Lateralized overgrowth with vascular malformation caused by a somatic PTPN11 pathogenic variant: Another piece added to the puzzle of mosaic RASopathies

Genes Chromosomes Cancer. 2022 Nov;61(11):689-695. doi: 10.1002/gcc.23086. Epub 2022 Jul 16.


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.

Keywords: FGFR1; PTPN11; RASopathies; astrocytoma; mosaicism; overgrowth.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytoma*
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Genotype
  • Humans
  • Mutation
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Vascular Malformations* / genetics


  • Class I Phosphatidylinositol 3-Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11