2,966 results on '"Noonan syndrome"'
Search Results
2. Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
- Published
- 2024
3. A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9 (REAL 9)
- Published
- 2024
4. Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
- Published
- 2024
5. Familial Investigations of Childhood Cancer Predisposition (SJFAMILY)
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- 2024
6. Prevalence and Characterization of Pain in RASopathies (3717)
- Published
- 2024
7. Solid Tumors in RASopathies (4218)
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- 2024
8. Effect of RAS/MAPK Pathway Hyperactivation on Growth' and Bone' Profile of the RASopathies (3776)
- Author
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Leoni Chiara, MD, PhD
- Published
- 2024
9. Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders (DANNIgene)
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- 2024
10. Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders (LENS)
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- 2024
11. LZTR1 loss-of-function variants associated with café au lait macules with or without freckling.
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Horn, Svea, Neuhann, Teresa, Hennig, Corina, Abad-Perez, Angela, Prott, Eva-Christina, Cardellini, Lisa, Potratz, Cornelia, Leubner, Jonas, Eichhorn, Birgit, Merkel, Martin, Abicht, Angela, and Kaindl, Angela M.
- Subjects
GENETIC variation ,REGULATOR genes ,NOONAN syndrome ,PANEL analysis ,NEUROFIBROMATOSIS 1 - Abstract
Pathogenic variants in the leucine zipper-like transcriptional regulator 1 gene (LZTR1) have been identified in schwannomatosis and Noonan syndrome. Here, we expand the phenotype spectrum of LZTR1 variants. We identified four loss-of-function heterozygous LZTR1 variants in five children with multiple café au lait macules and one adult with multiple café au lait macules and axillar freckling, by applying gene panel analysis in four families. The three LZTR1 variants, namely, c.184del/p.Glu62Serfs*39, c.1927C < T/p.Gln643*, and c.857_858delinsT/p. Gly286Valfs*65, were novel, whereas the variant c.1018C > T/p.Arg340* had been previously reported in a patient with schwannomatosis. Similar to what is known from other LZTR1-associated conditions, penetrance of the skin manifestations was reduced in two carriers of the familial variants. Our study expands the LZTR1 phenotype to the presence of isolated café au lait macules with or without freckling. Thus, variants in the LZTR1 gene should be considered in patients with multiple café au lait macules. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
12. Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS‐positive variant patients.
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Bessis, Didier, Bursztejn, Anne‐Claire, Morice‐Picard, Fanny, Capri, Yline, Barbarot, Sébastien, Aubert, Hélène, Bodet, Damien, Bourrat, Emmanuelle, Chiaverini, Christine, Poujade, Laura, Willems, Marjolaine, Rouanet, Jacques, Dompmartin‐Blanchère, Anne, Geneviève, David, Gerard, Marion, Ginglinger, Emmanuelle, Hadj‐Rabia, Smaïl, Martin, Ludovic, Mazereeuw‐Hautier, Juliette, and Bibas, Nathalie
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NOONAN syndrome , *RESEARCH personnel , *EYEBROWS , *HAIR , *LONGITUDINAL method - Abstract
Background: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. Objectives: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype–genotype correlations. Methods: We performed a 10‐year, large, prospective, multicentric, collaborative dermatological and genetic study. Results: Thirty‐one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype–genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). Conclusions and Relevance: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Noonan syndrome‐like phenotype associated with an ERF frameshift variant.
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Hirano, Yasuhiro, Kuroda, Yukiko, Enomoto, Yumi, Naruto, Takuya, Muroya, Koji, and Kurosawa, Kenji
- Abstract
Noonan syndrome is a so‐called "RASopathy," that is characterized by short stature, distinctive facial features, congenital heart defects, and developmental delay. Of individuals with a clinical diagnosis of Noonan syndrome, 80%–90% have pathogenic variants in the known genes implicated in the disorder, but the molecular mechanism is unknown in the remaining cases. Heterozygous pathogenic variants of ETS2 repressor factor (ERF), which functions as a repressor in the RAS/MAPK signaling pathway, cause syndromic craniosynostosis. Here, we report an ERF frameshift variant cosegregating with a Noonan syndrome‐like phenotype in a family. The proband was a 3‐year‐old female who presented with dysmorphic facial features, including proptosis, hypertelorism, slightly down slanted palpebral fissures, low‐set posteriorly rotated ears, depressed nasal bridge, short stature, and developmental delay. Exome sequencing of the proband identified a heterozygous ERF variant [NM_006494.4: c.185del p.(Glu62Glyfs*15)]. Her mother and sister showed a similar phenotype and had the same heterozygous ERF variant. A large proportion of the previously reported patients with syndromic craniosynostosis and pathogenic ERF variants also showed characteristic features that overlap with those of Noonan syndrome. The present finding supports an association between heterozygous ERF variants and a Noonan syndrome‐like phenotype. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Automated Multi-Class Facial Syndrome Classification Using Transfer Learning Techniques.
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Sherif, Fayroz F., Tawfik, Nahed, Mousa, Doaa, Abdallah, Mohamed S., and Cho, Young-Im
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CONVOLUTIONAL neural networks , *WILLIAMS syndrome , *TURNER'S syndrome , *GENETIC disorders , *NOONAN syndrome , *DEEP learning - Abstract
Genetic disorders affect over 6% of the global population and pose substantial obstacles to healthcare systems. Early identification of these rare facial genetic disorders is essential for managing related medical complexities and health issues. Many people consider the existing screening techniques inadequate, often leading to a diagnosis several years after birth. This study evaluated the efficacy of deep learning-based classifier models for accurately recognizing dysmorphic characteristics using facial photos. This study proposes a multi-class facial syndrome classification framework that encompasses a unique combination of diseases not previously examined together. The study focused on distinguishing between individuals with four specific genetic disorders (Down syndrome, Noonan syndrome, Turner syndrome, and Williams syndrome) and healthy controls. We investigated how well fine-tuning a few well-known convolutional neural network (CNN)-based pre-trained models—including VGG16, ResNet-50, ResNet152, and VGG-Face—worked for the multi-class facial syndrome classification task. We obtained the most encouraging results by adjusting the VGG-Face model. The proposed fine-tuned VGG-Face model not only demonstrated the best performance in this study, but it also performed better than other state-of-the-art pre-trained CNN models for the multi-class facial syndrome classification task. The fine-tuned model achieved both accuracy and an F1-Score of 90%, indicating significant progress in accurately detecting the specified genetic disorders. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience †.
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Lucas, Bryony J., Connors, Jeremy S., Wang, Heping, Conneely, Shannon, Cuglievan, Branko, Garcia, Miriam B., and Rau, Rachel E.
