Search

Noonan syndrome (NS) is characterized by various abnormalities and is complicated with cardiac diseases, such as hypertrophic cardiomyopathy, in > 80% of cases. Minimum hemodynamic changes are a crucial factor during general anesthesia in such patients. We report the case of a patient with NS and hypertrophic obstructive cardiomyopathy (HOCM) who underwent general anesthesia using remimazolam, a new ultrashort-acting benzodiazepine anesthetic, which is expected to cause less circulatory depression. A 19-year-old woman with NS complicated with HOCM was scheduled to undergo extraction of the wisdom teeth and second molar under general anesthesia. Preoperative evaluation revealed HOCM with left ventricular outflow tract obstruction and the patient had chronic heart failure. After the placement of an arterial line under moderate sedation with remimazolam, general anesthesia was induced with remimazolam, fentanyl, and rocuronium, followed by anesthesia maintenance with remimazolam and remifentanil. Tracheal intubation was performed using videolaryngoscopy. Local anesthesia and inferior alveolar nerve block were performed using adrenaline-free local anesthetics. Intraoperatively, low-dose phenylephrine was administered continuously to maintain peripheral vascular resistance. At the end of surgery, the endotracheal tube was replaced with an i-gel® supraglottic airway device before emergence from general anesthesia. After full recovery from anesthesia, the i-gel® was removed, and the patient was transferred to the hospital ward. The perioperative blood pressure and heart rate were maintained within normal ranges, and no cardiovascular events occurred during anesthesia. Anesthesia management using remimazolam and low-dose phenylephrine with reduction in perioperative stress may provide an appropriate circulatory condition for noncardiac surgery in patients with HOCM. [ABSTRACT FROM AUTHOR]

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]

The protein tyrosine phosphatase SHP2 (PTPN11) is a negative regulator of glycoprotein VI (GPVI)-induced platelet signal under certain conditions. Clinical trials with derivatives of the allosteric drug SHP099, inhibiting SHP2, are ongoing as potential therapy for solid cancers. Gain-of-function mutations of the PTPN11 gene are observed in part of the patients with the Noonan syndrome, associated with a mild bleeding disorder. Assessment of the effects of SHP2 inhibition in platelets from controls and Noonan syndrome patients. Washed human platelets were incubated with SHP099 and stimulated with collagen-related peptide (CRP) for stirred aggregation and flow cytometric measurements. Whole-blood microfluidics assays using a dosed collagen and tissue factor coating were performed to assess shear-dependent thrombus and fibrin formation. Effects on clot formation were evaluated by thromboelastometry. Pharmacological inhibition of SHP2 did not alter GPVI-dependent platelet aggregation under stirring, but it enhanced integrin αIIbβ3 activation in response to CRP. Using whole-blood microfluidics, SHP099 increased the thrombus buildup on collagen surfaces. In the presence of tissue factor and coagulation, SHP099 increased thrombus size and reduced time to fibrin formation. Blood from PTPN11 -mutated Noonan syndrome patients, with low platelet responsiveness, after ex vivo treatment with SHP099 showed a normalized platelet function. In thromboelastometry, SHP2 inhibition tended to increase tissue factor-induced blood clotting profiles with tranexamic acid, preventing fibrinolysis. Pharmacological inhibition of SHP2 by the allosteric drug SHP099 enhances GPVI-induced platelet activation under shear conditions with a potential to improve platelet functions of Noonan syndrome patients. [Display omitted] • The PTPN11 inhibitor SHP099 was used to study effects in platelets. • SHP099 increased collagen-induced thrombus build-up in whole blood microfluidics. • SHP099 enhanced platelet- and shear-dependent coagulation. • SHP099 restored thrombus formation in Noonan syndrome patients with mutated PTPN11. [ABSTRACT FROM AUTHOR]

Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM. [Display omitted] [ABSTRACT FROM AUTHOR]

