{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:46:42Z","timestamp":1791953202809,"version":"4.3.4"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Dermatol Ther (Heidelb)"],"DOI":"10.1007\/s13555-026-01948-y","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:43:55Z","timestamp":1791927835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Investigational Mechanism-Informed Therapy for Netherton Syndrome: Introduction to QRX003 and A Pediatric Compassionate-Use Case Report"],"prefix":"10.1007","author":[{"given":"Alan D.","family":"Irvine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Hovnanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4823-8152","authenticated-orcid":false,"given":"Michael","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"1948_CR1","first-page":"1359","volume-title":"Textbook of pediatric dermatology","author":"C Ong","year":"2006","unstructured":"Ong C, Harper J. Netherton\u2019s syndrome. In: Harper J, Oranje A, Prose N, editors. Textbook of pediatric dermatology. Oxford, United Kingdom: Wiley\/Blackwell; 2006. p. 1359\u201366."},{"key":"1948_CR2","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1080\/21678707.2020.1857724","volume":"8","author":"E Petrova","year":"2020","unstructured":"Petrova E, Hovnanian A. Advances in understanding of Netherton syndrome and therapeutic implications. Expert Opin Orphan Drugs. 2020;8:455\u201387.","journal-title":"Expert Opin Orphan Drugs"},{"key":"1948_CR3","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1093\/bjd\/ljaf123","volume":"193","author":"AS Paller","year":"2025","unstructured":"Paller AS, Teng J, Mazereeuw-Hautier J, Hern\u00e1ndez-Mart\u00edn \u00c1, Granier Tournier C, Hovnanian A, et al. Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy. Br J Dermatol. 2025;193:592\u2013618.","journal-title":"Br J Dermatol"},{"key":"1948_CR4","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1586\/edm.11.85","volume":"7","author":"A Hovnanian","year":"2012","unstructured":"Hovnanian A. Netherton syndrome: new advances in the clinic, disease mechanisms and treatment. Expert Rev Dermatol. 2012;7:81\u201392.","journal-title":"Expert Rev Dermatol"},{"key":"1948_CR5","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1001\/archderm.1964.01590250052010","volume":"89","author":"RD Wilkinson","year":"1964","unstructured":"Wilkinson RD, Curtis GH, Hawk WA. Netherton\u2019s disease: trichorrhexis invaginata (bamboo hair), congenital ichthyosiform erythroderma and the atopic diathesis. A histopathologic study Arch Dermatol. 1964;89:46\u201354.","journal-title":"A histopathologic study Arch Dermatol"},{"key":"1948_CR6","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1046\/j.1523-1747.2002.01603.x","volume":"118","author":"E Bitoun","year":"2002","unstructured":"Bitoun E, Chavanas S, Irvine AD, Lonie L, Bodemer C, Paradisi M, et al. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J Invest Dermatol. 2002;118:352\u201361.","journal-title":"J Invest Dermatol"},{"key":"1948_CR7","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.645259","volume":"9","author":"F Barbati","year":"2021","unstructured":"Barbati F, Giovannini M, Oranges T, Lodi L, Barni S, Novembre E, et al. Netherton syndrome in children: management and future perspectives. Front Pediatr. 2021;9:645259.","journal-title":"Front Pediatr"},{"key":"1948_CR8","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1111\/j.1365-4632.2005.02637.x","volume":"45","author":"JD Sun","year":"2006","unstructured":"Sun JD, Linden KG. Netherton syndrome: a case report and review of the literature. Int J Dermatol. 2006;45:693\u20137.","journal-title":"Int J Dermatol"},{"key":"1948_CR9","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/j.jaci.2014.07.008","volume":"134","author":"K Hannula-Jouppi","year":"2014","unstructured":"Hannula-Jouppi K, Laasanen SL, Heikkil\u00e4 H, Tuomiranta M, Tuomi ML, Hilvo S, et al. IgE allergen component-based profiling and atopic manifestations in patients with Netherton syndrome. J Allergy Clin Immunol. 2014;134:985\u20138.","journal-title":"J Allergy Clin Immunol"},{"key":"1948_CR10","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.jaci.2009.06.009","volume":"124","author":"ED Renner","year":"2009","unstructured":"Renner ED, Hartl D, Rylaarsdam S, Young ML, Monaco-Shawver L, Kleiner G, et al. Com\u00e8l-Netherton syndrome defined as primary immunodeficiency. J Allergy Clin Immunol. 