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THERAPEUTIC use of antineoplastic agents , *THERAPEUTIC use of antimetabolites , *MYELOID leukemia genetics , *CYTOGENETICS , *NOONAN syndrome , *GERM cells , *AZACITIDINE , *MYELOPROLIFERATIVE neoplasms , *TREATMENT effectiveness , *RETROSPECTIVE studies , *CANCER chemotherapy , *MEDICAL records , *ACQUISITION of data , *MYELOID leukemia , *GENETIC mutation , *GENETICS , *ALLELES , *DISEASE complications , *CHILDREN - Abstract
Simple Summary: Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Given its rarity, management is not standardized and varies widely, ranging from observation to bone marrow transplant depending on genomic and clinical features. We describe the course of JMML or Noonan Syndrome-associated Myeloproliferative Disorder in 22 pediatric patients treated at three institutions to provide guidance for monitoring versus intervention, including transplant, supported by patient outcomes. We provide additional insight into the expected time to spontaneous resolution in those with germline PTPN11 mutations and treatment approaches for patients with germline CBL mutations where no standard exists. Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Cardiac Phenotype and Gene Mutations in RASopathies.
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Faienza, Maria Felicia, Meliota, Giovanni, Mentino, Donatella, Ficarella, Romina, Gentile, Mattia, Vairo, Ugo, and D'amato, Gabriele
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CONGENITAL heart disease , *NOONAN syndrome , *PULMONARY stenosis , *HEART diseases , *MITOGEN-activated protein kinases - Abstract
Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Early-Onset Pectus Excavatum Is More Likely to Be Part of a Genetic Variation.
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Billar, Ryan, Heyman, Stijn, Kant, Sarina, Wijnen, René, Sleutels, Frank, Demirdas, Serwet, and Schnater, J. Marco
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PECTUS excavatum , *GENETIC variation , *CONNECTIVE tissue diseases , *GENETIC counseling , *NOONAN syndrome , *PRECOCIOUS puberty - Abstract
Background Potential underlying genetic variations of pectus excavatum (PE) are quite rare. Only one-fifth of PE cases are identified in the first decade of life and thus are of congenital origin. The objective of this study is to test if early-onset PE is more likely to be part of genetic variations than PE that becomes apparent during puberty or adolescence. Materials and Methods Children younger than 11 years who presented with PE to the outpatient clinic of the Department of Pediatric Surgery at our center between 2014 and 2020 were screened by two clinical geneticists separately. Molecular analysis was performed based on the differential diagnosis. Data of all young PE patients who already had been referred for genetic counseling were analyzed retrospectively. Results Pathogenic genetic variations were found in 8 of the 18 participants (44%): 3 syndromic disorders (Catel–Manzke syndrome and two Noonan syndromes), 3 chromosomal disorders (16p13.11 microduplication syndrome, 22q11.21 microduplication syndrome, and genetic gain at 1q44), 1 connective tissue disease (Loeys–Dietz syndrome), and 1 neuromuscular disorder (pathogenic variation in BICD2 gene). Conclusion Early-onset PE is more likely to be part of genetic variations than PE that becomes apparent during puberty or adolescence. Referral for genetic counseling should therefore be considered. Trial Registration: NCT05443113 [ABSTRACT FROM AUTHOR]
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- 2024
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18. Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.
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Stellacci, Emilia, Carter, Jennefer N., Pannone, Luca, Stevenson, David, Moslehi, Dorsa, Venanzi, Serenella, Acosta, Maria T., Adams, David R., Afzali, Ben, Al‐Beshri, Ali, Allenspach, Eric, Allworth, Aimee, Alvarez, Raquel L., Alvey, Justin, Andrews, Ashley, Ashley, Euan A., Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, and Baldridge, Dustin
- Abstract
Casitas B‐lineage lymphoma (CBL) encodes an adaptor protein with E3‐ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café‐au‐lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF‐induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Noonan syndrome‐like disorder: Case report and review of the literature.
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Mar, Kristie and Lam, Joseph M.
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LITERATURE reviews , *NEVUS , *JUVENILE xanthogranuloma , *NOONAN syndrome , *MACULES , *NEUROFIBROMA - Abstract
Of patients with a Noonan syndrome phenotype, only about 1% are found to be related to pathological variants in CBL, also known as Noonan syndrome‐like disorder (NSLD). We present a case of a 4‐year‐old boy diagnosed with NSLD, presenting with multiple melanocytic nevi and superficial neurofibromas. A literature review identified common cutaneous findings of NSLD, for example, café‐au‐lait macules (22%), juvenile xanthogranuloma (16%), and thin hair (10%). As there are no documented cases of neurofibromas associated with NSLD, and only a single report of multiple melanocytic nevi, inclusion of these features in the phenotype may be warranted and mitigate the necessity for future biopsies in other children. [ABSTRACT FROM AUTHOR]
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- 2024
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20. The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.
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van Vlimmeren, Anne E., Voleti, Rashmi, Chartier, Cassandra A., Ziyuan Jiang, Karandur, Deepti, Humphries, Preston A., Wan-Lin Lo, and Shah, Neel H.
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PROTEIN-tyrosine phosphatase , *ENZYME activation , *MOLECULAR dynamics , *NOONAN syndrome , *PROTEIN-protein interactions - Abstract
Mutations in the tyrosine phosphatase Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting autoinhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8 to 10 A from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine-binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein--protein interaction specificity that alters enzyme activation. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Feasibility of epicardial implantation of medtronic 3830 lead in a pediatric patient : case report.
- Author
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Yuan, Dou, Lin, Ke, and Xu, Yuanning
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CHILD patients , *VENTRICULAR septum , *CONGENITAL heart disease , *CARDIAC pacemakers , *SURGICAL complications - Abstract
Background: High-grade atrioventricular block is the primary reason for epicardial permanent pacemaker implantation during the perioperative period in patients with congenital heart disease. Due to the smaller diameter of venous vessels in children, epicardial permanent pacemaker implantation is usually a preferred choice, we report one pediatric patient who received epicardial permanent pacemaker implantation using a new approach. Case presentation: We present the case of a 2-year-old girl who underwent the modified Konno procedure and Pulmonary valvuloplasty surgery and presented after surgery with a High-grade atrioventricular block. At over 20 days after the patient underwent a redo-sternotomy which epicardial permanent pacemaker implantation. Medtronic Model 4965 Capsure Epi ® steroid-eluting unipolar epicardial pacing lead was immobilized on the surface of the right ear. The Medtronic 3830 pacing lead was screwed obliquely and clockwise under direct view from the surface of the right ventricle to the endocardium near the interventricular septum. The patient's recovery was uneventful. Conclusion: In this case report, we demonstrate the feasibility and potential benefits of using the Medtronic 3830 lead for epicardial pacing in a pediatric patient with severe cardiac complications following surgery for congenital heart disease. This approach offers a viable alternative to traditional epicardial pacing methods, particularly in complex cases where conventional leads fail to provide stable pacing thresholds. [ABSTRACT FROM AUTHOR]
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- 2024
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22. A case of systemic lupus erythematosus in a patient with Noonan syndrome with recurrent severe hypoglycaemia.
