{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T20:58:27Z","timestamp":1765486707192,"version":"3.40.5"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neurofibromatosis 1 (NF1) is caused by germline mutations in the <jats:italic>NF1<\/jats:italic> gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of <jats:italic>NF1<\/jats:italic>. In this study, we investigated a life\u2010threatening plexiform neurofibroma in a 9\u2010month\u2010old female infant with NF1. Germline mutations in two RASopathy\u2010associated genes were identified using whole\u2010exome sequencing\u2014a de novo pathogenic variant in the <jats:italic>NF1<\/jats:italic>\u00a0gene, and a known pathogenic variant in the <jats:italic>LZTR1<\/jats:italic>\u00a0gene. Somatic analysis of the plexiform neurofibroma revealed <jats:italic>NF1<\/jats:italic>\u00a0loss of heterozygosity and a variant in <jats:italic>GNAZ<\/jats:italic>, a gene encoding a G protein\u2010coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1\/2 activation compared to those expressing wild\u2010type GNAZ. Taken together, we suggest the variants in <jats:italic>NF1<\/jats:italic>, <jats:italic>LZRT1<\/jats:italic> and <jats:italic>GNAZ<\/jats:italic> act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non\u2010NF1 variants affecting the NF1\u00a0clinical phenotype and supports use of personalized, targeted therapy.<\/jats:p>","DOI":"10.1111\/exd.14514","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T12:53:15Z","timestamp":1639572795000},"page":"775-780","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Concomitant variants in <i>NF1<\/i>, <i>LZTR1<\/i> and <i>GNAZ<\/i> genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5454-7242","authenticated-orcid":false,"given":"Eran","family":"Cohen\u2010Barak","sequence":"first","affiliation":[{"name":"Department of Dermatology \u201cEmek\u201d Medical Center  Afula Israel"},{"name":"Bruce and Ruth Rappaport Faculty of 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