Low-Grade Gliomas in Patients with Noonan Syndrome: Case-Based Review of the Literature

Lodi, Mariachiara; Boccuto, Luigi; Carai, Andrea; Cacchione, Antonella; Miele, Evelina; Colafati, Giovanna Stefania; Camassei, Francesca Diomedi; Palma, Luca De; Benedictis, Alessandro De; Ferretti, Elisabetta; Catanzaro, Giuseppina; Pò, Agnese; Luca, Alessandro De; Rinelli, Martina; Lepri, Francesca Romana; Tartaglia, Marco; Locatelli, Franco; Mastronuzzi, Angela

doi:10.3390/diagnostics10080582

Cited by 29 publications

(28 citation statements)

References 40 publications

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“…NF1 is characterized by an extremely variable clinical spectrum, ranging from isolated skin manifestations to a more complex multi-system involvement, and approximately 10% of individuals with NF1 share phenotypic features with Noonan syndrome, a RASopathy caused in about half of patients by mutations in PTPN11 [16,26,27]. This was the case with patient 8, who carried an activating PTPN11 variant together with a loss-of-function NF1 variant, resulting in typical NF1 skin findings associated with a severe NF1 neuroradiological phenotype, peculiar cortical hyperintensities and Noonan-like features [16].…”

Section: Discussionmentioning

confidence: 99%

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study

et al. 2022

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Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3–26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14–26) versus 10 (3–17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify “high-risk” patients and to better individualize treatment.

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Section: Discussionmentioning

confidence: 99%

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study

et al. 2022

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“…Heterozygous mutations in PTPN11 cause ~50% of all Noonan Syndrome cases 74 , a germline overgrowth disorder where multiple cases of co-occurring epileptic tumors have been reported. 52,75,76 Interestingly, PTPN11 regulates the PI3K-AKT-MTOR and the RAS-RAF-MAPK pathway 77 and plays a role in the development of human white matter microstructure. 53 Furthermore, two individuals with FCD type 3 and somatic PTPN11 mutation have been recently reported.…”

Section: Discussionmentioning

confidence: 99%

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

López-Rivera

Leu

Macnee

et al. 2022

Preprint

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Understanding the exact molecular mechanisms involved in the etiology of epileptogenic pathologies with or without tumor activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350 ×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants (SNV) in low-grade epilepsy-associated tumors (LEAT; 7.92±5.65 SNV) than in brain tissue from malformations of cortical development (MCD; 6.11±4 SNV) or hippocampal sclerosis (HS; 5.1±3.04 SNV). Tumor tissues also had the largest number of likely pathogenic variant carrying cells. LEAT had the highest proportion of samples with one or more somatic copy number variants (CNV; 24.7%), followed by MCD (5.4%) and HS (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among LEAT. For germline variant-associated MCD genes such as TSC2, DEPDC5, and PTEN, germline SNV were frequently identified within large loss of heterozygosity regions, supporting the recently proposed second hit disease mechanism in these genes. We detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (e.g., BRAF) and MCD (e.g., SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with LEAT and NRAS Q61 mutated protein with a complex MCD characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical genetic analyses showed that the numbers of somatic SNV across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with LEAT. Finally, we report that identifying a likely pathogenic variant enabled us to refine or reclassify previous histopathological classifications post hoc in 20.5% of diagnoses. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening, and guides future directions for clinical implementation of epilepsy surgery genetics.

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“…In the case presented here, there is a background of NS, an autosomal dominant condition with a variable phenotype, in which 50% of cases are due to a germline “gain of function” mutation of the PTPN11 gene; this particular gene is responsible for encoding the nonreceptor protein tyrosine phosphatase SHP2, positively controlling the RAS function within the RAS–mitogen-activated protein kinase (MAPK) signaling pathway. 13 , 14 …”

Section: Discussionmentioning

confidence: 99%

“…In the case presented here, there is a background of NS, an autosomal dominant condition with a variable phenotype, in which 50% of cases are due to a germline "gain of function" mutation of the PTPN11 gene; this particular gene is responsible for encoding the nonreceptor protein tyrosine phosphatase SHP2, positively controlling the RAS function within the RAS-mitogen-activated protein kinase (MAPK) signaling pathway. 13,14 Considering the nature of the RAS-MAPK pathway and its role in oncogenesis, patients with certain mutations (so-called RASopathies), and thereby NS, are at an increased risk of certain cancers. Somatic mutations of PTPN11 have been reported as being present in 35% of persons with juvenile myelomonocytic leukemia, alongside other hematological malignancies and solid organ tumors, such as lung and colon cancer and neuroblastoma.…”

Section: General Aspects Relevant To This Casementioning

confidence: 99%

“…15,16 Overall, individuals with NS have an estimated cancer risk of 4% by 20 years old. 13,17,18 Currently, limited evidence details the relationship between CNS tumors and NS, with most articles providing case reports of pediatric glial tumors. A case report and literature review of these tumors occurring alongside NS by Lodi and colleagues in 2020 demonstrated that most cases occurred in the pediatric population and were dysembryoplastic neuroepithelial tumors.…”

Section: General Aspects Relevant To This Casementioning

confidence: 99%

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Malignant intracerebral nerve sheath tumor in a patient with Noonan syndrome: illustrative case

Allison

Shumon²,

Joshi

et al. 2021

Journal of Neurosurgery: Case Lessons

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BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) within the neuroaxis are rare, usually arising from peripheral and cranial nerves. Even more scarce are cranial subclassifications of MPNSTs termed “malignant intracerebral nerve sheath tumors” (MINSTs). These tumors are aggressive, with a strong tendency for metastasis. With this presentation, alongside resistance to adjunctive therapy, complete excision is the mainstay of treatment, although it is often insufficient, resulting in a high rate of mortality. OBSERVATIONS The authors report the case of an adult patient with a history of Noonan syndrome (NS) presenting with slowly progressive right-sided hemiparesis and right-sided focal motor seizures. Despite initial imaging and histology suggesting a left frontal lobe high-grade intrinsic tumor typical of a glioblastoma, subsequent molecular analysis confirmed a diagnosis of MINST. The patient’s neurological condition improved after gross-total resection and adjuvant chemo-radiation; he remains on follow-up. LESSONS MINSTs are rare neoplasms with a poor prognosis; management options are limited, with surgery being the cornerstone of treatment. Reports on rare tumors such as this will increase awareness of this particular pathology and disclose clinical experience. In this case, the authors were unable to establish a definite cause-and-effect relation between NS and MINST. Nevertheless, it remains the first reported case in the literature.

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Low-Grade Gliomas in Patients with Noonan Syndrome: Case-Based Review of the Literature

Cited by 29 publications

References 40 publications

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Malignant intracerebral nerve sheath tumor in a patient with Noonan syndrome: illustrative case

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