{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:37:53Z","timestamp":1790951873880,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T00:00:00Z","timestamp":1595203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca corrente 2018-2019"],"award-info":[{"award-number":["Ricerca corrente 2018-2019"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Transforming growth factor \u03b2 (TGF-\u03b2) superfamily signaling pathways are ubiquitous and essential for several cellular and physiological processes. The overexpression of TGF-\u03b2 results in excessive fibrosis in multiple human disorders. Among them, stiff skin syndrome (SSS) is an ultrarare and untreatable condition characterized by the progressive thickening and hardening of the dermis, and acquired joint limitations. SSS is distinct in a widespread form, caused by recurrent germline variants of FBN1 encoding a key molecule of the TGF-\u03b2 signaling, and a segmental form with unknown molecular basis. Here, we report a 12-year-old female with segmental SSS, affecting the right upper limb with acquired thickening of the dermis evident at the magnetic resonance imaging, and progressive limitation of the elbow and shoulder. To better explore the molecular and cellular mechanisms that drive segmental SSS, several functional studies on patient\u2019s fibroblasts were employed. We hypothesized an impairment of TGF-\u03b2 signaling and, consequently, a dysregulation of the associated downstream signaling. Lesional fibroblast studies showed a higher phosphorylation level of extracellular signal-regulated kinase 1\/2 (ERK1\/2), increased levels of nuclear factor-kB (NFkB), and a nuclear accumulation of phosphorylated Smad2 via Western blot and microscopy analyses. Quantitative PCR expression analysis of genes encoding key extracellular matrix proteins revealed increased levels of COL1A1, COL3A1, AGT, LTBP and ITGB1, while zymography assay reported a reduced metalloproteinase 2 enzymatic activity. In vitro exposure of patient\u2019s fibroblasts to losartan led to the partial restoration of normal transforming growth factor \u03b2 (TGF-\u03b2) marker protein levels. Taken together, these data demonstrate that in our patient, segmental SSS is characterized by the overactivation of multiple TGF-\u03b2 signaling pathways, which likely results in altered extracellular matrix composition and fibroblast homeostasis. Our results for the first time reported that aberrant TGF-\u03b2 signaling may drive the pathogenesis of segmental SSS and might open the way to novel therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms21145141","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T10:59:38Z","timestamp":1595242778000},"page":"5141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pro-Fibrotic Phenotype in a Patient with Segmental Stiff Skin Syndrome via TGF-\u03b2 Signaling Overactivation"],"prefix":"10.3390","volume":"21","author":[{"given":"Carmela","family":"Fusco","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Nardella","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7475-6976","authenticated-orcid":false,"given":"Bartolomeo","family":"Augello","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-5447","authenticated-orcid":false,"given":"Francesca","family":"Boccafoschi","sequence":"additional","affiliation":[{"name":"Health Science Department University of Piemonte Orientale, Novara 28100, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-3482","authenticated-orcid":false,"given":"Orazio","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Fusaro","sequence":"additional","affiliation":[{"name":"Tissuegraft srl, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelantonio","family":"Notarangelo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaela","family":"Barbano","sequence":"additional","affiliation":[{"name":"Laboratory of Oncology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6031-9636","authenticated-orcid":false,"given":"Paola","family":"Parrella","sequence":"additional","affiliation":[{"name":"Laboratory of Oncology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Annicchiarico","sequence":"additional","affiliation":[{"name":"Coordinamento Regionale Malattie Rare Puglia, Agenzia Regionale per la Salute ed il Sociale, Bari, 70132 Puglia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"De Meco","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3604-194X","authenticated-orcid":false,"given":"Lucia","family":"Micale","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7066-7896","authenticated-orcid":false,"given":"Paolo","family":"Graziano","sequence":"additional","affiliation":[{"name":"Unit of Pathology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Castori","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1542\/peds.47.2.360","article-title":"Stiff skin syndrome","volume":"47","author":"Esterly","year":"1971","journal-title":"Pediatrics"},{"key":"ref_2","first-page":"802","article-title":"Dysmorphism in Stiff Skin syndrome","volume":"118","author":"Amoric","year":"1991","journal-title":"Annales de Dermatologie et de V\u00e9n\u00e9r\u00e9ologie"},{"key":"ref_3","first-page":"805","article-title":"A new case of Stiff Skin syndrome","volume":"118","author":"Bodemer","year":"1991","journal-title":"Annales de Dermatologie et de V\u00e9n\u00e9r\u00e9ologie"},{"key":"ref_4","first-page":"360","article-title":"Stiff skin syndrome","volume":"11","author":"Bundy","year":"1975","journal-title":"Birth Defects Orig. 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