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Shotaro Masuoka, Takashi Tanaka, Miwa Kanaji, Karin Furukawa, Keiko Koshiba, Zento Yamada, Eri Watanabe, Mai Kawazoe, Shun Ito, Ayako Fuchigami, and Toshihiro Nanki
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AUTOIMMUNE thyroiditis , *SOMATOMEDIN C , *METABOLIC syndrome , *B cell receptors , *AUTOIMMUNE hepatitis , *ANTIPHOSPHOLIPID syndrome - Abstract
This article presents a case study of a patient with Noonan syndrome (NS) who developed systemic lupus erythematosus (SLE) and experienced recurrent severe hypoglycemia. NS is a genetic disorder that can lead to the development of autoimmune diseases, including SLE. The patient in this case exhibited various symptoms of SLE and was successfully treated with glucocorticoids. The article suggests a potential association between NS and autoimmune diseases, but further research is needed to understand the underlying mechanisms. [Extracted from the article]
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- 2024
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23. Trametinib restores the central conducting lymphatic flow in a premature infant with Noonan syndrome.
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Leenders, Erika K. S. M., Kleimeier, Lotte E. R., Weeke, Lauren C., Coppens, Catelijne H., Klein, Willemijn M., and Draaisma, Jos M.T.
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NOONAN syndrome , *PREMATURE infants , *CHYLOTHORAX , *INFANTS - Abstract
Key Clinical Message: We describe a premature hydropic infant with Noonan syndrome and a therapy refractory chylothorax. This was shown to be due to a central conducting lymphatic anomaly. After therapy with a MEK‐inhibitor the infant recovered clinically and radiologically completely, possibly by restoring lymphatic valve function. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Phenotypic Expansion of Autosomal Dominant LZTR1 -Related Disorders with Special Emphasis on Adult-Onset Features.
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Uliana, Vera, Ambrosini, Enrico, Taiani, Antonietta, Cesarini, Sofia, Cannizzaro, Ilenia Rita, Negrotti, Anna, Serra, Walter, Quintavalle, Gabriele, Micale, Lucia, Fusco, Carmela, Castori, Marco, Martorana, Davide, Bortesi, Beatrice, Belli, Laura, Percesepe, Antonio, Pisani, Francesco, and Barili, Valeria
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NOONAN syndrome , *JOINT hypermobility , *RAS proteins , *PARKINSON'S disease , *PHENOTYPIC plasticity - Abstract
Leucine zipper-like transcription regulator 1 (LZTR1) acts as a negative factor that suppresses RAS function and MAPK signaling; mutations in this protein may dysregulate RAS ubiquitination and lead to impaired degradation of RAS superfamily proteins. Germline LZTR1 variants are reported in Noonan syndrome, either autosomal dominant or autosomal recessive, and in susceptibility to schwannomatosis. This article explores the genetic and phenotypic diversity of the autosomal dominant LZTR1-related disorders, compiling a cohort of previously published patients (51 with the Noonan phenotype and 123 with schwannomatosis) and presenting two additional adult-onset cases: a male with schwannomatosis and Parkinson's disease and a female with Noonan syndrome, generalized joint hypermobility, and breast cancer. This review confirms that autosomal dominant LZTR1-related disorders exhibit an extreme phenotypic variability, ranging from relatively mild manifestations to severe and multi-systemic involvement, and offers updated frequences of each clinical feature. The aim is to precisely define the clinical spectrum of LZTR1-related diseases, using also two new emblematic clinical cases. Gaining insight into the mechanisms underneath this variability is crucial to achieve precision diagnostics and the development of therapeutic interventions. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Noonan syndrome: molecular and clinical findings in individuals with PTPN11 pathogenic variants.
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Karaer, Derya, Durak, Taner, and Karaer, Kadri
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NOONAN syndrome ,FACIAL abnormalities ,CONGENITAL heart disease diagnosis ,PHENOTYPES ,CLINICAL trials - Abstract
Copyright of Pamukkale Medical Journal is the property of Pamukkale Journal of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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26. Cephalometric Evaluation of Children with Short Stature of Genetic Etiology: A Review.
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Paltoglou, George, Ziakas, Nickolas, Chrousos, George P., and Yapijakis, Christos
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PRADER-Willi syndrome ,SKELETAL muscle ,NOONAN syndrome ,DOWN syndrome ,HEALTH ,CEPHALOMETRY ,INFORMATION resources ,PEPTIDE hormones ,STATURE ,22Q11 deletion syndrome ,PARATHYROID hormone ,ACHONDROPLASIA ,TURNER'S syndrome ,FIBROBLAST growth factors ,GROWTH disorders ,CRANIOFACIAL abnormalities ,SYMPTOMS ,CHILDREN - Abstract
Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and "Turner syndrome"; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Noonan Syndrome and Celiac Disease in an Adolescent With Short Stature and Delayed Puberty
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Justin Lee, BA, Sabitha Sasidharan Pillai, MD, Avani Ganta, MD, Chanika Phornphutkul, MD, and Jose Bernardo Quintos, MD
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Noonan syndrome ,celiac disease ,BRAF mutation ,growth hormone ,gluten-free diet ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Background/Objective: We present an adolescent male with Noonan syndrome (NS) and celiac disease (CD) who attained normal adult height with growth hormone (GH) treatment and gluten-free diet (GFD). Case Report: A 15 ½ year old healthy male presented with short stature and delayed puberty. His mother and maternal grandmother were short with heights 142.2 cm and 147.3 cm, respectively. Examination showed bilateral epicanthal folds and down slanting eyes like his mother, fifth finger clinodactyly, height 147.5 cm (
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- 2024
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28. Feasibility of epicardial implantation of medtronic 3830 lead in a pediatric patient : case report
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Dou Yuan, Ke Lin, and Yuanning Xu
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Noonan syndrome ,Modified Konno procedure ,Permanent epicardial pacemaker ,Children. Medtronic 3830 pacing lead ,Case-report ,Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
Abstract Background High-grade atrioventricular block is the primary reason for epicardial permanent pacemaker implantation during the perioperative period in patients with congenital heart disease. Due to the smaller diameter of venous vessels in children, epicardial permanent pacemaker implantation is usually a preferred choice, we report one pediatric patient who received epicardial permanent pacemaker implantation using a new approach. Case presentation We present the case of a 2-year-old girl who underwent the modified Konno procedure and Pulmonary valvuloplasty surgery and presented after surgery with a High-grade atrioventricular block. At over 20 days after the patient underwent a redo-sternotomy which epicardial permanent pacemaker implantation. Medtronic Model 4965 Capsure Epi ® steroid-eluting unipolar epicardial pacing lead was immobilized on the surface of the right ear. The Medtronic 3830 pacing lead was screwed obliquely and clockwise under direct view from the surface of the right ventricle to the endocardium near the interventricular septum. The patient’s recovery was uneventful. Conclusion In this case report, we demonstrate the feasibility and potential benefits of using the Medtronic 3830 lead for epicardial pacing in a pediatric patient with severe cardiac complications following surgery for congenital heart disease. This approach offers a viable alternative to traditional epicardial pacing methods, particularly in complex cases where conventional leads fail to provide stable pacing thresholds.
