltrasio2023nethertonsyndromecaused pages 1-2)

Receptors / innate signaling - PAR-2 (protease-activated receptor 2) is directly implicated as protease-activated inflammatory signaling node. (petrova2024comparativeanalysesof pages 1-2, moltrasio2023nethertonsyndromecaused pages 5-7)

3.2 Chemical entities (CHEBI-level concepts)

No specific metabolites were directly quantified in the retrieved NS-specific mechanistic primary sources. Relevant therapeutic chemical entities appearing in current implementations include biologics (dupilumab, secukinumab) and small-molecule JAK inhibitors (baricitinib, upadacitinib) noted in expert reviews; additionally, antibiotics are used for infection control. (morizane2025biologicsandsmall‐molecule pages 8-9, NCT07151508 chunk 1, moltrasio2023nethertonsyndromecaused pages 2-5)

3.3 Cell types (CL-level concepts)

Primary affected cell type - Keratinocytes (epidermal keratinocytes) are the key cell type where LEKTI is processed and where protease/alarmin/cytokine cascades are initiated. (pawlowski2024interleukin36ishighly pages 6-8)

Immune cell involvement - Neutrophils are implicated in systemic inflammation of Spink5 cKO mice and are consistent with Th17/IL-17/IL-36-driven neutrophil recruitment (via CXCL8/CCL20 pathways described in Pawlowski et al.). (petrova2024comparativeanalysesof pages 1-2, pawlowski2024interleukin36ishighly pages 2-5) - CD4+ lymphocytes are explicitly measured for IL-17A levels in the observational combination-biologic cohort. (NCT07151508 chunk 1)

3.4 Anatomical locations/tissues (UBERON-level concepts)

Skin and epidermal layers - Epidermis and stratum corneum; LEKTI secretion occurs at the granular–cornified interface; superficial stratum granulosum is referenced. (petrova2024comparativeanalysesof pages 1-2, pawlowski2024interleukin36ishighly pages 6-8)

Hair - Hair shaft abnormalities (e.g., trichorrhexis invaginata) are part of the disease triad and are explicitly linked to NS definition in Moltrasio et al. (2023). (moltrasio2023nethertonsyndromecaused pages 5-7)

Thymus / immune organs - Petrova et al. (2024) notes LEKTI expression in thymic medullary epithelium and reports systemic inflammation in Spink5 cKO mice correlating with severity and associated with thymic atrophy and lymphoid organ enlargement. (petrova2024comparativeanalysesof pages 1-2)

Other epithelia - Moltrasio et al. (2023) mentions mucous epithelia, trachea and sinonasal epithelium as sites where LEKTI may be relevant. (moltrasio2023nethertonsyndromecaused pages 1-2)

  1. Biological processes disrupted (GO-style terms)

Directly supported processes (examples for GO annotation) - Proteolysis / protease activity: enriched and central to NS pathogenesis in shared transcriptomic signatures. (petrova2024comparativeanalysesof pages 6-7) - Negative regulation of peptidase activity: enriched among upregulated genes (reflecting compensatory protease-inhibitor induction such as SLPI, SPINK7, CSTA, SERPINB3/4). (petrova2024comparativeanalysesof pages 6-7) - Keratinization / cornification: enriched GO terms and described clinically as abnormal cornification. (petrova2024comparativeanalysesof pages 6-7, moltrasio2023nethertonsyndromecaused pages 1-2) - Immune and inflammatory response: shared transcriptomic signature with IL-17/IL-36/IL-1/IL-23 genes. (petrova2024comparativeanalysesof pages 6-7) - Desquamation (conceptually): LEKTI fragments “control desquamation through a pH-dependent interaction.” (petrova2024comparativeanalysesof pages 22-22)

  1. Cellular components: where key processes occur

  2. Lamellar granules: LEKTI is localized to lamellar granules and secreted in superficial stratum granulosum, supporting an epidermal secretory pathway/vesicular compartment for protease inhibition. (pawlowski2024interleukin36ishighly pages 6-8, petrova2024comparativeanalysesof pages 22-22)

