Update Noonan Syndrome

references_cache/DOI_10.1002_ajmga.70060.md

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+---
+reference_id: "DOI:10.1002/ajmga.70060"
+title: "Neuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and Noonan Syndrome With Multiple Lentigines: Health‐Related Quality of Life and Neurologic Symptoms"
+authors:
+- Jos M. T. Draaisma
+- Wesley Reintjes
+- Erika Leenders
+- Fieke Draaisma
+- Melanie Burgers
+- Lotte Kleimeier
+- Marco Tartaglia
+- Merel Klaassens
+- Ruud Becks
+- Steven Renes
+- Ellen Wingbermühle
+- Nicol C. Voermans
+- Nens van Alfen
+journal: American Journal of Medical Genetics Part A
+year: '2026'
+doi: 10.1002/ajmga.70060
+content_type: abstract_only
+---
+
+# Neuropathic Pain and Enlarged Nerves in Adult Noonan Syndrome and Noonan Syndrome With Multiple Lentigines: Health‐Related Quality of Life and Neurologic Symptoms
+**Authors:** Jos M. T. Draaisma, Wesley Reintjes, Erika Leenders, Fieke Draaisma, Melanie Burgers, Lotte Kleimeier, Marco Tartaglia, Merel Klaassens, Ruud Becks, Steven Renes, Ellen Wingbermühle, Nicol C. Voermans, Nens van Alfen
+**Journal:** American Journal of Medical Genetics Part A (2026)
+**DOI:** [10.1002/ajmga.70060](https://doi.org/10.1002/ajmga.70060)
+
+## Content
+
+ABSTRACT
+Noonan syndrome (NS) and the clinically related Noonan syndrome with multiple lentigines (NSML) belong to the group of RASopathies. Although pain is not mentioned as a characteristic feature, it has recently been reported as a clinically significant problem. This pain is likely multifactorial in origin, with a significant contribution from neuropathic mechanisms. Patients with NS also have a high chance of having multifocally enlarged nerves, and sometimes show clinical features of neuropathy. The relationship between these nerve findings, pain, health‐related quality of life and neurological symptoms remains unclear. This case series aims to provide more insight into the perceived health‐related quality of life and neurological symptoms in nine adults with NS or NSML who reported neuropathic pain and had enlarged nerves. Features of some of these patients were already reported in an earlier article. The perceived health‐related quality of life was markedly below average. All patients reported somatosensory symptoms consistent with peripheral neuropathy. Six of nine patients reported muscle weakness. Sensory testing was abnormal in five patients, but muscle strength was normal in all patients. Electrodiagnostic testing was consistent with peroneal neuropathy in one patient, muscle and nerve ultrasound imaging confirmed neuromuscular involvement in five of the six patients who reported muscle weakness. No muscle ultrasound imaging was performed in the sixth patient. This study thus shows that adults with NS and NSML with neuropathic pain and enlarged nerves have a significantly impaired perceived health‐related quality of life with a variable clinical neurologic phenotype.

references_cache/DOI_10.1007_s00431-023-05263-y.md

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+---
+reference_id: "DOI:10.1007/s00431-023-05263-y"
+title: Novel therapeutic perspectives in Noonan syndrome and RASopathies
+authors:
+- Céline Saint-Laurent
+- Laurène Mazeyrie
+- Armelle Yart
+- Thomas Edouard
+journal: European Journal of Pediatrics
+year: '2023'
+doi: 10.1007/s00431-023-05263-y
+content_type: abstract_only
+---
+
+# Novel therapeutic perspectives in Noonan syndrome and RASopathies
+**Authors:** Céline Saint-Laurent, Laurène Mazeyrie, Armelle Yart, Thomas Edouard
+**Journal:** European Journal of Pediatrics (2023)
+**DOI:** [10.1007/s00431-023-05263-y](https://doi.org/10.1007/s00431-023-05263-y)
+
+## Content
+
+AbstractNoonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. Many specific agents (e.g. SHP2 and MEK inhibitors) have already been developed for the treatment of RAS/MAPK-driven malignancies. In addition, other molecules with the property of modulating RAS/MAPK activation are indicated in non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolemia).  Conclusion: Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies.
+
+
+What is Known:• Noonan syndrome and related disorders are caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in increased activation of this pathway.• This group of disorders is now known as RASopathies and represents one of the largest groups of multiple congenital anomaly diseases known.
+
+
+What is New:• The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation.• Drug repositioning of specific agents already developed for the treatment of malignant (e.g. SHP2 and MEK inhibitors) or non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolaemia) represents a challenging approach to the treatment of RASopathies.

