Lateralized overgrowth with vascular malformation caused by a somaticPTPN11pathogenic variant: Another piece added to the puzzle of mosaicRASopathies

Abstract

Lateralized/segmental overgrowth disorders (LOs) encompass a heterogeneous group of congenital conditions with excessive body tissue growth. Documented molecular alterations in LOs mostly consist of somatic variants in genes of the PI3KCA/AKT/mTOR pathway or of chromosome band 11p15.5 imprinted region anomalies. In some cases, somatic pathogenic variants in genes of the RAS/MAPK pathway have been reported. We present the first case of a somatic pathogenic variant (T507K) in PTPN11 causing a LO phenotype characterized by severe lateralized overgrowth, vascular proliferation, and cerebral astrocytoma. The T507K variant was detected in DNA from overgrown tissue in a leg with capillary malformation. The astrocytoma tissue showed a higher PTPN11 variant allele frequency. A pathogenic variant in FGFR1 was also found in tumor tissue, representing a second hit on the RAS/MAPK pathway. These findings indicate that RAS/MAPK cascade overactivation can cause mosaic overgrowth phenotypes resembling PIK3CA‐related overgrowth disorders (PROS) with cancer predisposition and are consistent with the hypothesis that RAS/MAPK hyperactivation can be involved in the pathogenesis of astrocytoma. This observation raises the issue of cancer predisposition in patients with RAS/MAPK pathway gene variants and expands genotype spectrum of LOs and the treatment options for similar cases through inhibition of the RAS/MAPK oversignaling.

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

“…It is likely increased in individuals harboring pathogenic mosaic somatic variants in HRAS and KRAS, as it has been largely demonstrated in individuals with germline Costello syndrome (Davies et al, 2022) but not yet defined for those with mosaic RASopathies caused by pathogenic variants in other genes. Despite several case reports (Chang et al, 2021;Davies et al, 2022;Mussa, Turchiano, et al, 2022;Om et al, 2017;Prieto-Barrios et al, 2018;Slack et al, 2021) of individuals having mosaic RASopathies (e.g., in the HRAS, KRAS, and PTPN11 genes), who developed cancer (e.g., Wilms tumor, rhabdomyosarcoma, and astrocytoma), there is no consensus on the need and appropriateness of cancer screening in germline and/or mosaic RASopathies.…”

“…A somatic mosaic pathogenic variant in PTPN11 has been recently described in an individual with LO, vascular malformation, and cerebral astrocytoma (Mussa, Turchiano, et al, 2022), identifying a new form of syndromic mosaic RASopathy.…”