Tumor spectrum in children with Noonan syndrome and <i>SOS1</i> or <i>RAF1</i> mutations

Denayer, Ellen; Devriendt, Koen; Ravel, Thomy de; Buggenhout, Griet G. Van; Smeets, Eric; François, Inge; Sznajer, Yves; Craen, Margarita; Leventopoulos, George; Mutesa, Léon; Vandecasseye, Willy W.; Massa, Guy; Kayserili, Hülya; Sciot, Raf; Fryns, Jean‐Pierre; Legius, Eric

doi:10.1002/gcc.20735

Cited by 62 publications

(74 citation statements)

References 55 publications

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“…The p.R552G is a known pathogenic mutation, the most frequent one in this gene associated with NS (9,11,(24)(25)(26). Concerning the novel p.A708T, additional analysis (in silico analysis and a control group test) showed that this gene alteration is a polymorphism in our population and most probably is not associated to significant phenotypic effects.…”

Section: Discussionmentioning

confidence: 69%

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil

Malaquias²,

Wanderley

et al. 2010

Arq Bras Endocrinol Metab

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Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.

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Section: Discussionmentioning

confidence: 69%

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil

Malaquias²,

Wanderley

et al. 2010

Arq Bras Endocrinol Metab

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“…51-55 Granular cell tumour in an affected mother and child, pilocytic astrocytoma, and Sertoli tumour in a cryptorchid testis have also been reported. 56 Three cases of neuroblastoma have been reported in.…”

Section: Organ Dysfunctionmentioning

confidence: 99%

Noonan syndrome

et al. 2013

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Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS–MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype–phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.

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“…RAS Mutations [12,13] SHH Activation [14] IGF2 Loss of imprinting [15,16] EGFR Overexpression [17,18] translocation-positive RMS PAX/FKHR Translocation [11,19] NMYC Amplification [20] FGFR4 Mutations [21,22] CB1 - [23] IL4R…”

Section: Translocation-negative Rmsmentioning

confidence: 99%

Multidisciplinary management of childhood sarcoma: time to expand

Schäfer

Niggli

2010

Expert Review of Anticancer Therapy

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"…our knowledge regarding different entities in sarcoma has considerably increased over the last two decades, and this information among others has helped to classify sarcomas more precisely and to identify new subgroups."Sarcomas are a heterogeneous group of tumors. In the last 20 years, the finding of specific acquired chromosomal alterations in sarcomas has helped, in many cases, to understand their underlying genetic basis. Each of the various recurrent chromosomal translocations in sarcomas ultimately results in the creation of a novel chimeric or fusion gene. With the discovery of these new chromosomal alterations in sarcomas, and subsequently of the fusion genes, it was believed that remarkable progress would be possible in the treatment approach for these tumors. Certainly, our knowledge regarding different entities in sarcoma has considerably increased over the last two decades, and this information among others has helped to classify sarcomas more precisely and to identify new subgroups. However, whether this information has also translated into a better treatment approach is questionable. In children, rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor. Although combined treatment modalities including surgery, chemotherapy and/or radiotherapy have increased overall survival in many RMSs and other groups of soft-tissue sarcomas, conventional treatment has not yet resolved the problem of metastatic disease and many situations of disease relapse.Furthermore, another important concern is the side effects of conventional chemotherapy and especially radio therapy. Since most current therapies are not specifically targeted to tumor cells, a variety of normal cells in the body may also be affected by these therapeutic modalities, resulting in undesired and long-term side effects in the developing child."Although combined treatment modalities … have increased overall survival in many rhabdomyosarcomas and other groups of soft-tissue sarcomas, conventional treatment has not yet resolved the problem of metastatic disease and many situations of disease relapse."Optimization of chemotherapy has certainly brought some improvement but it is unlikely to deliver a real breakthrough in the therapeutic approach. Combination therapies including vincristine, dactinomycin and cyclophosphamide or ifosfamide can be considered as the backbone of current treatment protocols. Other antineoplastic agents including doxorubicin, cisplatin, carboplatin, etoposide, topotecan, irinotecan, melphalan and methotrexate are active against RMS and have been combined in various combinations with backbone drugs. The overall survival rate in non-metastatic RMS has reached approximately 70%. However, substantial differences can be observed according to tumor site and clinical stage, ranging from approximately 60%, for example, in RMS of the limbs, to 90% or higher in orbital RMS or in genitourinary and nonbladder

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Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations

Cited by 62 publications

References 55 publications

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Noonan syndrome

Multidisciplinary management of childhood sarcoma: time to expand

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