references_cache/DOI_10.1007_s00431-026-06764-2.md

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+---
+reference_id: "DOI:10.1007/s00431-026-06764-2"
+title: "Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort"
+authors:
+- Barbora Jirova
+- Maria Najdekova
+- Jana Cerna
+- Petra Dusatkova
+- Kristina Holotova
+- Stanislava Kolouskova
+- Ivana Kotvalova
+- Olga Magnova
+- Martin Modrak
+- Dana Novotna
+- Barbora Obermannova
+- Jan Pavlicek
+- Lukas Plachy
+- Renata Pomahacova
+- Stepanka Pruhova
+- Jitka Rezabkova
+- Jiri Strnadel
+- Marta Snajderova
+- Zdenek Sumnik
+- Jirina Zapletalova
+- Jan Lebl
+journal: European Journal of Pediatrics
+year: '2026'
+doi: 10.1007/s00431-026-06764-2
+content_type: abstract_only
+---
+
+# Noonan syndrome spectrum disorders in real life: patient characteristics and response to growth hormone therapy in a genetically defined single-country multicenter cohort
+**Authors:** Barbora Jirova, Maria Najdekova, Jana Cerna, Petra Dusatkova, Kristina Holotova, Stanislava Kolouskova, Ivana Kotvalova, Olga Magnova, Martin Modrak, Dana Novotna, Barbora Obermannova, Jan Pavlicek, Lukas Plachy, Renata Pomahacova, Stepanka Pruhova, Jitka Rezabkova, Jiri Strnadel, Marta Snajderova, Zdenek Sumnik, Jirina Zapletalova, Jan Lebl
+**Journal:** European Journal of Pediatrics (2026)
+**DOI:** [10.1007/s00431-026-06764-2](https://doi.org/10.1007/s00431-026-06764-2)
+
+## Content
+
+Abstract
+
+                      The variety of genes associated with Noonan syndrome spectrum disorders (NSSD) is expanding, and real-life experience with its management is increasing; however, phenotypic differences among genotypes remain poorly defined. We aimed to assess clinical characteristics and response to growth hormone (GH) therapy in a genetically confirmed, single-country multicentre NSSD cohort. We included 101 patients with NSSD (56 males) from six centres: 76 with (likely) pathogenic
+                      PTPN11
+                      variants, 7 with
+                      SOS1
+                      variants, and 18 with other gene variations. All completed at least one year of GH therapy; 23 reached final height. Parental heights were below average (fathers: − 0.33 SDS [− 1.19; 0.39],
+                      p
+                       < 0.01; mothers: − 0.68 SDS [− 1.47; 0.12],
+                      p
+                       < 0.001; medians [IQR]). SOS1-NS patients were born earlier (gestational week 36 [31; 37]) compared to
+                      PTPN11
+                      -NS. Birth length (− 1.23 SDS [− 1.74; − 0.57]) was more reduced than weight (− 0.29 SDS [− 1.10; 0.54];
+                      p
+                       < 0.0001);
+                      PTPN11-
+                      NS
+                      /SOS1
+                      -NS had the lowest birth weights (
+                      p
+                       < 0.05). GH was started at 6.4 years (3.8; 9.5), with baseline height-SDS − 2.92 (− 3.64; − 2.47). Median annual height-SDS increments were similar across genotypes: 0.61 (year 1;
+                      n
+                       = 101), 0.28 (year 2;
+                      n
+                       = 92), 0.21 (year 3;
+                      n
+                       = 77), 0.07 (year 4;
+                      n
+                       = 63), and 0.09 (year 5;
+                      n
+                       = 41), leading to height-SDS − 1.97 (− 2.81; − 1.42) after 5 years. Menarche occurred at age 15.7 (13.8; 17.2) years (
+                      n
+                       = 13), and final height-SDS (available in 23 patients) reached − 1.68 (− 2.65; − 0.41).
+                    
+
+Conclusions
+                      Growth restriction in NSSD begins prenatally, especially in PTPN11-NS and SOS1-NS. GH therapy was associated with improved height SDS, with the largest height gains observed before puberty. Earlier treatment initiation may therefore be beneficial for growth outcomes.
+
+
+
+
+
+
+
+What is Known:
+                                •
+                                Noonan syndrome spectrum disorders (NSSD) are genetically heterogeneous, with pathogenic variants in the PTPN11 and SOS1 genes being most prevalent. Phenotypic differences among genotypes remain poorly defined.
+                                •
+                                Short stature is a key NSSD feature. Growth hormone (GH) therapy is beneficial, but prior studies lacked genetic justification or had limited sample sizes.
+
+
+
+
+What is New:
+                                •
+                                We analysed perinatal data and real-life GH outcomes in 101 genetically confirmed NSSD cases.
+                                •
+                                SOS1-NS was linked to prematurity. Birth length was more reduced than weight across genotypes; PTPN11/SOS1 cases had the lowest birth weights. GH therapy was associated with an increase in height SDS from − 2.92 to − 1.97 (median) following 5 years, and to − 1.68 in those with final height.