2009;124:536\u201343.","journal-title":"J Allergy Clin Immunol"},{"key":"1948_CR11","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1111\/all.14197","volume":"75","author":"K Stuvel","year":"2020","unstructured":"Stuvel K, Heeringa JJ, Dalm V, Meijers RWJ, van Hoffen E, Gerritsen SAM, et al. Comel-Netherton syndrome: a local skin barrier defect in the absence of an underlying systemic immunodeficiency. Allergy. 2020;75:1710\u201320.","journal-title":"Allergy"},{"key":"1948_CR12","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1515\/hsz-2014-0137","volume":"395","author":"L Furio","year":"2014","unstructured":"Furio L, Hovnanian A. Netherton syndrome: defective kallikrein inhibition in the skin leads to skin inflammation and allergy. Biol Chem. 2014;395:945\u201358.","journal-title":"Biol Chem"},{"key":"1948_CR13","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/75977","volume":"25","author":"S Chavanas","year":"2000","unstructured":"Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25:141\u20132.","journal-title":"Nat Genet"},{"key":"1948_CR14","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1007\/s00441-013-1558-1","volume":"351","author":"A Hovnanian","year":"2013","unstructured":"Hovnanian A. Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res. 2013;351:289\u2013300.","journal-title":"Cell Tissue Res"},{"key":"1948_CR15","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/ng1493","volume":"37","author":"P Descargues","year":"2005","unstructured":"Descargues P, Deraison C, Bonnart C, Kreft M, Kishibe M, Ishida-Yamamoto A, et al. Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by kallikrein 5. Nat Genet. 2005;37:56\u201365.","journal-title":"Nat Genet"},{"key":"1948_CR16","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/s42003-024-05780-y","volume":"7","author":"E Petrova","year":"2024","unstructured":"Petrova E, L\u00f3pez-Gay JM, Fahrner M, Leturcq F, de Villartay JP, Barbieux C, et al. Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice uncover disease-relevant pathways. Commun Biol. 2024;7:152.","journal-title":"Commun Biol"},{"key":"1948_CR17","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1194\/jlr.RA120000639","volume":"61","author":"J van Smeden","year":"2020","unstructured":"van Smeden J, Al-Khakany H, Wang Y, Visscher D, Stephens N, Absalah S, et al. Skin barrier lipid enzyme activity in Netherton patients is associated with protease activity and ceramide abnormalities. J Lipid Res. 2020;61:859\u201369.","journal-title":"J Lipid Res"},{"key":"1948_CR18","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1084\/jem.20082242","volume":"206","author":"A Briot","year":"2009","unstructured":"Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C, et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med. 2009;206:1135\u201347. https:\/\/doi.org\/10.1084\/jem.20082242.","journal-title":"J Exp Med"},{"key":"1948_CR19","first-page":"747","volume":"137","author":"A Allen","year":"2001","unstructured":"Allen A, Siegfried E, Silverman R, Williams ML, Elias PM, Szabo SK, et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol. 2001;137:747\u201350.","journal-title":"Arch Dermatol"},{"key":"1948_CR20","doi-asserted-by":"publisher","first-page":"1074243","DOI":"10.3389\/fped.2022.1074243","volume":"10","author":"M Pontone","year":"2022","unstructured":"Pontone M, Giovannini M, Filippeschi C, Oranges T, Pedaci FA, Mori F, et al. Biological treatments for pediatric Netherton syndrome. Front Pediatr. 2022;10:1074243.","journal-title":"Front Pediatr"},{"key":"1948_CR21","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1111\/1346-8138.17923","volume":"52","author":"S Morizane","year":"2025","unstructured":"Morizane S, Mukai T, Sunagawa K, Hasui KI, Morita A, Nomura H, et al. Biologics and small-molecule therapies in Netherton syndrome: a comprehensive review. J Dermatol. 2025;52:1483\u201393.","journal-title":"J Dermatol"},{"key":"1948_CR22","doi-asserted-by":"publisher","DOI":"10.1111\/pai.70039","volume":"36","author":"BE Wilson","year":"2025","unstructured":"Wilson BE, Grebe TA, Prakash S, Bauer CS. Systemic JAK inhibitors for treatment of cutaneous manifestations in a patient with SPINK5 variants: a case report and review of the literature. Pediatr Allergy Immunol. 2025;36:e70039.","journal-title":"Pediatr Allergy Immunol"},{"issue":"4","key":"1948_CR23","doi-asserted-by":"publisher","DOI":"10.3390\/biom13040634","volume":"13","author":"H Olbrich","year":"2023","unstructured":"Olbrich H, Sadik CD, Ludwig RJ, Tha\u00e7i D, Boch K. Dupilumab in inflammatory skin diseases: a systematic review. Biomolecules. 