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Genet."],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in <jats:italic>FGFR2<\/jats:italic> have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning\u2013Feuerstein\u2013Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in <jats:italic>HRAS<\/jats:italic>, <jats:italic>KRAS,<\/jats:italic> and <jats:italic>NRAS<\/jats:italic>. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=\/T\u2009&gt;\u2009G p.(Asn549=\/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate <jats:italic>FGFR2<\/jats:italic>-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of <jats:italic>FGFR<\/jats:italic>-associated disorders. We conclude that molecular analysis of <jats:italic>FGFR2<\/jats:italic> should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options.<\/jats:p>","DOI":"10.1007\/s00439-023-02634-1","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T09:02:38Z","timestamp":1706086958000},"page":"159-168","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes"],"prefix":"10.1007","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5942-2924","authenticated-orcid":false,"given":"Julia","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Kaulfu\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagen","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Gaubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Reintjes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Bremmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffi","family":"Dreha-Kulaczewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Stroebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6khan","family":"Yigit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Wollnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,24]]},"reference":[{"issue":"04","key":"2634_CR1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3934\/genet.2016.3.205","volume":"03","author":"C Apra","year":"2016","unstructured":"Apra C, Collet C, Arnaud E, Di Rocco F (2016) Changes in FGFR2 amino-acid residue Asn549 lead to Crouzon and Pfeiffer syndrome with hydrocephalus. 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