references_cache/DOI_10.1007_s10557-022-07324-0.md

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+---
+reference_id: "DOI:10.1007/s10557-022-07324-0"
+title: An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
+authors:
+- Jae-Sung Yi
+- Sravan Perla
+- Anton M. Bennett
+journal: Cardiovascular Drugs and Therapy
+year: '2023'
+doi: 10.1007/s10557-022-07324-0
+content_type: unavailable
+---
+
+# An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
+**Authors:** Jae-Sung Yi, Sravan Perla, Anton M. Bennett
+**Journal:** Cardiovascular Drugs and Therapy (2023)
+**DOI:** [10.1007/s10557-022-07324-0](https://doi.org/10.1007/s10557-022-07324-0)
+
+## Content

references_cache/DOI_10.1016_j.jacc.2019.01.066.md

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+---
+reference_id: "DOI:10.1016/j.jacc.2019.01.066"
+title: Hypertrophic Cardiomyopathy in Noonan Syndrome Treated by MEK-Inhibition
+authors:
+- Gregor Andelfinger
+- Christopher Marquis
+- Marie-Josée Raboisson
+- Yves Théoret
+- Stephan Waldmüller
+- Gesa Wiegand
+- Bruce D. Gelb
+- Martin Zenker
+- Marie-Ange Delrue
+- Michael Hofbeck
+journal: Journal of the American College of Cardiology
+year: '2019'
+doi: 10.1016/j.jacc.2019.01.066
+content_type: unavailable
+---
+
+# Hypertrophic Cardiomyopathy in Noonan Syndrome Treated by MEK-Inhibition
+**Authors:** Gregor Andelfinger, Christopher Marquis, Marie-Josée Raboisson, Yves Théoret, Stephan Waldmüller, Gesa Wiegand, Bruce D. Gelb, Martin Zenker, Marie-Ange Delrue, Michael Hofbeck
+**Journal:** Journal of the American College of Cardiology (2019)
+**DOI:** [10.1016/j.jacc.2019.01.066](https://doi.org/10.1016/j.jacc.2019.01.066)
+
+## Content

references_cache/DOI_10.1016_j.jaccas.2026.107006.md

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+---
+reference_id: "DOI:10.1016/j.jaccas.2026.107006"
+title: Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome–Associated Hypertrophic Cardiomyopathy
+authors:
+- Camden Hebson
+- Sydney Escott
+- Guillermo Beltran-Ale
+- Robert Dabal
+- Gregor Andelfinger
+- Kristin Linscott
+journal: "JACC: Case Reports"
+year: '2026'
+doi: 10.1016/j.jaccas.2026.107006
+content_type: unavailable
+---
+
+# Atrial Septal Defect Surgical Closure Following Trametinib Utilization in Noonan Syndrome–Associated Hypertrophic Cardiomyopathy
+**Authors:** Camden Hebson, Sydney Escott, Guillermo Beltran-Ale, Robert Dabal, Gregor Andelfinger, Kristin Linscott
+**Journal:** JACC: Case Reports (2026)
+**DOI:** [10.1016/j.jaccas.2026.107006](https://doi.org/10.1016/j.jaccas.2026.107006)
+
+## Content