2023;13(4):634. https:\/\/doi.org\/10.3390\/biom13040634.","journal-title":"Biomolecules"},{"key":"1948_CR24","unstructured":"ClinicalTrials.gov. Evaluation of topical ATR12-351 in adults with Netherton syndrome. Identifier: NCT06137157 [Internet]. Bethesda (MD): National Library of Medicine; 2023 [cited 2026 Sep 18]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT06137157"},{"key":"1948_CR25","unstructured":"ClinicalTrials.gov. A study of the safety, tolerability, pharmacokinetics, and immunogenicity of BCX17725. Identifier: NCT06539507 [Internet]. Bethesda (MD): National Library of Medicine; 2024 [cited 2026 Sep 18]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT06539507"},{"key":"1948_CR26","unstructured":"ClinicalTrials.gov. A placebo-controlled trial to evaluate the efficacy and safety of spesolimab in the treatment of patients with Netherton syndrome. Identifier: NCT05856526 [Internet]. Bethesda (MD): National Library of Medicine; 2023 [cited 2026 May 3]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT05856526"},{"key":"1948_CR27","unstructured":"Quoin Pharmaceuticals Ltd. Annual report\/form 10-K for fiscal year ended December 31, 2025 [Internet]. Ashburn (VA): Quoin Pharmaceuticals Ltd.; 2026 [cited 2026 May 3]. Available from: https:\/\/quoinpharma.gcs-web.com\/node\/10186\/html"},{"key":"1948_CR28","unstructured":"ClinicalTrials.gov. Clinical study of QRX003 lotion in subjects with Netherton syndrome. Identifier: NCT06953466 [Internet]. Bethesda (MD): National Library of Medicine; [cited 2026 May 3]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT06953466"},{"key":"1948_CR29","unstructured":"SEPPIC. SEPILIFT DPHP product page [Internet]. La Garenne-Colombes: SEPPIC; [cited 2026 May 3]. Available from: https:\/\/www.seppic.com\/product\/sepilift-dphp"},{"key":"1948_CR30","doi-asserted-by":"publisher","first-page":"3607","DOI":"10.1091\/mbc.e07-02-0124","volume":"18","author":"C Deraison","year":"2007","unstructured":"Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell. 2007;18:3607\u201319.","journal-title":"Mol Biol Cell"},{"key":"1948_CR31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006566","volume":"13","author":"P Kasparek","year":"2017","unstructured":"Kasparek P, Ileninova Z, Zbodakova O, Kanchev I, Benada O, Chalupsky K, et al. KLK5 and KLK7 ablation fully rescues lethality of Netherton syndrome-like phenotype. PLoS Genet. 2017;13:e1006566.","journal-title":"PLoS Genet"},{"key":"1948_CR32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005389","volume":"11","author":"L Furio","year":"2015","unstructured":"Furio L, Pampalakis G, Michael IP, Nagy A, Sotiropoulou G, Hovnanian A. KLK5 inactivation reverses cutaneous hallmarks of Netherton syndrome. PLoS Genet. 2015;11:e1005389.","journal-title":"PLoS Genet"},{"key":"1948_CR33","doi-asserted-by":"crossref","unstructured":"Chavarria-Smith J, Pham TH, Dancik V, Li J, Liddle J, et al. Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis. Sci Transl Med. 2022;14:eabp9159.","DOI":"10.1126\/scitranslmed.abp9159"},{"key":"1948_CR34","unstructured":"European Commission. CosIng database: dipalmitoyl hydroxyproline [Internet]. Brussels: European Commission; [cited 2026 May 3]. Available from: https:\/\/ec.europa.eu\/growth\/tools-databases\/cosing\/details\/75923"},{"key":"1948_CR35","unstructured":"SpecialChem. Dipalmitoyl hydroxyproline: cosmetic ingredient information [Internet]. Paris: SpecialChem; [cited 2026 May 3]. Available from: https:\/\/www.specialchem.com\/cosmetics\/inci-ingredients\/dipalmitoyl-hydroxyproline"},{"key":"1948_CR36","unstructured":"Environmental Working Group. Skin Deep: dipalmitoyl hydroxyproline [Internet]. Washington, DC: Environmental Working Group; [cited 2026 May 3]. Available from: https:\/\/www.ewg.org\/skindeep\/ingredients\/702101-DIPALMITOYL_HYDROXYPROLINE\/"},{"key":"1948_CR37","unstructured":"SEPPIC. Safety data sheet: SEPILIFT DPHP [Internet]. La Garenne-Colombes: SEPPIC; 2014 Apr 12 [cited 2026 May 3]. Available from: https:\/\/www.biohope.com.cn\/vancheerfile\/files\/profile\/2017072017262886.pdf"},{"key":"1948_CR38","unstructured":"ClinicalTrials.gov. Open label, safety and efficacy study of QRX003 lotion in subjects with Netherton syndrome. Identifier: NCT05789056 [Internet]. Bethesda (MD): National Library of Medicine; [cited 2026 May 