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.

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

Mussa, Alessandro
First
;
Cardaropoli, Simona;Ranieri, Carlotta;Vallero, Stefano Gabriele;Bertin, Daniele;Carli, Diana;Ferrero, Giovanni Battista;
2022-01-01

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.
2022
61
11
689
695
FGFR1; PTPN11; RASopathies; astrocytoma; mosaicism; overgrowth; Class I Phosphatidylinositol 3-Kinases; Genotype; Humans; Mutation; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Astrocytoma; Vascular Malformations
Mussa, Alessandro; Turchiano, Antonella; Cardaropoli, Simona; Coppo, Paola; Pantaleo, Antonino; Bagnulo, Rosanna; Ranieri, Carlotta; Iacoviello, Matteo; Garganese, Antonella; Stella, Alessandro; Vallero, Stefano Gabriele; Bertin, Daniele; Santoro, Federica; Carli, Diana; Ferrero, Giovanni Battista; Resta, Nicoletta
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1875559
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