  3. Extracellular space / stratum corneum interface: major protease–inhibitor interactions occur at/near the granular–cornified interface, affecting corneodesmosomes and lipid-processing enzymes. (petrova2024comparativeanalysesof pages 1-2)

  4. Disease progression model (molecular → cellular → clinical)

Stage 0: Genetic cause and early-life onset - Loss-of-function SPINK5 variants reduce functional LEKTI. (moltrasio2023nethertonsyndromecaused pages 1-2, petrova2024comparativeanalysesof pages 1-2)

Stage 1: Protease dysregulation and barrier breakdown - Uncontrolled KLK activity drives cleavage of corneodesmosomal cadherins and lipid-processing enzymes, causing premature detachment of stratum corneum and impaired barrier function. (petrova2024comparativeanalysesof pages 1-2)

Stage 2: Protease-triggered innate signaling and epithelial cytokine release - Proteolytic activation of PAR-2 signaling and processing of IL-1B/complement contributes to inflammation; KLK5→PAR2→TSLP links protease dysregulation to atopic inflammation. (petrova2024comparativeanalysesof pages 1-2, moltrasio2023nethertonsyndromecaused pages 5-7)

Stage 3: Adaptive immune skewing and chronic inflammation - NS skin shows overlapping Th2 and Th17 programs; Th17/IL-17/IL-36 signature is supported by multi-omics (Petrova 2024) and IL-36 IHC (Pawlowski 2024). (petrova2024comparativeanalysesof pages 1-2, pawlowski2024interleukin36ishighly pages 1-2)

Stage 4: Systemic consequences (subset / modeled) - In Spink5 cKO mice, systemic inflammation correlates with severity, is marked by neutrophils and IL-17/IL-22 signaling, and associates with thymic atrophy and lymphoid organ enlargement, independent of bacterial infection. (petrova2024comparativeanalysesof pages 1-2)

  1. Phenotypic manifestations (HP-style concepts) and mechanistic links

Core clinical triad - Congenital ichthyosis / erythroderma and scaling: driven by barrier failure from protease-mediated corneodesmosome degradation and altered keratinization. (petrova2024comparativeanalysesof pages 1-2, moltrasio2023nethertonsyndromecaused pages 5-7) - Atopic diathesis / hyper-IgE: linked to TSLP induction and Th2 skewing; Moltrasio case reports IgE 200–1000 IU/mL (normal <120), and Pawlowski reports a case IgE 5251 kU/L. (moltrasio2023nethertonsyndromecaused pages 2-5, pawlowski2024interleukin36ishighly pages 1-2) - Hair shaft defect (trichorrhexis invaginata): hallmark phenotype documented in Moltrasio. (moltrasio2023nethertonsyndromecaused pages 5-7)

Histopathology (mechanistic correlates) - Pawlowski describes psoriasiform epidermal hyperplasia/parakeratosis and diminished granular layer, consistent with Th17/IL-36 and hyperproliferative programs. (pawlowski2024interleukin36ishighly pages 1-2)

  1. Recent developments and latest research (prioritizing 2023–2024)

8.1 Conserved multi-omics disease framework and KLK/IL-36 axis (2024)

8.2 Diagnostic adjunct: IL-36 immunostaining (2024)

8.3 Quantitative/omics thresholds for shared pathways (2024)

  • Petrova et al. (2024) describes differential expression thresholds (adjusted P<0.05; |log2FC|>1) and shows enrichment of keratinization and protease activity GO terms, supporting protease activity as a central mechanism and a rational therapeutic target class (protease inhibitors, cytokine blockade). (petrova2024comparativeanalysesof pages 6-7)

8.4 Visual mechanistic synthesis (2024)

  • Petrova et al. (2024) includes a schematic summary of up/downregulated pathways in the Spink5 cKO model (protease activity and immune/inflammatory responses including IL-17/IL-22). (petrova2024comparativeanalysesof media 61a4f2db)

  • Current applications and real-world implementation (therapies)

9.1 Standard-of-care symptomatic management - Moltrasio et al. (2023) notes that “no fully satisfactory therapies exist,” and describes current real-world management including emollients and topical corticosteroids, antibacterial agents, and in severe cases intravenous immunoglobulin or biologics such as dupilumab; experimental approaches include bacteriophage- and gene-based therapies. (moltrasio2023nethertonsyndromecaused pages 2-5)

