The seventh international <scp>RASopathies</scp> symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery

Kontaridis, Maria I.; Roberts, Amy; Schill, Lisa; Schoyer, Lisa; Stronach, Beth; Andelfinger, Grégor; Aoki, Yoko; Axelrad, Marni E.; Bennett, Anton M.; Broniscer, Alberto; Castel, Pau; Chang, Caitlin; Cyganek, Lukas; Das, Tirtha K.; Hertog, Jeroen den; Galperin, Emilia; Garg, Shruti; Gelb, Bruce D.; Gordon, Kristiana; Green, Tamar; Gripp, Karen W.; Itkin, Maxim; Kiuru, Maija; Korf, Bruce R.; Livingstone, Jeff R; López‐Juárez, Alejandro; Magoulas, Pilar L.; Mansour, Sahar; Milner, Theresa; Parker, Elisabeth; Pierpont, Elizabeth I.; Plouffe, Kevin; Shankar, Suma P.; Smith, Shane B; Stevenson, David A.; Tartaglia, Marco; Van, Richard; Wagner, Morgan E.; Ware, Stephanie M.; Zenker, Martin

doi:10.1002/ajmg.a.62716

Cited by 12 publications

(14 citation statements)

References 54 publications

(65 reference statements)

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“… 116 , 117 Indeed the development of therapies targeting these pathways has opened a way to approach RASopathies by selective inhibition of the dysregulated cascades implicated in pathogenesis. 118 , 119 First evidence of such potential beneficial effects is supported by the recent approval of MEK inhibitors (MEKi) such as selumetinib for the treatment of symptomatic inoperable plexiform neurofibromas in children affected by NF1. 120 , 121 Recent evidences also support the use of trametinib for the treatment of HCM in Noonan syndrome.…”

Section: Discussionmentioning

confidence: 99%

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Leoni¹,

Viscogliosi²,

Tartaglia³

et al. 2022

JMDH

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Costello syndrome (CS) is a rare neurodevelopmental disorder caused by germline mutations in HRAS . It belongs among the RASopathies, a group of syndromes characterized by alterations in components of the RAS/MAPK signaling pathway and sharing overlapping phenotypes. Its typical features include a distinctive facial appearance, growth delay, intellectual disability, ectodermal, cardiac, and musculoskeletal abnormalities, and cancer predisposition. Due to the several comorbidities having a strong impact on the quality of life, a multidisciplinary team is essential in the management of such a condition from infancy to adult age, to promptly address any detected issue and to develop appropriate personalized follow-up protocols and treatment strategies. With the present paper we aim to highlight the core and ancillary medical disciplines involved in managing the health challenges characterizing CS from pediatric to adult age, according to literature and to our large clinical experience.

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Section: Discussionmentioning

confidence: 99%

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Leoni¹,

Viscogliosi²,

Tartaglia³

et al. 2022

JMDH

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“…It is encouraging that much progress has been made in our understanding of the molecular genetic causes of NS, and novel therapeutic drugs have been given to patients. To date, there are some publications describing the use of RAS pathway inhibition as useful for NS ( Andelfinger et al, 2019 ; Mek Inhibitor Reverses Hypertrophic Cardiomyopathy, 2019 ; Dori et al, 2020 ; Meisner et al, 2021 ; Mussa et al, 2021 ; Kontaridis et al, 2022 ). Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome