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- 2024
- Full Text
- View/download PDF
29. Coronary arteriopathy in a patient with Noonan phenotype: Case report
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Simran Jain, M. S. Ravindra, Yogesh Chintaman Sathe, Snehal M. Kulkarni, and Ashish Banpurkar
- Subjects
coronary arteriopathy ,noonan phenotype ,noonan syndrome ,rasopathy ,Medicine ,Pediatrics ,RJ1-570 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Noonan syndrome (NS) is a pleomorphic genetic disorder. Up to 50-80% of individuals have associated congenital heart disease. The scope of cardiac disease in NS is quite variable depending on the gene mutation. The most common forms of cardiac defects include pulmonary stenosis, hypertrophic cardiomyopathy (HCM), atrial septal defect and left-sided lesions. Amongst the rare vascular abnormalities few case reports have been mentioned about coronary artery lesions apart from sinus of Valsalva aneurysm, aortic dissection, intracranial aneurysm. This is a case report a rare case of asymptomatic coronary artery aneurysm in a young male with NS. There is lack of unified protocol for the screening, diagnosis, treatment, and follow-up of coronary artery disease in patients with NS. We conclude, echocardiography is sufficient in most cases in children. But a CT scan is appropriate in adults or when other lesions are suspected.
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- 2024
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30. Computer-based facial recognition as an assisting diagnostic tool to identify children with Noonan syndrome
- Author
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Yulu Huang, Haomiao Sun, Qinchang Chen, Junjun Shen, Jin Han, Shiguang Shan, and Shushui Wang
- Subjects
Noonan syndrome ,Genetic syndrome ,Convolution neural network ,Facial recognition ,Batch normalization ,Pediatrics ,RJ1-570 - Abstract
Abstract Background Noonan syndrome (NS) is a rare genetic disease, and patients who suffer from it exhibit a facial morphology that is characterized by a high forehead, hypertelorism, ptosis, inner epicanthal folds, down-slanting palpebral fissures, a highly arched palate, a round nasal tip, and posteriorly rotated ears. Facial analysis technology has recently been applied to identify many genetic syndromes (GSs). However, few studies have investigated the identification of NS based on the facial features of the subjects. Objectives This study develops advanced models to enhance the accuracy of diagnosis of NS. Methods A total of 1,892 people were enrolled in this study, including 233 patients with NS, 863 patients with other GSs, and 796 healthy children. We took one to 10 frontal photos of each subject to build a dataset, and then applied the multi-task convolutional neural network (MTCNN) for data pre-processing to generate standardized outputs with five crucial facial landmarks. The ImageNet dataset was used to pre-train the network so that it could capture generalizable features and minimize data wastage. We subsequently constructed seven models for facial identification based on the VGG16, VGG19, VGG16-BN, VGG19-BN, ResNet50, MobileNet-V2, and squeeze-and-excitation network (SENet) architectures. The identification performance of seven models was evaluated and compared with that of six physicians. Results All models exhibited a high accuracy, precision, and specificity in recognizing NS patients. The VGG19-BN model delivered the best overall performance, with an accuracy of 93.76%, precision of 91.40%, specificity of 98.73%, and F1 score of 78.34%. The VGG16-BN model achieved the highest AUC value of 0.9787, while all models based on VGG architectures were superior to the others on the whole. The highest scores of six physicians in terms of accuracy, precision, specificity, and the F1 score were 74.00%, 75.00%, 88.33%, and 61.76%, respectively. The performance of each model of facial recognition was superior to that of the best physician on all metrics. Conclusion Models of computer-assisted facial recognition can improve the rate of diagnosis of NS. The models based on VGG19-BN and VGG16-BN can play an important role in diagnosing NS in clinical practice.
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- 2024
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31. Developmental effect of RASopathy mutations on neuronal network activity on a chip.
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Weiss, Eva-Maria, Guhathakurta, Debarpan, Petrušková, Aneta, Hundrup, Verena, Zenker, Martin, and Fejtová, Anna
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NEURAL circuitry ,NETWORKS on a chip ,SKELETAL abnormalities ,GENETIC mutation ,GENETIC disorders ,SYMPTOMS ,RAS oncogenes - Abstract
RASopathies are a group of genetic disorders caused by mutations in genes encoding components and regulators of the RAS/MAPK signaling pathway, resulting in overactivation of signaling. RASopathy patients exhibit distinctive facial features, cardiopathies, growth and skeletal abnormalities, and varying degrees of neurocognitive impairments including neurodevelopmental delay, intellectual disabilities, or attention deficits. At present, it is unclear how RASopathy mutations cause neurocognitive impairment and what their neuronspecific cellular and network phenotypes are. Here, we investigated the effect of RASopathy mutations on the establishment and functional maturation of neuronal networks. We isolated cortical neurons from RASopathy mouse models, cultured them on multielectrode arrays and performed longitudinal recordings of spontaneous activity in developing networks as well as recordings of evoked responses in mature neurons. To facilitate the analysis of large and complex data sets resulting from long-term multielectrode recordings, we developed MATLAB-based tools for data processing, analysis, and statistical evaluation. Longitudinal analysis of spontaneous network activity revealed a convergent developmental phenotype in neurons carrying the gain-of-function Noonan syndrome-related mutations Ptpn
11D61Y and KrasV14l . The phenotype was more pronounced at the earlier time points and faded out over time, suggesting the emergence of compensatory mechanisms during network maturation. Nevertheless, persistent differences in excitatory/inhibitory balance and network excitability were observed in mature networks. This study improves the understanding of the complex relationship between genetic mutations and clinical manifestations in RASopathies by adding insights into functional network processes as an additional piece of the puzzle. [ABSTRACT FROM AUTHOR]- Published
- 2024
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32. Indocyanine green lymphography in the congenital chylothorax and chylous ascites.