9.2 Targeted immune modulation (off-label and early clinical trials)

Dupilumab (IL-4Rα; IL-4/IL-13 axis) - Randomized controlled trial in progress/registered: NCT04244006 (University Hospital, Toulouse; start date 2020-07-23; primary completion estimated 2024-06-01). Design: Phase 2/3 pilot RCT, double-blind placebo-controlled, 2:1 randomization, n=24. Primary endpoint: NASA score at week 16. Secondary endpoints include pruritus/pain, infections, TEWL, microbiome, and skin biomarkers including protease markers. (NCT04244006 chunk 1) - Expert interpretation: case reports show variable benefit, often pruritus reduction; some responses may be transient. (pawlowski2024interleukin36ishighly pages 5-6)

Secukinumab (IL-17A) and combination biologic therapy - Real-world cohort/observational: NCT07151508 (completed; retrospective cohort; January 2021–June 2024) includes 15 pediatric NS patients treated with weight-adapted secukinumab and often add-on dupilumab (13 received combination therapy). Outcomes include ISS total score and biomarkers (IgE; IL-17A levels in CD4+ lymphocytes) with safety labs and AE recording, though results are not provided in the retrieved excerpt. (NCT07151508 chunk 1)

Broader biologic/JAK inhibitor landscape (expert synthesis) - A recent comprehensive therapeutics review emphasizes that targeted treatments remain largely limited to case reports and small series; dupilumab is most frequently reported, IL-17 blockade is rational for Th17/IL-36–dominant disease, and JAK inhibitors have been used in resistant cases. (morizane2025biologicsandsmall‐molecule pages 8-9)

  1. Statistics and data points from recent studies

Disease frequency - ~1:200,000 persons worldwide (Petrova 2024). (petrova2024comparativeanalysesof pages 1-2)

IgE values (clinical quantitative markers) - Moltrasio case: total IgE 200–1000 IU/mL (normal <120 IU/mL). (moltrasio2023nethertonsyndromecaused pages 2-5) - Pawlowski case: serum IgE 5251 kU/L. (pawlowski2024interleukin36ishighly pages 1-2)

Pathway quantitation - Transcriptomic DE calling used adjusted P<0.05 and |log2FC|>1 thresholds in Petrova 2024; immune signature lists IL17/IL36/IL22/IL23 and IL1 genes. (petrova2024comparativeanalysesof pages 6-7)

  1. Expert opinions and analysis (authoritative sources)

  2. Petrova et al. (2024) provides a conserved “molecular framework” and positions a KLK/IL-36 axis as a mechanistic and therapeutic target class, emphasizing shared human/mouse signatures and systemic inflammation correlations. (petrova2024comparativeanalysesof pages 1-2)

  3. Pawlowski et al. (2024) explicitly interprets their findings: “Data from this small case series further support the assertion that NS is, at least in part, driven by Th17 inflammation,” and notes IL-36 IHC’s diagnostic potential but limited specificity versus other Th17 dermatoses. (pawlowski2024interleukin36ishighly pages 5-6)

  4. Recent therapeutics reviews note the lack of approved targeted therapies and the heterogeneity of immunotypes, arguing for mechanistically stratified therapy (Th2 vs Th17/IL-36 vs IFN). (morizane2025biologicsandsmall‐molecule pages 7-8)

  5. Knowledge base–ready annotations (draft)

12.1 Pathophysiology description (narrative) Netherton syndrome (MONDO_0009735; OMIM #256500) is an autosomal recessive genodermatosis caused by SPINK5 loss-of-function, resulting in reduced functional LEKTI and loss of epidermal control over kallikrein-related proteases (KLKs). Unrestrained KLK activity degrades corneodesmosomal cadherins and lipid-processing enzymes, producing impaired cornification/keratinization, premature stratum corneum detachment, and barrier failure. Protease excess also activates PAR2 signaling and can proteolytically process inflammatory mediators (e.g., IL-1B, complement C3), inducing epithelial alarmins such as TSLP and inflammatory mediators (TNF-α, IL-8, ICAM-1). The downstream immune landscape includes mixed Th2 atopic and Th17 programs, with evidence for IL-17/IL-36 signatures in skin; IL-36 is robustly expressed in NS biopsies and may serve as an ancillary diagnostic marker. (petrova2024comparativeanalysesof pages 1-2, moltrasio2023nethertonsyndromecaused pages 1-2, pawlowski2024interleukin36ishighly pages 1-2)

