Browsing by Subject "Noonan syndrome"

Now showing 1 - 9 of 9
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    Bilateral Central Giant Cell Granulomas of the Mandible in An Eight Year-Old Girl with Noonan Syndrome (Noonan-Like/Multiple Giant Cell Lesions Syndrome)
    (2005-03) Edwards, Paul C.; Fox, Joyce; Fantasia, John E; Goldberg, Jeff; Kelsch, Robert D
    A number of conditions can present with lesions that histologically are indistinguishable from the central giant cell granuloma (CGCG) of bone, including brown tumors of hyperparathyroidism, cherubism, and, less commonly, a number of inherited syndromes. We report a case of an eight-year girl who presented with bilateral CGCGs of the posterior mandible. Characteristic facial features, reported increased post-operative bleeding and history of pulmonary stenosis led us to suspect a diagnosis of Noonan syndrome. A medical geneticist confirmed this on further evaluation. This case report will discuss the salient features of this diagnosis.
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    Cardiomyopathy in Children Identifying the Causes
    (Elsevier, 2018-11-06) Ware, Stephanie M.; Pediatrics, School of Medicine
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    Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum
    (Elsevier, 2020-09-03) Motta, Marialetizia; Pannone, Luca; Pantaleoni, Francesca; Bocchinfuso, Gianfranco; Radio, Francesca Clementina; Cecchetti, Serena; Ciolfi, Andrea; Di Rocco, Martina; Elting, Mariet W.; Brilstra, Eva H.; Boni, Stefania; Mazzanti, Laura; Tamburrino, Federica; Walsh, Larry; Payne, Katelyn; Fernández-Jaén, Alberto; Ganapathi, Mythily; Chung, Wendy K.; Grange, Dorothy K.; Dave-Wala, Ashita; Reshmi, Shalini C.; Bartholomew, Dennis W.; Mouhlas, Danielle; Carpentieri, Giovanna; Bruselles, Alessandro; Pizzi, Simone; Bellacchio, Emanuele; Piceci-Sparascio, Francesca; Lißewski, Christina; Brinkmann, Julia; Waclaw, Ronald R.; Waisfisz, Quinten; van Gassen, Koen; Wentzensen, Ingrid M.; Morrow, Michelle M.; Álvarez, Sara; Martínez-García, Mónica; De Luca, Alessandro; Memo, Luigi; Zampino, Giuseppe; Rossi, Cesare; Seri, Marco; Gelb, Bruce D.; Zenker, Martin; Dallapiccola, Bruno; Stella, Lorenzo; Prada, Carlos E.; Martinelli, Simone; Flex, Elisabetta; Tartaglia, Marco; Medical and Molecular Genetics, School of Medicine
    Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
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    Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes
    (Elsevier, 2018-02-01) Martinelli, Simone; Krumbach, Oliver H.F.; Pantaleoni, Francesca; Coppola, Simona; Amin, Ehsan; Pannone, Luca; Nouri, Kazem; Farina, Luciapia; Dvorsky, Radovan; Lepri, Francesca; Bucholzer, Marcel; Konopatzki, Raphael; Walsh, Laurence; Payne, Katelyn; Pierpont, Mary Ella; Vergano, Samantha Schrier; Langley, Katherine G.; Larsen, Douglas; Farwell, Kelly D.; Tang, Sha; Mroske, Cameron; Gallotta, Ivan; Schiavi, Elia Di; della Monica, Matteo; Lugli, Licia; Rossi, Cesare; Seri, Marco; Cocchi, Guido; Henderson, Lindsay; Baskin, Berivan; Alders, Mariëlle; Mendoza-Londono, Roberto; Dupuis, Lucie; Nickerson, Deborah A.; Chong, Jessica X.; Meeks, Naomi; Brown, Kathleen; Causey, Tahnee; Cho, Megan T.; Demuth, Stephanie; Digilio, Maria Cristina; Gelb, Bruce D.; Bamshad, Michael J.; Zenker, Martin; Ahmadian, Mohammad Reza; Hennekam, Raoul C.; Tartaglia, Marco; Mirzaa, Ghayda M.; Neurology, School of Medicine
    Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.
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    Genetics of paediatric cardiomyopathies
    (Wolters Kluwer, 2017-10) Ware, Stephanie M.; Pediatrics, School of Medicine
    PURPOSE OF REVIEW: Paediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the paediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. RECENT FINDINGS: With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified at a rapid rate. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences in pathogenesis from adult cardiomyopathy. Therapy targeted towards the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. SUMMARY: Genetics is moving at a rapid pace in paediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. Although interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted towards the underlying genetic cause is beginning to be realized.
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    Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus
    (American Society for Clinical Investigation, 2016-06-01) Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan; Bronson, Roderick; Finnell, Michele; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.; Zhang, Zhong-Yin; Kontaridis, Maria I.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain–containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.
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    Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients
    (Wiley, 2018-08) Levin, Mark D.; Saitta, Sulagna C.; Gripp, Karen W.; Wenger, Tara L.; Ganesh, Jaya; Kalish, Jennifer M.; Epstein, Michael R.; Smith, Rosemarie; Czosek, Richard J.; Ware, Stephanie M.; Goldenberg, Paula; Myers, Angela; Chatfield, Kathryn C.; Gillespie, Matthew J.; Zackai, Elaine H.; Lin, Angela E.; Pediatrics, School of Medicine
    Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.
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    Targeting SHP2 phosphatase in hematological malignancies
    (Taylor & Francis, 2022) Kanumuri, Rahul; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Ramdas, Baskar; Kapur, Reuben; Pediatrics, School of Medicine
    Introduction: Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed, non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. Gain-of-function (GOF) mutations in PTPN11 are associated with the development of various hematological malignancies and Noonan syndrome with multiple lentigines (NS-ML). Preclinical studies performed with allosteric SHP2 inhibitors and combination treatments of SHP2 inhibitors with inhibitors of downstream regulators (such as MEK, ERK, and PD-1/PD-L1) demonstrate improved antitumor benefits. However, the development of novel SHP2 inhibitors is necessary to improve the therapeutic strategies for hematological malignancies and tackle drug resistance and disease relapse. Areas covered: This review examines the structure of SHP2, its function in various signaling cascades, the consequences of constitutive activation of SHP2 and potential therapeutic strategies to treat SHP2-driven hematological malignancies. Expert opinion: While SHP2 inhibitors have exhibited promise in preclinical trials, numerous challenges remain in translation to the clinic, including drug resistance. Although PROTAC-based SHP2 degraders show better efficacy than SHP2 inhibitors, novel strategies need to be designed to improve SHP2-specific therapies in hematologic malignancies. Genome-wide CRISPR screening should also be used to identify molecules that confer resistance to SHP2 inhibitors. Targeting these molecules together with SHP2 can increase the target specificity and reduce drug resistance.
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    The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery
    (Wiley, 2022) Kontaridis, Maria I.; Roberts, Amy E.; Schill, Lisa; Schoyer, Lisa; Stronach, Beth; Andelfinger, Gregor; Aoki, Yoko; Axelrad, Marni E.; Bakker, Annette; Bennett, Anton M.; Broniscer, Alberto; Castel, Pau; Chang, Caitlin A.; Cyganek, Lukas; Das, Tirtha K.; den Hertog, Jeroen; 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; Rauen, Katherine A.; Shankar, Suma P.; Smith, Shane B.; Stevenson, David A.; Tartaglia, Marco; Van, Richard; Wagner, Morgan E.; Ware, Stephanie M.; Zenker, Martin; Pediatrics, School of Medicine
    RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen‐activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.