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Lin, T., Shibasaki, J., Yamamoto, K., Shimokaze, T., and Toyoshima, K.
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LYMPHANGIOGRAPHY , *INDOCYANINE green , *CHYLOTHORAX , *ASCITES , *LYMPHATIC abnormalities - Abstract
BACKGROUND: The prognosis of congenital chylothorax and ascites ranges from spontaneous resolution to death, but no established examination exists to predict the prognosis. We aimed to develop a clinically useful method to evaluate lymphatic abnormalities using indocyanine green (ICG) lymphography in infants with congenital chylothorax and ascites. METHODS: We retrospectively evaluated infants with congenital chylothorax and chylous ascites who underwent ICG lymphography in our hospital between 2012 and 2022. The ICG lymphography findings was evaluated. We defined the dermal backflow in the trunk as the lymphatic flow from the end of the limb back through the lymphatic vessels on the surface of the trunk. The association between the dermal backflow in the trunk and clinical outcomes, as follows, are investigated: the duration of the drainage period, the duration of endotracheal intubation, and the length of hospital stay. RESULTS: Twenty infants had a dermal backflow in the trunk, and ten did not. Clinical outcomes in infants with and without dermal backflow in the trunk were as follows (median): the duration of the drainage period (20 vs. 0 days, p = 0.001), the duration of endotracheal intubation (12 vs. 2 days, p = 0.04), and the length of hospital stay (62 vs. 41 days, p = 0.04), respectively. In multivariate linear regression analysis adjusted for gestational age, the duration of the drainage period was correlated with the dermal backflow in the trunk [exp(B) = 2.62; p = 0.003]. CONCLUSIONS: The dermal backflow in the trunk in ICG lymphography was useful in predicting the clinical course of congenital chylothorax and ascites. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Recurrent cellulitis and bacteremia in a patient with Noonan syndrome: A case report.
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Koike, Takayuki, Fukushiro, Michihito, Ueno, Ayaka, Nakashima, Shigeki, Yamakawa, Sho, Suda, Shota, Hayashida, Kenji, and Yamasaki, Osamu
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- *
NOONAN syndrome , *CELLULITIS , *BACTEREMIA , *INTESTINAL lymphangiectasia , *MITOGEN-activated protein kinases , *PROTEIN-losing enteropathy - Abstract
A 28-year old Japanese man with Noonan syndrome (NS) presented to our emergency department with painful erythema of the trunk and lower extremities since the previous day. He had been diagnosed with protein-losing enteropathy (PLE) with intestinal lymphangiectasia at age 25 years, and undergone lymphaticovenular anastomosis (LVA) twice. Three episodes of cellulitis of both lower extremities had occurred in the past 2 years. Extensive cellulitis with sepsis was diagnosed and piperacillin/tazobactam was started, which was de-escalated to ceftriaxone. He was discharged after 13 days of antibiotic therapy. After discharge, low-dose trimethoprim-sulfamethoxazole (SMZ-TMP) was started as the primary prophylaxis, but three episodes of cellulitis occurred in the next year and were treated with other antibiotics. NS, an autosomal dominant disease known as a RASopathy, is caused by germline mutations in RAS-MAPK pathway genes. Lymphedema resulting from lymphatic abnormalities is a concomitant manifestation in 20 % of patients with NS, and can be a risk factor for cellulitis. Hypoalbuminemia and hypoglobulinemia associated with PLE facilitate infections such as cellulitis. As a treatment for lymphedema in the extremities, LVA has shown objective and subjective improvements in most patients, and some studies have also reported its efficacy for lymphedema in patients with NS. Targeted molecular therapy with mitogen-activated protein kinase enzyme (MEK) inhibitor is used in treatment of cancers with activation of the RAS/MAPK pathway. MEK inhibitors have recently been tried in patients with RASopathies and severe lymphatic disorders, and can lead to rapid resolution of symptoms. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Epidemiology of Pediatric Cardiomyopathy in a Mediterranean Population.
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Bagkaki, Alena, Parthenakis, Fragiskos, Chlouverakis, Gregory, Anastasakis, Aris, Papagiannis, Ioannis, Galanakis, Emmanouil, and Germanakis, Ioannis
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HEART murmurs ,CARDIOMYOPATHIES ,VENTRICULAR ejection fraction ,NOONAN syndrome ,SEX distribution ,FISHER exact test ,PROBABILITY theory ,SYNCOPE ,RETROSPECTIVE studies ,DILATED cardiomyopathy ,CARDIAC hypertrophy ,AGE distribution ,HEART failure ,TREATMENT effectiveness ,DESCRIPTIVE statistics ,RACE ,AGE factors in disease ,GLYCOGEN storage disease ,HEART transplantation ,MEDICAL records ,ACQUISITION of data ,SEIZURES (Medicine) ,IMPLANTABLE cardioverter-defibrillators ,DISEASE complications ,CONFIDENCE intervals ,CARDIAC arrest ,FATTY acids ,MEDITERRANEAN peoples ,ECHOCARDIOGRAPHY ,PHENOTYPES ,GENETIC testing - Abstract
Background. Our knowledge regarding the epidemiology of pediatric cardiomyopathy is based on large national population studies reporting an annual incidence of 1 case per 100,000 children, with a higher incidence observed in infancy and among selected populations. The aim here is to document the epidemiology of pediatric cardiomyopathy in a Mediterranean population. Methods. Children younger than 18 years of age living on the Mediterranean island of Crete, Greece, who have been evaluated since the establishment of tertiary pediatric cardiology services (2002–2022) were included in this retrospective study. Results. A total of 40 children were included, corresponding to an average annual incidence of pediatric cardiomyopathy of 1.59 cases (95% CI: 1.4–2.3) and a prevalence of 26 cases per 100,000 children. In decreasing order of frequency, most cases corresponded to dilated (50%), followed by hypertrophic (42.5%), arrhythmogenic (5%), and restrictive (2.5%) cardiomyopathy. An etiology was identified in 40%, including a genetic diagnosis in 22.5%. Conclusions. The incidence of pediatric cardiomyopathy in the Mediterranean island of Crete is higher compared with that reported previously for other Caucasian populations. Further study is needed to investigate the exact prevalence and specific genetic factors associated with the epidemiology of pediatric cardiomyopathy in Mediterranean populations. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Multiple central giant cell granuloma of the jaws: diagnostic signposts of Noonan syndrome and RASopathy.
