Blunt Trauma-Induced Chylothorax in Noonan Syndrome: A Rare Clinical Presentation

Phosphoproteomics elucidates the functional impact of the PTPN11 p.Asn308Ser variant in a Noonan syndrome pedigree

Purpose:To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies.Methods:Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed.Results:Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline PTPN11 variant; Nineteen of 24 participants (79%) were male. Seventeen (89%) patients with NS developed CNS cancers, including low-grade glioma, (LGG; pure pilocytic/pilomyxoid astrocytoma; n=9) and mixed dysembryoplastic neuroepithelial tumor (DNET; n=6). Five patients incidentally diagnosed did not undergo histological confirmation. Radiological review showed multifocal parenchymal tumors in 9 patients with NS, including histologically confirmed neoplasm (n=2), radiologic progression (n=6), or typical tumoral imaging (n=1). All LGGs in patients with NS and germline PTPN11 variants except one (14/15; 93%) harbored somatic FGFR1 abnormalities. RNA sequencing of 12 tumors detected FGFR1 internal tandem duplication in one patient. Comparison with published data showed a statistically significant association between brain tumor occurrence and PTPN11-related NS, driven by two genotypes: NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly) and c.417G>T (p.Glu139Asp). Ten patients with LGGs, including 7 (41%) with NS, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS cancer.Conclusion:PTPN11-related NS predisposes to multifocal pure and mixed LGGs confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and LGGs.

Advancing Obstetric Care: The Role of Targeted Next-Generation Sequencing in Pregnancies with Structurally Normal Fetuses.

Noonan syndrome (NS) is a genetic disease characterized by dysregulation in the RAS/MAPK pathway. Affected individuals present peculiar physical features, short stature, and congenital cardiovascular defects. Autoimmune hepatitis is a chronic immunoinflammatory liver disease. A 17-year-old boy with NS due to PTPN11 gene variation and type 1 autoimmune hepatitis (AIH-1; biopsy proven) is described. A literature search on the association between NS and AIH1 showed additional two cases. This report highlights the importance of monitoring patients with NS for signs of autoimmune diseases, mainly liver dysfunction. Precise mechanisms linking NS and AIH-1 remain unclear. Anyway, the dysregulation of the RAS/MAPK pathway may be involved. Periodic monitoring of transaminases and prompt evaluation with liver biopsy should be done to optimize diagnosis and treatment of people with NS.

Pulmonary valve stenosis (PVS) is the most common congenital heart defect in Noonan syndrome (NS) and related RASopathies, yet the molecular mechanisms linking pathogenic variants to the valve pathology remain poorly defined. Here, we utilized a human iPSC-based valve differentiation platform to generate the cardiac valve cell lineages—including fibrosa and spongiosa valve interstitial cell (VIC) subtypes. CRISPR-edited iPSCs harboring NS gain-of-function RAS/MAPK and Noonan syndrome with multiple lentigines (NSML) dominant-negative RAS/MAPK variants exhibited early defects in mesodermal and endocardial specification in all genotypes. Additionally, NS-iPSC endocardial cells exhibited defects in endothelial-to-mesenchymal transition (EndMT) specifically towards fibrosa VICs, which was most pronounced in PTPN11N308D (N308D) cells. Single-cell transcriptomics revealed widespread dysregulation of extracellular matrix (ECM) programs in N308D fibrosa VICs, including increased expression of collagens and proteoglycans, as well as dysregulation of multiple genes involved in ECM remodeling. We also detected activation of RAS-MAPK, TGFβ, and fibrosis-associated pathways in our transcriptional dataset. Mass spectrometry-based phosphoproteomics confirmed coordinated increases in ERK, PKC, and stress-related kinases, as well as enhanced activity of the TGFβ receptor. Functionally, N308D fibrosa VICs exhibited exaggerated upregulation of ECM genes in the presence of TGFβ2 ligand, suggesting that these cells are hypersensitive to TGFβ stimulation. Furthermore, we demonstrated that this pathological ECM-program occurs independently of BAMBI, a negative regulator of TGFβ signaling that was found to be decreased in N308D fibrosa VICs. Lastly, we performed histopathological analyses of stenotic pulmonary valves from two NS infants, which demonstrated marked overproduction and disorganization of ECM, mirroring the findings from our iPSC-based disease model. Together, our data reveal a central mechanism where NS-associated alleles sensitize fibrosa VICs to TGFβ, which leads to aberrant downstream signaling and drives the pathological ECM program in NS-associated PVS.