3]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT05789056"},{"key":"1948_CR39","unstructured":"ClinicalTrials.gov. Safety, tolerability and efficacy of QRX003 lotion in subjects with Netherton syndrome. Identifier: NCT05521438 [Internet]. Bethesda (MD): National Library of Medicine; [cited 2026 May 3]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT05521438"},{"key":"1948_CR40","unstructured":"ClinicalTrials.gov. Phase 2\/3 clinical study of QRX003 lotion in subjects with Netherton syndrome. Identifier: NCT07538583 [Internet]. Bethesda (MD): National Library of Medicine; [cited 2026 May 3]. Available from: https:\/\/clinicaltrials.gov\/study\/NCT07538583"},{"key":"1948_CR41","unstructured":"Quoin Pharmaceuticals Ltd. Quoin Pharmaceuticals announces European Medicines Agency grants Orphan Drug Designation for QRX003 for the treatment of Netherton syndrome [Internet]. Ashburn (VA): Quoin Pharmaceuticals Ltd.; 2025 May 20 [cited 2026 May 3]. Available from: https:\/\/www.globenewswire.com\/news-release\/2025\/05\/20\/3084739\/0\/en\/Quoin-Pharmaceuticals-Announces-European-Medicines-Agency-EMA-Grants-Orphan-Drug-Designation-for-QRX003-for-the-Treatment-of-Netherton-Syndrome.html"},{"key":"1948_CR42","unstructured":"Quoin Pharmaceuticals Ltd. Quoin Pharmaceuticals announces FDA grants Rare Pediatric Disease Designation for QRX003 in Netherton syndrome [Internet]. Ashburn (VA): Quoin Pharmaceuticals Ltd.; 2025 Jun 24 [cited 2026 May 3]. Available from: https:\/\/investors.quoinpharma.com\/news-releases\/news-release-details\/quoin-pharmaceuticals-announces-fda-grants-rare-pediatric\/"},{"key":"1948_CR43","unstructured":"Quoin Pharmaceuticals Ltd. Quoin Pharmaceuticals announces U.S. FDA grants Orphan Drug Designation for QRX003 in Netherton syndrome [Internet]. Ashburn (VA): Quoin Pharmaceuticals Ltd.; 2025 Oct 21 [cited 2026 May 3]. Available from: https:\/\/investors.quoinpharma.com\/news-releases\/news-release-details\/quoin-pharmaceuticals-announces-us-fda-grants-orphan-drug\/"},{"key":"1948_CR44","unstructured":"Quoin Pharmaceuticals Ltd. Quoin Pharmaceuticals announces FDA grants Fast Track Designation for QRX003 for the treatment of Netherton syndrome [Internet]. Ashburn (VA): Quoin Pharmaceuticals Ltd.; 2026 Mar 11 [cited 2026 May 3]. Available from: https:\/\/investors.quoinpharma.com\/news-releases\/news-release-details\/quoin-pharmaceuticals-announces-fda-grants-fast-track\/"}],"container-title":["Dermatology and Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13555-026-01948-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13555-026-01948-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13555-026-01948-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:07:30Z","timestamp":1791950850000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13555-026-01948-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,13]]},"references-count":44,"alternative-id":["1948"],"URL":"https:\/\/doi.org\/10.1007\/s13555-026-01948-y","relation":{},"ISSN":["2193-8210","2190-9172"],"issn-type":[{"value":"2193-8210","type":"print"},{"value":"2190-9172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,13]]},"assertion":[{"value":"19 June 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Alan D. Irvine has served as a consultant for AbbVie, Eli Lilly, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Quoin Pharmaceuticals, Sanofi, Sitryx, and UCB; as a speaker for AbbVie, Eli Lilly, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi; and as an investigator for AbbVie, Novartis, and Sanofi-Regeneron Pharmaceuticals Inc. He is a patent holder with Quoin Pharmaceuticals and Regeneron Pharmaceuticals Inc. Alain Hovnanian has served as a consultant for BioCryst Pharmaceuticals and as an investigator for Kamari Pharma. Michael Myers is an employee and stockholder of Quoin Pharmaceuticals. Denise Carter is an employee and stockholder of Quoin Pharmaceuticals.","order":1,"name":"Ethics","label":"Conflict of Interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Use of QRX003 on a named-patient\/compassionate-use basis was approved by the Children\u2019s Health Ireland Drugs and Therapeutics Committee prior to initiation. Written informed consent for treatment was obtained from the patient\u2019s parent\/legal guardian. Written informed consent for publication of the case details and clinical images was obtained from the patient\u2019s parent\/legal guardian.","order":2,"name":"Ethics","label":"Ethical Approval","group":{"name":"EthicsHeading","label":"Declarations"}}]}}