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Friedrich, Reinhard E., Rutkowski, Rico, and Gosau, Martin
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NOONAN syndrome ,GRANULOMA ,JAWS ,SURGICAL diagnosis ,FACIAL injuries - Abstract
Noonan syndrome (NS) is a phenotypically variable inherited multi-system disorder. Maxillofacial findings can be diagnostic, especially in the evaluation of discrete facial dysmorphia. Diagnostic landmark findings of therapeutic relevance for the jaws such as central giant cell granuloma (CGCG) are rare in NS. However, recent molecular genetic studies indicate that these rare, benign lesions are neoplasms and more common in specific syndromes grouped under the umbrella term RASopathies. A specialist surgical diagnosis can be helpful in identifying the underlying disease. This report outlines diagnosis and treatment of a case of CGCG for which jaw diagnosis became the key to identifying a syndromic disease. [ABSTRACT FROM AUTHOR]
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- 2024
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36. Hyperbaric oxygen treatment in bilateral orchiopexy and post-circumcision haematoma in a thrombocytopenic patient with Noonan syndrome.
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Dereli, Dilşad, Çakiroğlu, Selahattin, Köse, Ayse Aydan, and Tokar, Baran
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HYPERBARIC oxygenation ,ORCHIOPEXY ,HEMATOMA ,SOFT tissue injuries ,NOONAN syndrome - Abstract
Hyperbaric oxygen treatment (HBOT) can be utilised for necrotising soft tissue infections, clostridial myonecrosis (gas gangrene), crush injuries, acute traumatic ischaemia, delayed wound healing, and compromised skin grafts. Our case was a 17-month-old male patient with Noonan syndrome, idiopathic thrombocytopenic purpura, and bilateral undescended testicles. Haematoma and oedema developed in the scrotum and penis the day after bilateral orchiopexy and circumcision. Ischaemic appearances were observed on the penile and scrotal skin on the second postoperative day. Enoxaparin sodium and fresh frozen plasma were started on the recommendation of haematology. Hyperbaric oxygen treatment was initiated considering the possibility of tissue necrosis. We observed rapid healing within five days. We present this case to emphasise that HBOT may be considered as an additional treatment option in patients with similar conditions. To our knowledge, no similar cases have been reported in the literature. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Computer-based facial recognition as an assisting diagnostic tool to identify children with Noonan syndrome.
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Huang, Yulu, Sun, Haomiao, Chen, Qinchang, Shen, Junjun, Han, Jin, Shan, Shiguang, and Wang, Shushui
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FACE perception ,NOONAN syndrome ,CONVOLUTIONAL neural networks ,SYNDROMES in children ,PHYSICIANS - Abstract
Background: Noonan syndrome (NS) is a rare genetic disease, and patients who suffer from it exhibit a facial morphology that is characterized by a high forehead, hypertelorism, ptosis, inner epicanthal folds, down-slanting palpebral fissures, a highly arched palate, a round nasal tip, and posteriorly rotated ears. Facial analysis technology has recently been applied to identify many genetic syndromes (GSs). However, few studies have investigated the identification of NS based on the facial features of the subjects. Objectives: This study develops advanced models to enhance the accuracy of diagnosis of NS. Methods: A total of 1,892 people were enrolled in this study, including 233 patients with NS, 863 patients with other GSs, and 796 healthy children. We took one to 10 frontal photos of each subject to build a dataset, and then applied the multi-task convolutional neural network (MTCNN) for data pre-processing to generate standardized outputs with five crucial facial landmarks. The ImageNet dataset was used to pre-train the network so that it could capture generalizable features and minimize data wastage. We subsequently constructed seven models for facial identification based on the VGG16, VGG19, VGG16-BN, VGG19-BN, ResNet50, MobileNet-V2, and squeeze-and-excitation network (SENet) architectures. The identification performance of seven models was evaluated and compared with that of six physicians. Results: All models exhibited a high accuracy, precision, and specificity in recognizing NS patients. The VGG19-BN model delivered the best overall performance, with an accuracy of 93.76%, precision of 91.40%, specificity of 98.73%, and F1 score of 78.34%. The VGG16-BN model achieved the highest AUC value of 0.9787, while all models based on VGG architectures were superior to the others on the whole. The highest scores of six physicians in terms of accuracy, precision, specificity, and the F1 score were 74.00%, 75.00%, 88.33%, and 61.76%, respectively. The performance of each model of facial recognition was superior to that of the best physician on all metrics. Conclusion: Models of computer-assisted facial recognition can improve the rate of diagnosis of NS. The models based on VGG19-BN and VGG16-BN can play an important role in diagnosing NS in clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
38. High frequency of hotspot mutation in PTPN11 gene among Moroccan patients with Noonan syndrome.
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Ouboukss, Fatima, Adadi, Najlae, Amasdl, Saadia, Smaili, Wiam, Laarabi, Fatima Zahra, Lyahyai, Jaber, Sefiani, Abdelaziz, and Ratbi, Ilham
- Abstract
Noonan syndrome (NS; OMIM 163950) is an autosomal dominant RASopathy with variable clinical expression and genetic heterogeneity. Clinical manifestations include characteristic facial features, short stature, and cardiac anomalies. Variants in protein-tyrosine phosphatase, non-receptor-type 11 (PTPN11), encoding SHP-2, account for about half of NS patients, SOS1 in approximately 13%, RAF1 in 10%, and RIT1 each in 9%. Other genes have been reported to cause NS in less than 5% of cases including SHOC2, RASA2, LZTR1, SPRED2, SOS2, CBL, KRAS, NRAS, MRAS, PRAS, BRAF, PPP1CB, A2ML1, MAP2K1, and CDC42. Several additional genes associated with a Noonan syndrome–like phenotype have been identified. Clinical presentation and variants in patients with Noonan syndrome are this study's objectives. We performed Sanger sequencing of PTPN11 hotspot (exons 3, 8, and 13). We report molecular analysis of 61 patients with NS phenotype belonging to 58 families. We screened for hotspot variants (exons 3, 8, and 13) in PTPN11 gene by Sanger sequencing. Twenty-seven patients were carrying heterozygous pathogenic variants of PTPN11 gene with a similar frequency (41.4%) compared to the literature. Our findings expand the variant spectrum of Moroccan patients with NS phenotype in whom the analysis of hotspot variants showed a high frequency of exons 3 and 8. This screening test allowed us to establish a molecular diagnosis in almost half of the patients with a good benefit–cost ratio, with appropriate management and genetic counseling. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Gonadal dysfunction in a man with Noonan syndrome from the LZTR1 variant: case report and review of literature.
