Malignant Diseases in Noonan Syndrome and Related Disorders

Hasle, Henrik

doi:10.1159/000243773

Cited by 61 publications

(45 citation statements)

References 82 publications

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“…About 25% of pediatric NS patients display some degree of hepatosplenomegaly. A more limited number develop a benign form of MPD that regresses spontaneously in most cases (17,18). However, some NS patients occasionally develop JMML, a fatal form of MPD characterized by cytokine hypersensitivity of myeloid progenitors (18).…”

Section: Discussionmentioning

confidence: 99%

K-Ras ^V14I recapitulates Noonan syndrome in mice

Hernández-Porras

Fabbiano

Schuhmacher

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Noonan syndrome (NS) is a developmental disorder caused by germ-line mutations in various components of the RAS signaling pathway. The pathophysiological mechanisms underlying the clinical manifestations in NS patients and the basis for the observed phenotypic variability are poorly understood. To date, mouse models carrying mutations in Protein Tyrosine Phosphatase Non-Receptor type 11 ( Ptpn11 ), Son of Sevenless homolog 1 ( Sos1 ), and Raf1 loci have been described. The new model described here, induced by K- Ras V14I expression, recapitulates most of the NS features including small size, craniofacial dysmorphism, cardiac defects, and myeloproliferative disorders, highly reminiscent of juvenile myelomonocytic leukemia. These mice should help us understand better the phenotypic variations of NS and serve as a preclinical tool to test forthcoming therapies based on the design of novel inhibitors of the RAS pathway.

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Section: Discussionmentioning

confidence: 99%

K-Ras ^V14I recapitulates Noonan syndrome in mice

Hernández-Porras

Fabbiano

Schuhmacher

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…This includes Costello syndrome (HRAS gene), Noonan syndrome (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, MEK1, and RIT1 genes), neurofibromatosis type 1 (NF1), and others (90)(91)(92)(93)(94)(95)(96). Indeed, homozygous inactivation of the NF1 gene has been described in primary NBs (97,98), although the overall prevalence of NF1 mutations in NBs is very low.…”

Section: Rasopathiesmentioning

confidence: 99%

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Kamihara

Bourdeaut

Foulkes

et al. 2017

Clinical Cancer Research

188

137

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Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop.

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“…Indeed it is well known that, as a consequence of harboring mutation of genes of the Ras/MAPK pathway, subjects with NS display spontaneously an increased risk of developing cancer, and notably juvenile hematological malignancies [3,45]. This susceptibility to cancer is certainly a consequence of the mutations causing NS which are located in genes of the Ras/MAPK pathway, a signaling module that regulates cell proliferation or survival in a variety of different tissues.…”

Section: Potential Adverses Effects Of Gh Therapymentioning

confidence: 99%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

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Malignant Diseases in Noonan Syndrome and Related Disorders

Cited by 61 publications

References 82 publications

K-Ras ^V14I recapitulates Noonan syndrome in mice

K-Ras ^V14I recapitulates Noonan syndrome in mice

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

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Malignant Diseases in Noonan Syndrome and Related Disorders

Cited by 61 publications

References 82 publications

K-Ras V14I recapitulates Noonan syndrome in mice

K-Ras V14I recapitulates Noonan syndrome in mice

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

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Product

Resources

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K-Ras ^V14I recapitulates Noonan syndrome in mice

K-Ras ^V14I recapitulates Noonan syndrome in mice