references_cache/DOI_10.1097_MD.0000000000046340.md

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+---
+reference_id: "DOI:10.1097/MD.0000000000046340"
+title: "Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report"
+authors:
+- Xiaoli Mou
+- Yong Liu
+- Yarong Zhang
+- Xinhe Cheng
+- Junshuai Feng
+journal: Medicine
+year: '2026'
+doi: 10.1097/MD.0000000000046340
+content_type: abstract_only
+---
+
+# Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report
+**Authors:** Xiaoli Mou, Yong Liu, Yarong Zhang, Xinhe Cheng, Junshuai Feng
+**Journal:** Medicine (2026)
+**DOI:** [10.1097/MD.0000000000046340](https://doi.org/10.1097/MD.0000000000046340)
+
+## Content
+
+Rationale:
+Noonan syndrome (NS) is a RASopathy most frequently associated with mutations in HRAS, NRAS, KRAS, and RRAS2. The contribution of MRAS variants to NS pathogenesis remains poorly characterized, and infective endocarditis (IE) is extremely rare in patients with NS.
+
+
+Patient concerns:
+A 22-year-old woman presented with typical dysmorphic features of NS, including short stature, broad forehead, hypertelorism, low-set posteriorly rotated ears, and a broad neck. She developed fever and progressive exertional dyspnea.
+
+
+Diagnoses:
+Echocardiography demonstrated obstructive hypertrophic cardiomyopathy with vegetation located in the left ventricular outflow tract. Blood cultures grew Streptococcus mutans. Whole-exome sequencing identified a heterozygous MRAS c.203C>T (p.Thr68Ile) mutation affecting a highly conserved residue among RASopathy-associated GTPases, supporting the diagnosis of MRAS-associated Noonan syndrome complicated by infective endocarditis.
+
+
+Interventions:
+Antibiotic therapy was escalated to intravenous gentamicin (60 mg daily) combined with ceftriaxone in accordance with the 2023 European Society of Cardiology guidelines for infective endocarditis.
+
+
+Outcomes:
+After one month of intravenous gentamicin and ceftriaxone therapy, fever resolved, and follow-up echocardiography showed disappearance of the vegetation. Residual cardiac abnormalities persisted, including marked left ventricular hypertrophy with left ventricular outflow tract obstruction, left atrial enlargement, moderate mitral regurgitation, patent foramen ovale with minor shunting, and impaired diastolic function. Exertional dyspnea remained despite resolution of the infection.
+
+
+Lessons:
+This case expands the genotypic spectrum of Noonan syndrome by supporting MRAS mutations as pathogenic drivers. It also identifies infective endocarditis as a previously unreported complication in MRAS-associated NS with outflow tract obstruction, highlighting the importance of careful cardiac surveillance in patients with RASopathies.

references_cache/DOI_10.1126_sciadv.adf4766.md

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+---
+reference_id: "DOI:10.1126/sciadv.adf4766"
+title: RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome–associated cardiac hypertrophy
+authors:
+- Antonio Cuevas-Navarro
+- Morgan Wagner
+- Richard Van
+- Monalisa Swain
+- Stephanie Mo
+- John Columbus
+- Madeline R. Allison
+- Alice Cheng
+- Simon Messing
+- Thomas J. Turbyville
+- Dhirendra K. Simanshu
+- Matthew J. Sale
+- Frank McCormick
+- Andrew G. Stephen
+- Pau Castel
+journal: Science Advances
+year: '2023'
+doi: 10.1126/sciadv.adf4766
+content_type: abstract_only
+---
+
+# RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome–associated cardiac hypertrophy
+**Authors:** Antonio Cuevas-Navarro, Morgan Wagner, Richard Van, Monalisa Swain, Stephanie Mo, John Columbus, Madeline R. Allison, Alice Cheng, Simon Messing, Thomas J. Turbyville, Dhirendra K. Simanshu, Matthew J. Sale, Frank McCormick, Andrew G. Stephen, Pau Castel
+**Journal:** Science Advances (2023)
+**DOI:** [10.1126/sciadv.adf4766](https://doi.org/10.1126/sciadv.adf4766)
+
+## Content
+
+RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of
+                    RIT1
+                    mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.