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Orsolini, Francesca, Pignata, Luisa, Baldinotti, Fulvia, Romano, Silvia, Tonacchera, Massimo, and Canale, Domenico
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NOONAN syndrome ,INHIBIN ,LITERATURE reviews ,GENETIC variation ,SERTOLI cells ,PROTEIN kinases - Abstract
Noonan syndrome (NS) is a genetic disorder characterized by multiple congenital defects caused by mutations in the RAS/mitogen-activated protein kinase pathway. Male fertility has been reported to be impaired in NS, but only a few studies have focused on fertility status in NS patients and underlying mechanisms are still incompletely understood. We describe the case of a 35-year-old man who underwent an andrological evaluation due to erectile dysfunction and severe oligospermia. A syndromic facial appearance and reduced testis size were present on clinical examination. Hormonal evaluation showed normal total testosterone level, high FSH level, and low–normal AMH and inhibin B, compatible with primary Sertoli cell dysfunction. Genetic analysis demonstrated the pathogenetic heterozygous variant c.742G>A, p.(Gly248Arg) of the LZTR1 gene (NM_006767.3). This case report provides increased knowledge on primary gonadal dysfunction in men with NS and enriches the clinical spectrum of NS from a rare variant in the novel gene LZTR1. [ABSTRACT FROM AUTHOR]
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- 2024
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40. Functional analysis of RRAS2 pathogenic variants with a Noonan-like phenotype.
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Takaya Iida, Arisa Igarashi, Kae Fukunaga, Taiga Aoki, Tomomi Hidai, Kumiko Yanagi, Masahiko Yamamori, Kazuhito Satou, Hayato Go, Tomoki Kosho, Ryuto Maki, Takashi Suzuki, Yohei Nitta, Atsushi Sugie, Yoichi Asaoka, Makoto Furutani-Seiki, Tetsuaki Kimura, Yoichi Matsubara, and Tadashi Kaname
- Subjects
RAS oncogenes ,FUNCTIONAL analysis ,PHENOTYPES ,NOONAN syndrome ,CELLULAR signal transduction ,TRANSITION to adulthood ,RAS proteins - Abstract
Introduction: RRAS2, a member of the R-Ras subfamily of Ras-like lowmolecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven RRAS2 pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel RRAS2 pathogenic variants (p.Gly23Val and p.Gly24Glu, respectively) and the results of their functional analysis. Materials and methods: Wild-type (WT) and mutant RRAS2 genes were transiently expressed in Human Embryonic Kidney293 cells. Expression of RRAS2 and phosphorylation of ERK1/2 were confirmed by Western blotting, and the RAS signaling pathway activity was measured using a reporter assay system with the serum response element-luciferase construct. WT and p.Gly23Val RRAS2 were expressed in Drosophila eye using the glass multiple reporter-Gal4 driver. Mutant mRNA microinjection into zebrafish embryos was performed, and the embryo jaws were observed. Results: No obvious differences in the expression of proteins WT, p.Gly23Val, and p.Gly24Glu were observed. The luciferase reporter assay showed that the activity of p.Gly23Val was 2.45 ± 0.95-fold higher than WT, and p.Gly24Glu was 3.06 ± 1.35-fold higher than WT. For transgenic flies, the p.Gly23Val expression resulted in no adults flies emerging, indicating lethality. For mutant mRNA-injected zebrafish embryos, an oval shape and delayed jaw development were observed compared with WT mRNA-injected embryos. These indicated hyperactivity of the RAS signaling pathway. Discussion: Recurrent and novel RRAS2 variants that we reported showed increased in vitro or in vivo RAS signaling pathway activity because of gain-offunction RRAS2 variants. Clinical features are similar to those previously reported, suggesting that RRAS2 gain-of-function variants cause this disease in patients. [ABSTRACT FROM AUTHOR]
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- 2024
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41. SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic‐related fetal hydrops and facial dysmorphology.
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Vanden Broek, Kara, Ryu, Jae‐Ryeon, Perrier, Renee, Tyndall, Amanda V., Childs, Sarah J., and Au, Ping Yee Billie
- Subjects
- *
HYDROPS fetalis , *PROTEIN-tyrosine kinases , *MISSENSE mutation , *EIGENFUNCTIONS , *PROTEIN expression , *FETUS - Abstract
Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation‐Arteriovenous Malformation syndrome 2 and lymphatic‐related (non‐immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine‐kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development. [ABSTRACT FROM AUTHOR]
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- 2024
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42. Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome.
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Yasuko Shoji, Ayaha Hata, Takatoshi Maeyama, Tamaki Wada, Yuiko Hasegawa, Eriko Nishi, Shinobu Ida, Yuri Etani, Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto, and Masanobu Kawai
- Subjects
- *
JAPANESE people , *NOONAN syndrome , *SHORT stature , *CONGENITAL heart disease , *BODY mass index - Abstract
Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS. [ABSTRACT FROM AUTHOR]
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- 2024
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43. Autism spectrum disorder profiles in RASopathies: A systematic review.
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Debbaut, Edward, Steyaert, Jean, and El Bakkali, Mouna
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- *
AUTISM spectrum disorders , *NOONAN syndrome , *NEUROFIBROMATOSIS 1 , *SYMPTOMS - Abstract
Background: RASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually. Methods: We conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers. Results: We included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio‐facio‐cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies. Conclusions: Our systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review.
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Han, Ji Yoon and Park, Joonhong
- Subjects
- *
NOONAN syndrome , *LITERATURE reviews , *SYMPTOMS , *DISABILITIES , *GENOTYPE-environment interaction , *SHORT stature - Abstract
Background: Noonan syndrome (NS)/Noonan syndrome with multiple lentigines (NSML) is commonly characterized by distinct facial features, a short stature, cardiac problems, and a developmental delay of variable degrees. However, as many as 50% of individuals diagnosed with NS/NSML have a mildly affected parent or relative due to variable expressivity and possibly incomplete penetrance of the disorder, and those who are recognized to have NS only after a diagnosis are established in a more obviously affected index case. Methods: In order to collect intergenerational data reported from previous studies, electronic journal databases containing information on the molecular genetics of PTPN11 were searched from 2000 to 2022. Results: We present a case of a proband with a PTPN11 variant (c.1492C > T/p.Arg498Trp) inherited from an asymptomatic father, displaying only mild intellectual disability without classical symptoms of NS. Among our cases and the reported NS cases caused by the PTPN11 p.Arg498Trp variant, cardiac abnormalities (6/11), facial dysmorphism (7/11), skin pigmentation (4/11), growth problems (4/11), and sensorineural hearing loss (2/11) have been observed. NS/NSML patients with the PTPN11 p.Arg498Trp variant tend to exhibit relatively lower frequencies of skin pigmentation, facial dysmorphism and cardiac abnormalities and mild symptoms compared to those carrying any other mutated PTPN11. Conclusions: Paternally inherited NS/NSML caused by a PTPN11 p.Arg498Trp variant, including our cases, may exhibit relatively lower frequencies of abnormal features and mild symptoms. This could be ascribed to potential gene–gene interactions, gene–environment interactions, the gender and phenotype of the transmitting parent, or ethnic differences that influence the clinical phenotype. [ABSTRACT FROM AUTHOR]
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- 2024
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45. Natural history and outcomes in paediatric RASopathy‐associated hypertrophic cardiomyopathy.