We reviewed the long-term outcome of children with hypertrophic cardiomyopathy (HCM) based on the type. We reviewed the medical records of 100 patients (male 54 female 46) with HCM at our hospital between 1977 and 2015. The survival and cardiac event-free survival rates were calculated by the Kaplan–Meier method. The age at the time of the diagnosis ranged from 0 to 15 years with a median of 8 years. The number of patients with Noonan syndrome and hypertrophic obstructive cardiomyopathy (HOCM), idiopathic HCM (i-HCM), and secondary HCM (s-HCM) was 13, 13, 65, and 9 respectively. A dilated phase of HCM occurred in 24 patients. Nineteen (79 %) of the 24 patients died of heart failure, and two underwent a heart transplantation. Eight (33 %) of the 24 patients had s-HCM. The median age when a dilated phase occurred was 15 years old, and the median interval from the initial diagnosis to the dilated phase was 8 years. The median time from the diagnosis of a dilated phase to death was 1.6 years. Sudden death and implantable cardioverter defibrillator implantations occurred in 6 and 11 patients at around 15 years old, respectively. The 20-year survival rates were as follows: Noonan syndrome 84 %; HOCM 82 %; i-HCM 71 %; and s-HCM 17 %. Overall, the survival rates at 10, 20, and 30 years were 83 % (95 % confidence interval 73–89), 69 % (58–78), and 63 % (50–74), respectively. The overall cardiac event-free survival rates at 10, 20, and 30 years were 57 % (47–67), 39 % (31–50), and 32 % (21–44), respectively. The long-term outcome in children with HCM was poor, and the outcome of s-HCM was very poor. The occurrence of a dilated phase worsened the outcome in HCM patients. Sudden death and d-HCM often occurred at around 15 years old. [Display omitted] • The overall 30-year cardiac event free survival rate was 32 %. • The long-term outcome in children with hypertrophic cardiomyopathy was poor. • The median age when a dilated phase occurred was 15 years old. • Sudden death often occurred at around 15 years old. • The outcome of secondary hypertrophic cardiomyopathy was very poor. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a genetic syndrome causing obstructive hypertrophic cardiomyopathy (HCM) in infants. Studies of cardiac surgery in pediatric HCM patients with NS (NS-HCM) are lacking. We aim to characterize the early disease course of young NS-HCM patients before adolescence and assess their complications and survival condition after septal myectomy. Pediatric obstructive HCM patients who underwent septal myectomy at age 10 years or under were enrolled consecutively between 2009 and 2019. Ten patients with NS and 43 non-NS patients were enrolled in our study. NS-HCM patients were diagnosed at a younger age (5.00 ± 7.48 months vs. 18.73 ± 26.96 months) and more often had biventricular outflow tract obstruction (90.00% vs 30.23%). The surgical treatment can significantly reduce the pressure gradient of the outflow tract. More NS-HCM patients had biventricular reconstruction (70.00% vs 25.58%). The overall survival rates in all patients were 98.04% during 5-year follow-up, respectively. Complete heart block (CHB) was the most prevalent complication in patients with NS and tended to be more common than in non-NS patients (20% vs 7.32%). No sudden cardiac death (SCD) occurred in CHB patients who had pacemaker implantation. Biventricular reconstruction was the risk factor for CHB. Septal myectomy is safe and effective surgery to relieve obstruction in young age pediatric obstructive NS-HCM patients. Postoperative CHB is a common complication, especially in patients who underwent biventricular reconstruction. The implantation of pacemaker can protect CHB patients from SCD and improve their prognosis. [ABSTRACT FROM AUTHOR]

Early-life critical periods allow initial sensory experience to remodel brain circuitry so that synaptic connectivity can be optimized to environmental input. In the Drosophila juvenile brain, olfactory sensory neuron (OSN) synaptic glomeruli are pruned by glial phagocytosis in dose-dependent response to early odor experience during a well-defined critical period. Extracellular signal-regulated kinase (ERK) separation of phases-based activity reporter of kinase (SPARK) biosensors reveal experience-dependent signaling in glia during this critical period. Glial ERK-SPARK signaling is depressed by removal of Draper receptors orchestrating glial phagocytosis. Cell-targeted genetic knockdown of glial ERK signaling reduces olfactory experience-dependent glial pruning of the OSN synaptic glomeruli in a dose-dependent mechanism. Noonan Syndrome is caused by gain-of-function mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) inhibiting ERK signaling, and a glial-targeted patient-derived mutation increases experience-dependent glial ERK signaling and impairs experience-dependent glial pruning of the OSN synaptic glomeruli. We conclude that critical period experience drives glial ERK signaling that is required for dose-dependent pruning of brain synaptic glomeruli, and that altered glial ERK signaling impairs this critical period mechanism in a Noonan Syndrome disease model. • Drosophila brain glia exhibit sensory experience-dependent MAPK/ERK signaling in an early-life critical period. • Glial ERK signlaing facilitates experience-dependent brain synaptic glomeruli pruning within this critical period. • A Noonan Syndrome patient-derived PTPN11 mutation targeted to glia elevates ERK signaling and synaptic pruning. [ABSTRACT FROM AUTHOR]

Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1 L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1 L580P -specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1 L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies. [Display omitted] • LZTR1L580P in homozygosity is causative for Noonan syndrome and hypertrophic cardiomyopathy • LZTR1L580P fosters assembly of LZTR1 polymers, resulting in complex dysfunction • Pathological LZTR1 results in impaired RAS GTPase degradation, causing cellular hypertrophy • CRISPR correction of one allele is sufficient to normalize cardiac disease phenotype Using patient-specific and CRISPR-Cas9-corrected iPSC cardiomyocytes, Busley et al. describe an LZTR1 L580P -specific disease mechanism provoking Noonan syndrome-associated cardiac hypertrophy. Mutation-induced polymerization of LZTR1 complexes results in the accumulation of RAS GTPases, leading to molecular and cellular impairments associated with cardiac hypertrophy, whereas CRISPR correction of the missense variant rescues the disease phenotype. [ABSTRACT FROM AUTHOR]

