Mosaic RASopathy due to KRAS variant G12D with segmental overgrowth and associated peripheral vascular malformations. Issue 10 (11th June 2021)

• Record Type: Journal Article
• Authors: Schmidt, Vanessa Franziska; Wieland, Ilse; Wohlgemuth, Walter A.; Ricke, Jens; Wildgruber, Moritz; Zenker, Martin
• Is Part Of: American journal of medical genetics. Volume 185:Issue 10(2021)
• Page Start: 3122
• Page End: 3128
• Publication Date: 2021-06-11
• Subjects: arteriovenous malformation -- capillary malformation -- KRAS -- mosaic RASopathy -- segmental overgrowth; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.62386
• Languages: English
• ISSNs: 1552-4825

Abstract

Abstract: Oncogenic RAS variants lead to constitutive overactivation and increased signal transduction into downstream pathways. They are found as somatic driver events in various types of human cancer. In a somatic mosaic status, the same RAS variants have been associated with a wide spectrum of focal or segmental tissue dysplasia and overgrowth including various types of congenital nevi, vascular malformations, and other changes (mosaic RASopathies). We present a 3‐year‐old male patient with segmental overgrowth of the subcutaneous fatty tissue of the right lower extremity with colocalized arteriovenous and capillary malformations and dysplastic draining veins in combination with talipes equinovarus of the right foot. In tissue biopsies of the affected extremity, we identified a mosaic KRAS variant, c.35G>A (p.Gly12Asp), while this variant was absent in the DNA extracted from a biopsy of the normal extremity. This report provides further evidence for the wide clinical and phenotypic variability associated with mosaic KRAS variants. The described pattern confirms that the combination of segmental overgrowth and vascular anomalies in the form of arteriovenous and capillary malformations is a possible manifestation of a mosaic RASopathy. The accurate genetic diagnosis is crucial for molecular‐targeted therapy, which might be a future therapeutic target for mosaic RASopathies.