{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:41:00Z","timestamp":1792431660522,"version":"4.5.0"},"reference-count":18,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic\n                    <jats:italic>NRAS<\/jats:italic>\n                    variants and characterized by melanocytic\/sebaceous naevi, eye, and brain malformations, and FGF23\u2010mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS\/MAPK pathway, is a candidate for CSHS therapy. A 4\u2010year\u2010old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A\u2009&gt;\u2009G;p.(Gln61Arg) somatic\n                    <jats:italic>NRAS<\/jats:italic>\n                    variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15\u2009months investigating the transcriptional effects at different time points by whole blood RNA\u2010seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch\u2010up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS\/MAPK, PI3 kinase, WNT and YAP\/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified \u201ccore\u201d genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action.\n                  <\/jats:p>","DOI":"10.1002\/gcc.23092","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T22:55:02Z","timestamp":1661295302000},"page":"740-746","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Successful treatment with\n                    <scp>MEK<\/scp>\n                    \u2010inhibitor in a patient with\n                    <scp>\n                      <i>NRAS<\/i>\n                    <\/scp>\n                    \u2010related cutaneous skeletal hypophosphatemia syndrome"],"prefix":"10.1002","volume":"61","author":[{"given":"Diana","family":"Carli","sequence":"first","affiliation":[{"name":"Department of Public Health and Pediatrics University of Torino  Torino Italy"},{"name":"Pediatric Onco\u2010Hematology, Stem Cell Transplantation and Cell Therapy Division Regina Margherita Children's Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Cardaropoli","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatrics University of Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Tessaris","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit Regina Margherita Children's Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Coppo","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit Regina Margherita Children's Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"La Selva","sequence":"additional","affiliation":[{"name":"Pediatric Dermatology Unit Regina Margherita Children's Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cesario","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit Bambino Ges\u00f9 Children's Hospital, IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Romana","family":"Lepri","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit Bambino Ges\u00f9 Children's Hospital, IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verdiana","family":"Pullano","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences University of Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogenomics Candiolo Cancer Institute, FPO\u2010IRCCS  Candiolo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugo","family":"Ramenghi","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatrics University of Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Brusco","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences University of Torino  Torino Italy"},{"name":"Medical Genetics Unit Citt\u00e0 della Salute e della Scienza University Hospital  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Medico","sequence":"additional","affiliation":[{"name":"Laboratory of Oncogenomics Candiolo Cancer Institute, FPO\u2010IRCCS  Candiolo Italy"},{"name":"Department of Oncology University of Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"De Sanctis","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatrics University of Torino  Torino Italy"},{"name":"Pediatric Endocrinology Unit Regina Margherita Children's Hospital, Citt\u00e0 Della Salute e Della Scienza di Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Battista","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences University of Torino  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Mussa","sequence":"additional","affiliation":[{"name":"Department of Public Health and Pediatrics University of Torino  Torino Italy"},{"name":"Pediatric Clinical Genetics Unit Regina Margherita Children Hospital  Torino 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