Noonan syndrome is an autosomal dominant genetic disorder characterized by multisystem involvement and frequent cardiac anomalies such as hypertrophic cardiomyopathy (HCM), left ventricular outflow tract (LVOT) obstruction, pulmonary stenosis, and valve abnormalities. These clinical features significantly increase perioperative risk. We present the anesthetic management of a 3-month-old infant with Noonan syndrome undergoing epicardial implantable cardioverter-defibrillator (ICD) placement. The patient had a history of cardiac arrest, HCM, LVOT obstruction, patent foramen ovale, and mild valvular regurgitations. General anesthesia was induced with midazolam, fentanyl, and rocuronium; maintenance was achieved with remifentanil infusion and sevoflurane. Invasive arterial monitoring and bispectral index (BIS) were used. Intraoperative hemodynamics remained stable, and the patient was transferred to the intensive care unit (ICU) intubated and sedated. However, postoperative deterioration occurred due to necrotizing enterocolitis on day 2, and despite resuscitative efforts following cardiac arrest on postoperative day 5, the patient died. This case highlights the complexity of anesthetic care in Noonan syndrome due to difficult airway features, severe cardiac involvement, and risk of perioperative complications.

BackgroundPre-existing medical conditions are known to increase the risk of severe coronavirus disease 2019 (COVID-19), even in pediatric populations. This study aimed to evaluate the symptoms and severity of COVID-19, as well as the side effects of the BNT162 vaccine, in children and adolescents with Noonan Syndrome (NS) compared to healthy controls.MethodsA retrospective and prospective multicenter study was conducted across Italy. Clinical characteristics, course, and duration of SARS-CoV-2 infection, as well as side effects of the BNT162 vaccine, were compared between 97 patients with NS and 97 age- and sex-matched healthy subjects.ResultsNo statistically significant differences were found in the severity or duration of COVID-19 between NS patients and controls. NS patients exhibited a higher rate of rhinorrhea during SARS-CoV-2 infection (69.2% vs. 46%, p < 0.05), whereas anosmia was more common among controls (1.5% vs. 12.7%, p < 0.05). No statistically significant differences in side effects from the BNT162 vaccine were observed between groups. 95% confidence intervals were calculated for key outcomes to improve comparability.ConclusionChildren and adolescents with Noonan Syndrome generally experience a mild course of COVID-19 and show no evidence of increased vaccine-related risk. Despite the small sample size and the rarity of severe events, these findings yield valuable insights for patients living with this rare disease.

RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2–RAS–PP1C complex. MRAS forms a high-affinity SHOC2–MRAS–PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2–KRAS–PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2–RAS–PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.

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.

Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on RAF1 variants is still lacking. We conducted a retrospective observational study combining newly collected cases of RAF1-related NS from a national multicenter retrospective cohort with systematically reviewed cases froma literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in RAF1-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.

