PTPN11-related Noonan syndrome predisposes to multifocal low-grade CNS tumors harboring FGFR1 variants

Gary Kohanbash; Scott Ryall; Sam E Gary; Lindsey M Hoffman; Robert Siddaway; Anne E Bendel; Karen W Gripp; Andrew W Walter; Jordan R Hansford; Amy A Smith; Hong Wang; John M Skaugen; Uri Tabori; Cynthia E Hawkins; Alberto Broniscer

doi:10.1007/s11060-026-05478-7

PTPN11-related Noonan syndrome predisposes to multifocal low-grade CNS tumors harboring FGFR1 variants

J Neurooncol. 2026 Mar 5;177(1):31. doi: 10.1007/s11060-026-05478-7.

Authors

Gary Kohanbash^{1

2}, Scott Ryall^{3

4

5}, Sam E Gary⁶, Lindsey M Hoffman^{7

8}, Robert Siddaway⁹, Anne E Bendel¹⁰, Karen W Gripp¹¹, Andrew W Walter¹², Jordan R Hansford^{13

14}, Amy A Smith¹⁵, Hong Wang¹⁶, John M Skaugen¹⁷, Uri Tabori¹⁸, Cynthia E Hawkins^{4

9}, Alberto Broniscer^{19

20

21}

Affiliations

¹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA. gary.kohanbash@pitt.edu.
² Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. gary.kohanbash@pitt.edu.
³ The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ Brigham and Women's Hospital, Boston, MA, USA.
⁶ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Division of Hematology-Oncology, Children's Hospital of Colorado, Aurora, CO, USA.
⁸ Johnson & Johnson, Phoenix, AZ, USA.
⁹ Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁰ Division of Hematology-Oncology, Children's Minnesota, Minneapolis, MN, USA.
¹¹ Division of Medical Genetics, Nemours Children's Health, Wilmington, DE, USA.
¹² Division of Hematology-Oncology, Nemours Children's Health, Wilmington, DE, USA.
¹³ Children's Cancer Centre, Royal Children's Hospital, Melbourne, Australia.
¹⁴ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
¹⁵ Division of Pediatric Hematology-Oncology, Arnold Palmer Hospital, Orlando, FL, USA.
¹⁶ School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁷ Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁸ Division of Pediatric Hematology-Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁹ Division of Pediatric Hematology-Oncology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. albertobroniscer5704@gmail.com.
²⁰ , 32 Academy Street, Arlington, MA, 02476, USA. albertobroniscer5704@gmail.com.
²¹ Servier Pharmaceuticals, Boston, MA, USA. albertobroniscer5704@gmail.com.

Abstract

Purpose: To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies.

Methods: Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed.

Results: Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline PTPN11 variant; Nineteen of 24 participants (79%) were male. Seventeen of 19 (89%) patients with NS developed CNS tumors, including low-grade glioma, (LGG; pilocytic/pilomyxoid astrocytoma; n = 9) and dysembryoplastic neuroepithelial tumor (DNET; n = 6). Five patients incidentally diagnosed did not undergo histological confirmation. Radiological review showed multifocal parenchymal tumors in 9 patients with NS, including histologically confirmed neoplasm (n = 2), radiologic progression (n = 6), or typical tumoral imaging (n = 1). Fourteen of 15 (93%) tumors collected from 13 patients with NS and germline PTPN11 variants harbored somatic FGFR1 abnormalities. RNA sequencing of 12 tumors detected FGFR1 internal tandem duplication in one patient. Comparison with published data showed a statistically significant association between brain tumor occurrence and PTPN11-related NS, driven by two genotypes: NM_002834.5(PTPN11):c.182 A > G (p.Asp61Gly) and c.417G > T (p.Glu139Asp). Ten patients with CNS tumors, including 7/17 (41%) with PTPN11 variants, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS tumor.

Conclusion: PTPN11-related NS predisposes to multifocal low-grade glial and glioneuronal tumors confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and low-grade CNS tumors.

Supplementary Information: The online version contains supplementary material available at 10.1007/s11060-026-05478-7.

Keywords: FGFR1; PTPN11; Brain tumor; Glioma; Noonan syndrome.

Abstract

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