Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes.

Autor: Schmidt J; Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany. julia.schmidt1@med.uni-goettingen.de., Kaulfuß S; Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany., Ott H; Department of Pediatric Dermatology, Children's Hospital Auf Der Bult, Academic Hospital, Hannover, Germany., Gaubert M; Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany., Reintjes N; Institute of Human Genetics, University Hospital Cologne, Cologne, Germany., Bremmer F; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Dreha-Kulaczewski S; Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany., Stroebel P; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Yigit G; Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany., Wollnik B; Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2024 Feb; Vol. 143 (2), pp. 159-168. Date of Electronic Publication: 2024 Jan 24.
DOI: 10.1007/s00439-023-02634-1
Abstrakt: 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 FGFR2 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-Feuerstein-Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G 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 FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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