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

Abstract

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.

Occurrence of high‐grade glioma in Noonan syndrome: Report of two cases

“…The most common brain tumors observed with NS were low‐grade glial and glioneuronal tumors. DNETs are rare WHO grade I glioneuronal tumors that comprise <1% of childhood brain tumors, but their incidence appears significantly higher in NS . In our search, nine out of 24 identified cases were DNETs, a fact that might suggest a noncoincidental relation between NS and the development of DNETs.…”

“…DNETs are rare WHO grade I glioneuronal tumors that comprise <1% of childhood brain tumors, 13 but their incidence appears significantly higher in NS. 5,6,15…”

“…5 The majority of brain tumors associated with NS are low-grade glial and glioneuronal tumors, primarily dysembryoplastic neuroepithelial tumors (DNET) and lowgrade glioma. 6 Here, we report two cases of anaplastic astrocytoma (AA; WHO grade III) in patients with PTPN11-related NS. We also provide a summary of CNS tumors previously reported in patients with NS to better define and assess the association of high-grade glioma (HGG) with NS.…”

“…Individuals with NS have an estimated 8.1‐fold increased risk of all childhood cancers . The majority of brain tumors associated with NS are low‐grade glial and glioneuronal tumors, primarily dysembryoplastic neuroepithelial tumors (DNET) and low‐grade glioma . Here, we report two cases of anaplastic astrocytoma (AA; WHO grade III) in patients with PTPN11 ‐related NS.…”

PTPN11 hypomethylation is associated with gastric cancer progression

“…PTPN11 mutations have been extensively investigated in the past years. Germline mutations in PTPN11 cause Noonan syndrome (9)(10)(11) and its clinically related Leopard syndrome (12), whereas somatic mutations of PTPN11 contribute to leukemogenesis (13)(14)(15)(16)(17), as well as in the development of specific solid tumors, including neuroblastoma (18,19), metachondromatosis (20,21), brain tumors (22)(23)(24), neurofibromatosis (25), optic nerve pilomyxoid astrocytoma (26), breast carcinoma (27,28), colorectal cancer (29,30) and Ewing sarcoma (31). However, oncogenic mutations of PTPN11 are rare in the majority of solid tumors including GC (32,33).…”