Introduction: Parachute mitral valve (PMV) is a rare congenital malformation characterized by all mitral chordae tendineae inserting into a single papillary muscle. The resultant unifocal attachment often leads to mitral inflow obstruction of varying severity. While PMV is sometimes isolated, it has also been reported in association with extracardiac anomalies and genetic syndromes, though this remains uncommon. Case Presentation: We report a case of a 2-year-old male toddler who presented with exertional dyspnea, easy fatigability, and recurrent chest infections since infancy. Clinical examination revealed dysmorphic facial features, short stature, and webbed neck, raising strong suspicion for Noonan syndrome. Cardiac auscultation demonstrated an apical mid-diastolic murmur. Echocardiography confirmed a parachute mitral valve with thickened mitral leaflets and restricted mobility, producing significant mitral inflow obstruction. No other structural cardiac malformations were detected. Work-up for extracardiac involvement further supported a syndromic diagnosis, although genetic testing was not available at the time of evaluation. The patient was managed conservatively with diuretics and regular cardiology follow-up. Symptom improvement was noted on medical therapy, though surgical intervention may be required if progression of obstruction occurs. This case highlights the importance of thorough evaluation in children presenting with dysmorphic features and cardiac murmurs. Conclusion: PMV is a rare congenital anomaly that may occur as part of a broader syndromic presentation. Early recognition, echocardiographic diagnosis, and multidisciplinary care are essential to optimize outcomes in affected children.

Noonan syndrome is characterised by typical facial features, short stature, CHDs, and other comorbidities, which are caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase pathway. Noonan syndrome is an inherited disease involving multiple systems, but ventricular arrhythmia in Noonan syndrome is rarely reported. Here we report a 15-year-old patient with leucine zipperlike transcription regulator 1-associated Noonan syndrome, who has CHD (left ventricular hypertrophy with left ventricular outflow tract obstruction), ventricular arrhythmia, bundle branch block, pectus excavatum, costal eversion, scoliosis, myopia, growth retardation, hearing loss, chest tightness, and fatigue. Chest tightness and fatigue are the main reasons for admission of the patient. The patient was treated with spironolactone, empagliflozin, tolasemide, potassium chloride, and bisoprolol. One month after treatment, the patient has no more chest tightness or fatigue. Genetic testing revealed that the patient had a novel heterozygous variant c.313delT (p.trp105Glyfs * 42) mutation in the leucine zipperlike transcription regulator 1. We provide a review of the literature of leucine zipperlike transcription regulator 1 mutations and find that ventricular arrhythmias have been reported in leucine zipperlike transcription regulator 1-related Noonan syndrome. Our findings expand on the Noonan syndrome phenotype and suggest that mutations in the leucine zipperlike transcription regulator 1 gene are involved in ventricular arrhythmia.

Reports on long-term safety and effectiveness of daily GH replacement therapy in Japanese children with short stature due to Noonan syndrome (NS) are limited. This post-marketing, prospective, non-interventional study (ClinicalTrials.gov NCT03435627) evaluated the long‑term safety and effectiveness of daily GH therapy in this patient population. The study took place at 22 sites in Japan during November 2017-January 2022. Seventy participants were enrolled and received Norditropin® at least once during the study as per routine clinical practice: new patients (n = 35) received Norditropin® (somatropin) after study initiation and existing patients (n = 35) were previously enrolled in a 4-year trial of Norditropin® for NS (ClinicalTrials.gov NCT01927861). The main outcome measures were adverse drug reactions (ADRs) and serious adverse events (SAEs). Improvements in height were also measured. In total, four new patients experienced five ADRs and one new patient experienced one SAE. Five existing patients experienced one ADR each and three existing patients experienced one SAE each. One existing patient with pre-existing cardiomyopathy who experienced an SAE (arrhythmia) died during the study; Norditropin® causality was judged 'unlikely.' Change from baseline in mean (SD) height standard deviation score (SDS), according to Japanese and NS standards, was 1.01 (0.5) and 0.92 (0.3) for new patients and 1.01 (1.0) and 1.31 (0.8) for existing patients, respectively. Our results show that Norditropin® effectively improved height outcomes in Japanese children with NS and was well tolerated with no new safety issues identified. For patients with NS and cardiomyopathy receiving GH therapy, careful monitoring is advised.

Natural history of coronary aneurysms associated with Noonan's syndrome

Five Years of Combined Newborn Screening Quantifying TREC and KREC in Switzerland.