12.2 Gene/protein annotations (HGNC) - SPINK5 (serine peptidase inhibitor Kazal type 5) → LEKTI; causal for NS. (moltrasio2023nethertonsyndromecaused pages 1-2) - KLK5, KLK6, KLK7, KLK13, KLK14: dysregulated epidermal serine proteases normally inhibited by LEKTI. (petrova2024comparativeanalysesof pages 1-2) - F2RL1 (PAR2): protease-activated receptor implicated in protease-driven inflammation/TSLP induction. (petrova2024comparativeanalysesof pages 1-2, moltrasio2023nethertonsyndromecaused pages 5-7)

12.3 Example GO biological processes disrupted - Proteolysis; keratinization; negative regulation of peptidase activity; immune/inflammatory response; desquamation. (petrova2024comparativeanalysesof pages 6-7, petrova2024comparativeanalysesof pages 22-22)

12.4 Cellular components - Lamellar granules (LEKTI localization) and extracellular stratum granulosum/stratum corneum interface. (pawlowski2024interleukin36ishighly pages 6-8)

12.5 Phenotype associations (HP-style; text-supported) - Ichthyosis/erythroderma and scaling; atopic diathesis/hyper-IgE; trichorrhexis invaginata (hair shaft defect). (moltrasio2023nethertonsyndromecaused pages 5-7, moltrasio2023nethertonsyndromecaused pages 2-5)

  1. Evidence items with PMIDs (limitations) The retrieved full-text excerpts did not consistently provide PubMed identifiers inline. Where PMIDs are requested, the key 2023–2024 mechanistic papers can be identified by DOI/URL in this report; PMIDs should be appended during curation using PubMed DOI→PMID mapping. (petrova2024comparativeanalysesof pages 1-2, pawlowski2024interleukin36ishighly pages 1-2, moltrasio2023nethertonsyndromecaused pages 1-2)

  2. Key references (with publication dates and URLs)

  3. Petrova E. et al. “Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice uncover disease-relevant pathways.” Communications Biology. Published Feb 2024. https://doi.org/10.1038/s42003-024-05780-y (petrova2024comparativeanalysesof pages 1-2)
  4. Pawlowski J. et al. “Interleukin-36 Is Highly Expressed in Skin Biopsies from Two Patients with Netherton Syndrome.” Dermatopathology. Published Aug 2024. https://doi.org/10.3390/dermatopathology11030024 (pawlowski2024interleukin36ishighly pages 1-2)
  5. Moltrasio C. et al. “Netherton Syndrome Caused by Heterozygous Frameshift Mutation Combined with Homozygous c.1258A>G Polymorphism in SPINK5 Gene.” Genes. Published May 2023. https://doi.org/10.3390/genes14051080 (moltrasio2023nethertonsyndromecaused pages 1-2)
  6. Clinical trial: NCT04244006 “A Pilot Study of the Efficacy and Safety of Dupilumab Versus Placebo in Patients With Netherton Syndrome.” Start 2020-07-23; primary completion estimated 2024-06-01. https://clinicaltrials.gov/study/NCT04244006 (NCT04244006 chunk 1)

  7. Real-world cohort: NCT07151508 “Successful Treatment of Netherton Syndrome With Combination of Secukinumab and Dupilumab.” Observational; Jan 2021–Jun 2024. https://clinicaltrials.gov/study/NCT07151508 (NCT07151508 chunk 1)

  8. Included mechanistic figure

  9. Petrova et al. 2024, schematic summary of Spink5 cKO pathway changes (protease activity and immune/inflammatory programs). (petrova2024comparativeanalysesof media 61a4f2db)

References

  1. (moltrasio2023nethertonsyndromecaused pages 1-2): Chiara Moltrasio, Maurizio Romagnuolo, Davide Riva, Davide Colavito, Silvia Ferrucci, Angelo Marzano, Gianluca Tadini, and Michela Brena. Netherton syndrome caused by heterozygous frameshift mutation combined with homozygous c.1258a>g polymorphism in spink5 gene. Genes, 14:1080, May 2023. URL: https://doi.org/10.3390/genes14051080, doi:10.3390/genes14051080. This article has 5 citations.