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Boleti, Olga, Norrish, Gabrielle, Field, Ella, Dady, Kathleen, Summers, Kim, Nepali, Gauri, Bhole, Vinay, Uzun, Orhan, Wong, Amos, Daubeney, Piers E. F., Stuart, Graham, Fernandes, Precylia, McLeod, Karen, Ilina, Maria, Ali, Muhammad Najih Liaqath, Bharucha, Tara, Donne, Grazia Delle, Brown, Elspeth, Linter, Katie, and Jones, Caroline B.
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HYPERTROPHIC cardiomyopathy ,NATURAL history ,CARDIAC arrest ,NOONAN syndrome ,VENTRICULAR tachycardia - Abstract
Aims: This study aimed to describe the natural history and predictors of all‐cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). Methods and results: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS‐LAH)]. One hundred forty‐nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan‐like syndrome, and 3 (2%) NS‐LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36–80) mmHg, P = 0.004]. Over a median follow‐up of 197.5 [inter‐quartile range (IQR) 93.58–370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6–175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69–98.51], 90.42% (95% CI 84.04–94.33), and 84.12% (95% CI 75.42–89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non‐sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all‐cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. Conclusions: These findings highlight a distinct category of patients with Noonan‐like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy‐related HCM. [ABSTRACT FROM AUTHOR]
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- 2024
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46. The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.
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Pierpont, Elizabeth I., Bennett, Anton M., Schoyer, Lisa, Stronach, Beth, Anschutz, April, Borrie, Sarah C., Briggs, Benjamin, Burkitt‐Wright, Emma, Castel, Pau, Cirstea, Ion C., Draaisma, Fieke, Ellis, Michelle, Fear, Vanessa S., Frone, Megan N., Flex, Elisabetta, Gelb, Bruce D., Green, Tamar, Gripp, Karen W., Khoshkhoo, Sattar, and Kieran, Mark W.
- Abstract
Germline pathogenic variants in the RAS/mitogen‐activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in‐person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician‐scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self‐advocates and early‐stage investigators were featured throughout the program to encourage a sustainable, diverse, long‐term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies. [ABSTRACT FROM AUTHOR]
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- 2024
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47. Noonan Syndrome and its Ophthalmic Implications: Insights from a Pediatric Case.
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DAL, Ali, ERDAĞ, Murat, and CANLEBLEBİCİ, Mehmet
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NOONAN syndrome ,BLEPHAROPTOSIS ,AMBLYOPIA ,NYSTAGMUS ,ASTIGMATISM - Abstract
Noonan syndrome (NS) is a rare genetic disorder and may present with extraocular findings such as ptosis, telecanthus, and downward-slanting palpebral fissures, as well as ocular signs including refractive errors, amblyopia, nystagmus, and optic atrophy. We present, a 7- year-old patient diagnosed with NS a year ago who was referred for ophthalmological evaluation. The patient had ptosis, nystagmus, esotropia, myopia, astigmatism and optic nerve hypoplasia. The best-corrected visual acuity, was 0.8 in the right eye and 0.1 in the left eye. He was prescribed spectacles and advised occlusion therapy for the right eye for 3 hours per day. At the one-year follow-up, the visual acuity in the right eye remained unchanged, whereas the visual acuity in the left eye improved to 0.2. Factors contributing to vision impairment in NS include ptosis, anisometropic amblyopia, and cataract. Early ophthalmological assessment is crucial for NS; because intervention for these conditions during childhood can lead to improvements in visual acuity. [ABSTRACT FROM AUTHOR]
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- 2024
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48. Molecular characterization of gliomas and glioneuronal tumors amid Noonan syndrome: cancer predisposition examined
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Margaret Shatara, Kathleen M. Schieffer, Marilena Melas, Elizabeth A. Varga, Diana Thomas, Brianna A. Bucknor, Heather M. Costello, Gregory Wheeler, Benjamin J. Kelly, Katherine E. Miller, Diana P. Rodriguez, Mariam T. Mathew, Kristy Lee, Erin Crotty, Sarah Leary, Vera A. Paulson, Bonnie Cole, Mohamed S. Abdelbaki, Jonathan L. Finlay, Margot A. Lazow, Ralph Salloum, Maryam Fouladi, Daniel R. Boué, Elaine R. Mardis, and Catherine E. Cottrell
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glioma ,glioneuronal tumor ,Noonan syndrome ,cancer predisposition ,PTPN11 ,germline ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionIn the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.MethodsWithin an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease–germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.ResultsThrough the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.DiscussionComparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.
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- 2024
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49. Trametinib restores the central conducting lymphatic flow in a premature infant with Noonan syndrome
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Erika K. S. M. Leenders, Lotte E. R. Kleimeier, Lauren C. Weeke, Catelijne H. Coppens, Willemijn M. Klein, and Jos M.T. Draaisma
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CCLA ,DCMRL ,MEK‐inhibition ,Noonan syndrome ,RAS/MAPK pathway ,Medicine ,Medicine (General) ,R5-920 - Abstract
Key Clinical Message We describe a premature hydropic infant with Noonan syndrome and a therapy refractory chylothorax. This was shown to be due to a central conducting lymphatic anomaly. After therapy with a MEK‐inhibitor the infant recovered clinically and radiologically completely, possibly by restoring lymphatic valve function.
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- 2024
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50. Treatment of RAF1-Related Obstructive Hypertrophic Cardiomyopathy by MEK Inhibition Using Trametinib
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Omid Kiamanesh, MD, Steven C. Greenway, MD, Franciscus Dicke, MD, MBA, Brennan Ballantyne, MD, Sasha Mitrovic, RDCS, Kaitlin McGrath, MD, James A. White, MD, William D.T. Kent, MD, and Gregor Andelfinger, MD
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cardiovascular genetics ,hypertrophic cardiomyopathy ,Noonan syndrome ,RASopathies ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
RASopathies cause nonsarcomeric hypertrophic cardiomyopathy via dysregulated signaling through RAS and upregulated mitogen-activated protein kinase activity. We provide the first report of the successful treatment of an adult with RAF1-associated hypertrophic cardiomyopathy using trametinib, a MEK inhibitor.
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- 2024
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