Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome

Nair, Sushmita; Fort, John; Yachnis, Anthony T.; Williams, Charles A.

doi:10.1002/pbc.25382

Cited by 8 publications

(7 citation statements)

References 19 publications

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“…Our update identified 25 tumors. Beside one medulloblastoma [Rankin et al, ], all were glial or glioneuronal tumors [Sanford et al, ; Takagi et al, ; Jongmans et al, ; Martinelli et al, ; Fryssira et al, ; Schuettpelz et al, ; Sherman et al, ; De Jong et al, ; Karafin et al, ; Bendel and Pond, ; Rush et al, ; Kratz et al, ; Nair et al, ]. There were nine DNTs which characteristics are summarized in Table .…”

Section: Discussionmentioning

confidence: 99%

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature

Siegfried

Cancés

Denuelle

et al. 2017

American J of Med Genetics Pt A

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Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature

Siegfried

Cancés

Denuelle

et al. 2017

American J of Med Genetics Pt A

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“…The PTPN11 gene is mutated in about 50 % of patients with Noonan syndrome and has been found also to be mutated (admittedly always together with FGFR1 mutations, see below) in sporadic PAs [ 32 ]. However, the number of PAs reported in patients with Noonan syndrome is small [ 22 , 46 , 50 ].…”

Section: Association With Familial Tumor Syndromesmentioning

confidence: 99%

Pilocytic astrocytoma: pathology, molecular mechanisms and markers

2015

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Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90 %. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed.

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“…Somatic mutations in PTPN11, also known as SHP-2, have not been reported in ONG, but mutations overlapping with the SH2 domain, as observed here, have been reported as key tumorigenesis drivers in other gliomas through activation of the AKT/mTOR signaling pathway [6,15]. Interestingly, a germline PTPN11-mutated ONG has been reported in a child with Noonan syndrome, characterized by germline gain-of-function mutations in PTPN11 and increased risk of myeloid and solid tumors [16]. Despite the family history of glioblastoma, no obvious pathogenic germline mutation was identified in our patient.…”

Section: Discussionmentioning

confidence: 52%

Genetic characterization of an aggressive optic nerve pilocytic glioma

et al. 2020

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Optic nerve glioma (ONG) is a rare, typically slow-growing WHO I grade tumor that affects the visual pathways. ONG is most commonly seen in the pediatric population, in association with neurofibromatosis type 1 syndrome. However, sporadic adult cases may also occur and may clinically behave more aggressively, despite benign histopathology. Genetic characterization of these tumors, particularly in the adult population, is lacking. A 39-year-old female presented with 1 month of progressive left-sided visual loss secondary to a enhancing mass along the left optic nerve sheath. Initial empiric management with focal radiotherapy failed to prevent tumor progression, prompting open biopsy which revealed a WHO I pilocytic astrocytoma of the optic nerve. Whole-exome sequencing of the biopsy specimen revealed somatic mutations in NF1,FGFR1 and PTPN11 that may provide actionable targets for molecularly guided therapies. Genetic characterization of ONG is lacking but is needed to guide the management of these rare but complex tumors. The genomic alterations reported in this case contributes to understanding the pathophysiology of adult sporadic ONG and may help guide future clinical prognostication and development of targeted therapies.

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Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome

Cited by 8 publications

References 19 publications

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature

Pilocytic astrocytoma: pathology, molecular mechanisms and markers

Genetic characterization of an aggressive optic nerve pilocytic glioma

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