  2. (petrova2024comparativeanalysesof pages 1-2): Evgeniya Petrova, Jesús María López-Gay, Matthias Fahrner, Florent Leturcq, Jean-Pierre de Villartay, Claire Barbieux, Patrick Gonschorek, Lam C. Tsoi, Johann E. Gudjonsson, Oliver Schilling, and Alain Hovnanian. Comparative analyses of netherton syndrome patients and spink5 conditional knock-out mice uncover disease-relevant pathways. Communications Biology, Feb 2024. URL: https://doi.org/10.1038/s42003-024-05780-y, doi:10.1038/s42003-024-05780-y. This article has 13 citations and is from a peer-reviewed journal.

  3. (moltrasio2023nethertonsyndromecaused pages 5-7): Chiara Moltrasio, Maurizio Romagnuolo, Davide Riva, Davide Colavito, Silvia Ferrucci, Angelo Marzano, Gianluca Tadini, and Michela Brena. Netherton syndrome caused by heterozygous frameshift mutation combined with homozygous c.1258a>g polymorphism in spink5 gene. Genes, 14:1080, May 2023. URL: https://doi.org/10.3390/genes14051080, doi:10.3390/genes14051080. This article has 5 citations.

  4. (petrova2024comparativeanalysesof pages 6-7): Evgeniya Petrova, Jesús María López-Gay, Matthias Fahrner, Florent Leturcq, Jean-Pierre de Villartay, Claire Barbieux, Patrick Gonschorek, Lam C. Tsoi, Johann E. Gudjonsson, Oliver Schilling, and Alain Hovnanian. Comparative analyses of netherton syndrome patients and spink5 conditional knock-out mice uncover disease-relevant pathways. Communications Biology, Feb 2024. URL: https://doi.org/10.1038/s42003-024-05780-y, doi:10.1038/s42003-024-05780-y. This article has 13 citations and is from a peer-reviewed journal.

  5. (pawlowski2024interleukin36ishighly pages 1-2): Johannes Pawlowski, Tatsiana Pukhalskaya, Kelly Cordoro, Marina Kristy Ibraheim, and Jeffrey P. North. Interleukin-36 is highly expressed in skin biopsies from two patients with netherton syndrome. Dermatopathology, 11:230-237, Aug 2024. URL: https://doi.org/10.3390/dermatopathology11030024, doi:10.3390/dermatopathology11030024. This article has 2 citations.

  6. (pawlowski2024interleukin36ishighly pages 5-6): Johannes Pawlowski, Tatsiana Pukhalskaya, Kelly Cordoro, Marina Kristy Ibraheim, and Jeffrey P. North. Interleukin-36 is highly expressed in skin biopsies from two patients with netherton syndrome. Dermatopathology, 11:230-237, Aug 2024. URL: https://doi.org/10.3390/dermatopathology11030024, doi:10.3390/dermatopathology11030024. This article has 2 citations.

  7. (moltrasio2023nethertonsyndromecaused pages 2-5): Chiara Moltrasio, Maurizio Romagnuolo, Davide Riva, Davide Colavito, Silvia Ferrucci, Angelo Marzano, Gianluca Tadini, and Michela Brena. Netherton syndrome caused by heterozygous frameshift mutation combined with homozygous c.1258a>g polymorphism in spink5 gene. Genes, 14:1080, May 2023. URL: https://doi.org/10.3390/genes14051080, doi:10.3390/genes14051080. This article has 5 citations.

  8. (kline2024staphylococcusaureusproteases pages 1-2): Sabrina N. Kline, Yoshine Saito, and Nathan K. Archer. staphylococcus aureus proteases: orchestrators of skin inflammation. DNA and Cell Biology, 43:483-491, Oct 2024. URL: https://doi.org/10.1089/dna.2024.0134, doi:10.1089/dna.2024.0134. This article has 4 citations and is from a peer-reviewed journal.