et al. 2022

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Background: Common cardiac abnormalities in Noonan syndrome (NS) include congenital heart diseases (CHD), pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Molecular diagnoses are enabling earlier and more precise diagnosis of patients who have a subtle or atypical presentation. The aims of this study were to investigate genotype-phenotype associations with respect to Noonan syndrome (NS)-associated cardiac abnormalities and catheter or surgery-based interventions conditions.Methods: From January 2019 to December 2021, 22 children with a confirmed molecular diagnosis of NS combined with cardiovascular abnormalities were consecutively enrolled into the current study. A comprehensive review was carried out of echocardiography and electrocardiogram results, second-generation whole-exome sequencing results and catheter or surgery-based interventions conditions.Results: The main manifestations of electrocardiogram abnormalities were QTc prolongation, abnormal Q wave in the precordial lead and limb lead, right ventricular hypertrophy and left or right deviation of the electrical axis. The most commonly detected abnormality was pulmonary valve dysplasia with stenosis, seen in 15 (68.2%) patients, followed by atrial septal defect in 11 (50%) patients. Seven genes (RAF1, RIT1, SOS1, PTPN11, BRAF, SOS2, and LZTR1) were found to contain disease-associated variants. The most commonly observed genetic mutations were PTPN11 (27%) and RAF1 (27%). Each genotype was associated with specific phenotypic findings. RIT1, SOS1, PTPN11, and SOS2 had common echocardiography features characterized by pulmonary valve stenosis, while RAF1 was characterized by HCM. Interestingly, patients with BRAF mutations were not only characterized by HCM, but also by pulmonary valve stenosis. In the cohort there was only one patient carrying a LZTR1 mutation characterized by left ventricle globose dilation. Ten cases underwent catheter or surgery-based interventions. All the operations had immediate results and high success rates. However, some of the cases had adverse outcomes during extended follow-up. Based on the genotype-phenotype associations observed during follow-up, BRAF and RAF1 genotypes seem to be poor prognostic factors, and multiple interventions may be required for NS patients with severe pulmonary stenosis or myectomy for HCM.Conclusions: The identification of causal genes in NS patients has enabled the evaluation of genotype-cardiac phenotype relationships and prognosis of the disease. This may be beneficial for the development of therapeutic approaches.

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“…The differential diagnosis of mosaic RASopathies mostly relies on other congenital/early onset segmental overgrowth syndromes associated with somatic mosaic pathogenic variants in the PI3K/AKT/ mTOR or the vascular proliferation pathways, like PIK3CA-related overgrowth spectrum (PROS) (Canaud, Hammill, Adams, Vikkula, & Keppler-Noreuil, 2021;Chang et al, 2021;Diociaiuti et al, 2022;Keppler-Noreuil et al, 2015;Lalonde et al, 2019;Mussa, Carli, Cardaropoli, Ferrero, & Resta, 2021) Cancer risk in germline and mosaic RASopathies is debated (Kontaridis et al, 2022). It is likely increased in individuals harboring pathogenic mosaic somatic variants in HRAS and KRAS, as it has been largely demonstrated in individuals with germline Costello syndrome (Davies et al, 2022) but not yet defined for those with mosaic RASopathies caused by pathogenic variants in other genes.…”

Section: Kras Nrasmentioning

confidence: 99%

“…Grouping all individuals with a common molecular mechanism under this term is not just an academic exercise: rather it has several implications, underlining the common pathogenic mechanism, many common clinical manifestations as well as the shared possibility of targeted medical treatments. Currently, RAS/MAPK pathway hyperactivation is commonly observed in cancer and has been largely studied in oncology allowing the development of specific inhibitors representing a promising treatment option for affected individuals with both germline and mosaic RASopathies (Chang et al, 2021; Hebron, Hernandez, & Yohe, 2022; Kontaridis et al, 2022).…”

Section: Overviewmentioning

confidence: 99%

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

Carli¹,

Resta

Ferrero

et al. 2022

American J of Med Genetics Pt C

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Mosaic RASopathies are a heterogeneous group of diseases characterized by the presence at birth or early onset of congenital anomalies, cutaneous and vascular anomalies, segmental overgrowth, and increased cancer risk. They are caused by somatic pathogenic variants of the genes belonging the RAt Sarcoma Mitogenactivated protein kinase (RAS/MAPK) pathway causing its hyperactivation. Here, we review the clinical and molecular characteristics of this heterogeneous group of diseases, including the possibilities of molecular diagnosis and new therapeutic perspectives.

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The seventh international RASopathies symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery

Cited by 12 publications

References 54 publications

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

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