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      Rosette forming glioneuronal tumor in association with Noonan syndrome: pathobiological implications

      case-report

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          Abstract

          Noonan syndrome, a distinctive syndrome characterized by dysmorphism, cardiac abnormalities and developmental delay, has been associated with a number of malignancies, however, only a few cases of primary glial or glioneuronal neoplasms have been reported. We report here the case of an 18-year-old with Noonan syndrome who developed a rosette forming glioneuronal tumor of the posterior fossa. The tumor demonstrated strong pERK immunoreactivity, suggesting MAPK/ERK pathway activation. Molecular testing did not reveal BRAF rearrangements (fusion transcripts) by PCR or a BRAF V600E mutation by sequencing. We review the literature regarding the molecular pathogenesis of Noonan syndrome and primary brain tumors, and consider the intriguing link between their common molecular pathways.

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          Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

          M. Tartaglia, E. L. Mehler, R. Goldberg … (2001)
          Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.
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            Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

            M Digilio, Francesca Lepri, Anna Sarkozy … (2007)
            Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.
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              Germline KRAS mutations cause Noonan syndrome.

              Suzanne Schubbert, Martin Zenker, Sara L Rowe … (2006)
              Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Clin Neuropathol
                Journal ID (iso-abbrev): Clin. Neuropathol
                Journal ID (publisher-id): Dustri
                Title: Clinical Neuropathology
                Publisher: Dustri-Verlag Dr. Karl Feistle
                ISSN (Print): 0722-5091
                Publication date (Print): Nov-Dec 2011
                Publication date (Electronic): 18 October 2011
                Volume: 30
                Issue: 6
                Pages: 297-300
                Affiliations
                [1 ]Department of Pathology, Division of Neuropathology
                [2 ]Neurosurgery, Johns Hopkins University, Baltimore, MD, USA
                Author notes
                Correspondence to F.J. Rodriguez, MD Department of Pathology, Division of Neuropathology, Johns Hopkins University, 720 Rutland Avenue, Ross Building, 512B, Baltimore, MD 21205, USA frodrig4@ 123456jhmi.edu
                Article
                DOI: 10.5414/NP300374
                PMC ID: 3657471
                PubMed ID: 22011734
                SO-VID: be57bbf0-9a39-40f2-afe4-508996eaa0d7
                Copyright © © Dustri-Verlag Dr. K. Feistle
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 12 January 2011
                Date accepted : 18 April 2011
                Categories
                Subject: Case Report
                Subject: Neuropathology

                Keywords: noonan syndrome,glioneuronal tumor,rosette forming glioneuronal tumor,ras,mapk/erk
                Data availability:
                Keywords: noonan syndrome, glioneuronal tumor, rosette forming glioneuronal tumor, ras, mapk/erk

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