Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous 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 inHRAS,KRAS, andNRAS. 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 activat ion. Overall, our findings indicateFGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum ofFGFR-associated disorders. We conclude that molecular analysis ofFGFR2 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.
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research