{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T06:17:35Z","timestamp":1771395455925,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      CYLD cutaneous syndrome (CCS) is a rare autosomal dominant disorder caused by germline\n                      <jats:italic>CYLD<\/jats:italic>\n                      variants and characterized by multiple skin adnexal tumors. Malignant transformation is uncommon, and cooperative genetic events remain poorly defined, particularly in underrepresented populations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      We report a 61-year-old Ecuadorian woman with multiple scalp cylindromas and spiradenomas, including one spiradenocarcinoma. Family history was notable for malignancies in first- and second-degree relatives. Whole-exome sequencing identified a heterozygous nonsense\n                      <jats:italic>CYLD<\/jats:italic>\n                      variant (c.1207C\u202f&amp;gt;\u202fT; p.Gln403Ter), classified as likely pathogenic, and a homozygous missense\n                      <jats:italic>MSH2<\/jats:italic>\n                      variant (c.1609A\u202f&amp;gt;\u202fG; p.Lys537Glu) of uncertain significance. Histopathology confirmed malignant transformation, while immunohistochemistry showed preserved MSH2 expression with a microsatellite-stable phenotype. Nevertheless, a functional impact of the\n                      <jats:italic>MSH2<\/jats:italic>\n                      variant cannot be excluded. Consistent with these observations,\n                      <jats:italic>in silico<\/jats:italic>\n                      modeling demonstrated that\n                      <jats:italic>CYLD<\/jats:italic>\n                      truncation eliminates the catalytic USP domain and regulatory motifs, abolishing deubiquitinase activity, whereas the\n                      <jats:italic>MSH2<\/jats:italic>\n                      substitution affects a conserved residue in the clamp domain, likely destabilizing the MSH2\u2013MSH6 complex despite intact nuclear localization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This is the first genetically confirmed case of CCS in Ecuador and among the few reported in South America. Beyond expanding the geographic spectrum, our findings highlight the value of integrating genomic and protein analyses to uncover cooperative mechanisms of malignant progression. Such integrative genomic approaches refine diagnosis, enhance genotype\u2013phenotype interpretation, and deepen understanding of malignant transformation in CCS, particularly in underrepresented populations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1703885","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T05:33:02Z","timestamp":1771392782000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: CYLD cutaneous syndrome with malignant transformation to spiradenocarcinoma: cooperative effects of CYLD truncation and an MSH2 clamp-domain variant in an Ecuadorian patient"],"prefix":"10.3389","volume":"13","author":[{"given":"Carlos","family":"Reyes-Silva","sequence":"first","affiliation":[{"name":"Unidad de Gen\u00e9tica, Hospital de Especialidades Eugenio Espejo","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Jaramillo-Koupermann","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular, Subproceso de Anatom\u00eda Patol\u00f3gica, Hospital de Especialidades Eugenio Espejo","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maritza","family":"Quishpe","sequence":"additional","affiliation":[{"name":"Anatom\u00eda Patol\u00f3gica, Hospital de Especialidades Eugenio Espejo","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Anatom\u00eda Patol\u00f3gica, Hospital de Especialidades Eugenio Espejo","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Skehirly","family":"Burgos-Tapia","sequence":"additional","affiliation":[{"name":"Escuela de Enfermer\u00eda, Facultad de Ciencias de la Salud, Universidad de Las Am\u00e9ricas","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Karina","family":"Zambrano","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud Eugenio Espejo, Centro de Investigaci\u00f3n Gen\u00e9tica y Gen\u00f3mica, Universidad UTE","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Cabrera-Andrade","sequence":"additional","affiliation":[{"name":"Grupo de Bio-Quimioinform\u00e1tica, Universidad de Las Am\u00e9ricas","place":["Quito, Ecuador"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"427","DOI":"10.2147\/TACG.S288274","article-title":"Genetic testing in CYLD cutaneous syndrome: an update","volume":"14","author":"Nagy","year":"2021","journal-title":"Appl Clin 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