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Purpose <p>To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies.</p> Methods <p>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.</p> Results <p>Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline <i>PTPN11</i> 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; <i>n</i> = 9) and dysembryoplastic neuroepithelial tumor (DNET; <i>n</i> = 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 (<i>n</i> = 2), radiologic progression (<i>n</i> = 6), or typical tumoral imaging (<i>n</i> = 1). Fourteen of 15 (93%) tumors collected from 13 patients with NS and germline <i>PTPN11</i> variants harbored somatic <i>FGFR1</i> abnormalities. RNA sequencing of 12 tumors detected <i>FGFR1</i> internal tandem duplication in one patient. Comparison with published data showed a statistically significant association between brain tumor occurrence and <i>PTPN11</i>-related NS, driven by two genotypes: NM_002834.5(PTPN11):c.182&#xa0;A &gt; G (p.Asp61Gly) and c.417G &gt; T (p.Glu139Asp). Ten patients with CNS tumors, including 7/17 (41%) with <i>PTPN11</i> variants, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS tumor.</p> Conclusion <p><i>PTPN11</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • 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

摘要

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.