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Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and\/or tumor specimens were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nineteen (79%) of 24 participants had NS, 17\/19 (89%) of which had a germline\n                      <jats:italic>PTPN11<\/jats:italic>\n                      variant; Nineteen of 24 participants (79%) were male. Seventeen of 19 (89%) patients with NS developed CNS tumors, including low-grade glioma, (LGG; pilocytic\/pilomyxoid astrocytoma;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20099) and dysembryoplastic neuroepithelial tumor (DNET;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096). Five patients incidentally diagnosed did not undergo histological confirmation. Radiological review showed multifocal parenchymal tumors in 9 patients with NS, including histologically confirmed neoplasm (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20092), radiologic progression (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096), or typical tumoral imaging (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20091). Fourteen of 15 (93%) tumors collected from 13 patients with NS and germline\n                      <jats:italic>PTPN11<\/jats:italic>\n                      variants harbored somatic\n                      <jats:italic>FGFR1<\/jats:italic>\n                      abnormalities. RNA sequencing of 12 tumors detected\n                      <jats:italic>FGFR1<\/jats:italic>\n                      internal tandem duplication in one patient. Comparison with published data showed a statistically significant association between brain tumor occurrence and\n                      <jats:italic>PTPN11<\/jats:italic>\n                      -related NS, driven by two genotypes: NM_002834.5(PTPN11):c.182\u00a0A\u2009&gt;\u2009G (p.Asp61Gly) and c.417G\u2009&gt;\u2009T (p.Glu139Asp). Ten patients with CNS tumors, including 7\/17 (41%) with\n                      <jats:italic>PTPN11<\/jats:italic>\n                      variants, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS tumor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>PTPN11<\/jats:italic>\n                      -related NS predisposes to multifocal low-grade glial and glioneuronal tumors confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and low-grade CNS tumors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-026-05478-7","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T09:27:12Z","timestamp":1772702832000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PTPN11-related Noonan syndrome predisposes to multifocal low-grade CNS tumors harboring FGFR1 variants"],"prefix":"10.1007","volume":"177","author":[{"given":"Gary","family":"Kohanbash","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Ryall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam E.","family":"Gary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey M.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Siddaway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E.","family":"Bendel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen W.","family":"Gripp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew W.","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan R.","family":"Hansford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Skaugen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uri","family":"Tabori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia E.","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Broniscer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"5478_CR1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/s43018-021-00172-1","volume":"2","author":"EM Fiala","year":"2021","unstructured":"Fiala EM, Jayakumaran G, Mauguen A, Kennedy JA, Bouvier N, Kemel Y, Fleischut MH, Maio A, Salo-Mullen EE, Sheehan M, Arnold AG, Latham A, Carlo MI, Cadoo K, Murkherjee S, Slotkin EK, Trippett T, Glade Bender J, Meyers PA, Wexler L, Dela Cruz FS, Cheung NK, Basu E, Kentsis A, Ortiz M, Francis JH, Dunkel IJ, Khakoo Y, Gilheeney S, Farouk Sait S, Forlenza CJ, Sulis M, Karajannis M, Modak S, Gerstle JT, Heaton TE, Roberts S, Yang C, Jairam S, Vijai J, Topka S, Friedman DN, Stadler ZK, Robson M, Berger MF, Schultz N, Ladanyi M, O\u2019Reilly RJ, Abramson DH, Ceyhan-Birsoy O, Zhang L, Mandelker D, Shukla NN, Kung AL, Offit K, Zehir A, Walsh MF (2021) Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. 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