  9. (morizane2025biologicsandsmall‐molecule pages 8-9): Shin Morizane, Tomoyuki Mukai, Ko Sunagawa, Ken‐ichi Hasui, Anri Morita, Hayato Nomura, and Mamoru Ouchida. Biologics and small‐molecule therapies in netherton syndrome: a comprehensive review. The Journal of Dermatology, 52:1483-1493, Sep 2025. URL: https://doi.org/10.1111/1346-8138.17923, doi:10.1111/1346-8138.17923. This article has 1 citations.

  10. (NCT07151508 chunk 1): Successful Treatment of Netherton Syndrome With Combination of Secukinumab and Dupilumab. Federal Research Institute of Pediatric Hematology, Oncology and Immunology. 2023. ClinicalTrials.gov Identifier: NCT07151508

  11. (pawlowski2024interleukin36ishighly pages 6-8): Johannes Pawlowski, Tatsiana Pukhalskaya, Kelly Cordoro, Marina Kristy Ibraheim, and Jeffrey P. North. Interleukin-36 is highly expressed in skin biopsies from two patients with netherton syndrome. Dermatopathology, 11:230-237, Aug 2024. URL: https://doi.org/10.3390/dermatopathology11030024, doi:10.3390/dermatopathology11030024. This article has 2 citations.

  12. (pawlowski2024interleukin36ishighly pages 2-5): Johannes Pawlowski, Tatsiana Pukhalskaya, Kelly Cordoro, Marina Kristy Ibraheim, and Jeffrey P. North. Interleukin-36 is highly expressed in skin biopsies from two patients with netherton syndrome. Dermatopathology, 11:230-237, Aug 2024. URL: https://doi.org/10.3390/dermatopathology11030024, doi:10.3390/dermatopathology11030024. This article has 2 citations.

  13. (petrova2024comparativeanalysesof pages 22-22): Evgeniya Petrova, Jesús María López-Gay, Matthias Fahrner, Florent Leturcq, Jean-Pierre de Villartay, Claire Barbieux, Patrick Gonschorek, Lam C. Tsoi, Johann E. Gudjonsson, Oliver Schilling, and Alain Hovnanian. Comparative analyses of netherton syndrome patients and spink5 conditional knock-out mice uncover disease-relevant pathways. Communications Biology, Feb 2024. URL: https://doi.org/10.1038/s42003-024-05780-y, doi:10.1038/s42003-024-05780-y. This article has 13 citations and is from a peer-reviewed journal.

  14. (petrova2024comparativeanalysesof media 61a4f2db): Evgeniya Petrova, Jesús María López-Gay, Matthias Fahrner, Florent Leturcq, Jean-Pierre de Villartay, Claire Barbieux, Patrick Gonschorek, Lam C. Tsoi, Johann E. Gudjonsson, Oliver Schilling, and Alain Hovnanian. Comparative analyses of netherton syndrome patients and spink5 conditional knock-out mice uncover disease-relevant pathways. Communications Biology, Feb 2024. URL: https://doi.org/10.1038/s42003-024-05780-y, doi:10.1038/s42003-024-05780-y. This article has 13 citations and is from a peer-reviewed journal.

  15. (NCT04244006 chunk 1): A Pilot Study of the Efficacy and Safety of Dupilumab Versus Placebo in Patients With Netherton Syndrome. University Hospital, Toulouse. 2020. ClinicalTrials.gov Identifier: NCT04244006

  16. (morizane2025biologicsandsmall‐molecule pages 7-8): Shin Morizane, Tomoyuki Mukai, Ko Sunagawa, Ken‐ichi Hasui, Anri Morita, Hayato Nomura, and Mamoru Ouchida. Biologics and small‐molecule therapies in netherton syndrome: a comprehensive review. The Journal of Dermatology, 52:1483-1493, Sep 2025. URL: https://doi.org/10.1111/1346-8138.17923, doi:10.1111/1346-8138.17923. This article has 1 citations.