Alagille Syndrome (ALGS) is a rare multisystem disorder of autosomal dominant type which is primarily caused due to mutations in the JAG1 gene and, less commonly, NOTCH2, both integral to Notch signalling. Clinically, ALGS is further characterised by cholestatic liver disease because of intrahepatic bile duct paucity, along with some cardiac and skeletal abnormalities, ocular defects, renal involvement, and distinct facial features. Diagnosis of ALGS depends upon the presence of at least three of five main clinical features, which are later supported through liver biopsy, genetic testing, and imaging. Differential diagnosis of ALGS includes biliary atresia, Progressive Familial Intrahepatic Cholestasis (PFIC), neonatal hepatitis, and syndromes with overlapping phenotypes such as Noonan and Kabuki syndromes. Management in such cases is largely supportive, which mainly focuses on relieving cholestasis and pruritus, along with proper nutritional adequacy, and addressing systemic complications. Liver transplant is reserved only for end-stage disease or intractable symptoms. A multidisciplinary approach is an essential aspect of treatment to improve patient outcomes, along with quality of life.

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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00431-026-06764-2.

LEOPARD syndrome and Noonan syndrome are clinically overlapping RASopathies, both frequently associated with pathogenic variants in the PTPN11 gene, which encodes the SHP-2 tyrosine phosphatase. Typically, Noonan syndrome arises from gain-of-function variants, while LEOPARD syndrome results from loss-of-function alterations, most often distinguished by the presence of lentigines and cardiac anomalies. We report a diagnostically challenging case of a 17-year-old male who presented with behavioural disturbances, seizure disorder, visual and auditory hallucinations, and history of right orchidectomy and left-eye cataract. Physical examination revealed hypertelorism, low-set ears, high-arched palate, and dental overcrowding, but notably lacked lentigines or cardiac findings. Genetic analysis identified a heterozygous PTPN11 variant, p.Phe285Ser in exon 8, previously described in both LEOPARD syndrome 1 and Noonan syndrome 1. Ancillary investigations confirmed seizure activity on EEG but showed no abnormalities on ECG or MRI. This case highlights the diagnostic ambiguity inherent to RASopathies, where identical PTPN11 variants may underlie divergent phenotypes. The absence of cutaneous and cardiac manifestations traditionally considered pathognomonic for LEOPARD syndrome underscores the limitations of relying solely on phenotype for classification. Instead, this case supports a genotype-first diagnostic framework, where molecular findings refine and sometimes challenge clinical labels. Recognition of such overlap is critical for genetic counselling, prognostic assessment, and surveillance planning, as patients may deviate from usually documented syndrome descriptions. Our report adds to the growing body of evidence that PTPN11 p.Phe285Ser represents a mutational hotspot bridging Noonan and LEOPARD syndromes, reinforcing the continuum model of RASopathies.

ABSTRACT Background Inherited bone marrow failure syndromes (IBMFS) often present with overlapping features and may be misdiagnosed as idiopathic aplastic anemia (iAA). Genetic testing is critical for accurate diagnosis, especially in consanguineous populations. Research design and methods We retrospectively analyzed 41 pediatric patients who underwent genetic evaluation for suspected bone marrow failure. Clinical features, diagnostic classifications, and genetic findings were reviewed to assess diagnostic yield and impact. Results The cohort included 21 males and 20 females (median age: 8 years). Pancytopenia was the most common presentation (27/41; 65%), half (20/41; 49%) were products of consanguineous marriage. iAA was the initial diagnosis in 56% (23/41). Genetic testing identified pathogenic/likely pathogenic (P/LP) variants in 14 patients (34%), enabling a molecular diagnosis. An additional 13 patients (32%) had variants of uncertain significance, one of which was later reclassified as LP, confirming Noonan syndrome. Genetic findings prompted diagnostic revisions, including Fanconi anemia, Congenital Amegakaryocytic Thrombocytopenia, Shwachman–Diamond syndrome, and Diamond–Blackfan anemia. Commonly affected genes included MPL, FANCA, followed by DANJC21. Conclusions In this Pakistani cohort, genetic testing clarified IBMFS diagnoses in 34% of cases, matching global yields. It enhanced diagnostic precision, informed management, and supported family counseling, though high VUS rates underscore the need for ongoing reclassification and multidisciplinary care.