This study sought to describe the characteristics and the natural course of left ventricular hypertrophy (LVH) in a well-characterized consecutive cohort of infants of diabetic mothers (IDMs). Sixty consecutive IDMs with LVH have been retrospectively identified and enrolled in the study. All IDMs were evaluated at baseline and every 6 months until LV wall thickness regression, defined as the decrease of wall thickness measurement into the normal reference range for cardiac parameters (z-score > −2 and < 2). A comprehensive assessment was performed in those patients with diagnostic markers suggestive of a different cause and/or without significant reduction of the LVH during follow-up. At 1-year follow-up, all IDMs showed a significant reduction of maximal wall thickness MWT (6.00 mm [IQR 5.00–712] vs. 5.50 mm [IQR 5.00–6.00], p-value <0.001; MWT-z-score: 4.86 [IQR 3.93–7.61] vs. 1.72 [IQR 1.08–2.85], p-value <0.001) compared to baseline, and all patients showed LV wall thickness regression or residual mild or moderate LVH (57%, 28%, and 12%, respectively), except 2 patients with persistent severe LVH, that after a comprehensive clinical-genetic assessment were diagnosed as Noonan syndrome with multiple lentigines. At multivariate analysis, MWT was negatively associated with LV wall thickness regression at 1-year follow-up (MWT-mm: OR 0.48[0.29–0.79], p-value = 0.004; MWT-z-score: OR 0.71[0.56–0.90], p-value = 0.004). LVH in IDMs represents a benign condition with complete regression during the first years of life. In those patients without LV wall thickness regression, combined with clinical markers suggesting a specific disease, a complete work-up is required for a definite diagnosis. [Display omitted] • 57% of IDMs showed left ventricular wall thickness regression in the first year of age. • Two IDMs with persistent severe LVH at 1-year follow-up were diagnosed as NSML. • All IDMs showed a LV wall thickness regression in the first 6 years of life. [ABSTRACT FROM AUTHOR]

Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation. Activating mutations in SOS1 are common in Noonan syndrome and oncogenic alterations in KRAS drive 1 in seven human cancers. Promising clinical efficacy has been observed for selective KRASG12C inhibitors, but the vast majority of oncogenic KRAS alterations remain undrugged. The discovery of a druggable pocket on SOS1 has led to potent SOS1 inhibitors such as BI-3406. SOS1 inhibition leads to antiproliferative effects against all major KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers. In this review, we provide an overview of SOS1 function, its association with cancer and RASopathies, known SOS1 activators and inhibitors, and a future perspective is provided. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is the most common genetic cause of infantile hypertrophic cardiomyopathy and the second most common syndromic cause of congenital heart disease. Several gene variants along the RAS-MAPK pathway can lead to NS, which is a multiorgan system disorder. Congenital heart disease is seen in over 80 % of NS patients, and severe lymphatic malformations can be seen in approximately 20 % of patients. Infants with NS have varying severity of presentations, and those diagnosed with congenital heart disease, hypertrophic cardiomyopathy, and lymphatic disease in early infancy face a high risk of mortality. Here, we describe the complex case of a 4-month-old female with known NS (SOS1 mutation), severe pulmonary stenosis, a moderate secundum atrial septal defect, and history of a chylothorax who presented acutely with chyloperitoneum and severe hypertrophic cardiomyopathy. Due to critical illness and an extremely poor prognosis, she was started on the mitogen-activated extracellular kinase (MEK) inhibitor, trametinib, with remarkable resolution of her hypertrophic cardiomyopathy, chylothorax, and ascites within 4–6 weeks of drug initiation. This is the first case describing an NS patient with an SOS1 mutation with congenital heart disease, including progressive, severe HCM and biventricular outflow tract obstruction, as well as severe, progressive lymphatic dysfunction successfully treated with trametinib. Certainly, further evaluation is needed, but our case adds a remarkably positive outcome, supporting further exploration and use of trametinib in patients with NS and associated HCM and lymphatic disorders. • Noonan syndrome is associated with RAS-MAPK pathway mutations • Molecular targeted treatment in RAS-MAPK pathay mutations with Mek inhibitors (Trametinib) 3- Consider genetic testing in patients with congenital chylous effusions [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a congenital genetic abnormality characterized by short stature, delayed onset of puberty, cardiac malformations, and characteristic external malformations. Congenital chromosomal or genetic abnormalities are sometimes associated with carcinomas. Furthermore, they are difficult to manage perioperatively because of multiple complications and mental retardation. The safety of kidney transplantation for patients with NS has not been established. We are reporting the case of a 31-year-old man with NS who received a kidney transplantation after a donor's brain death. He received kidney transplantation safely and was discharged without issues. Kidney transplantation for patients with congenital chromosomal or genetic abnormalities is feasible without serious complications, with a regular follow-up, and psychological support from patients and families. [ABSTRACT FROM AUTHOR]

Ras family proteins play an essential role in several cellular functions, including growth, differentiation, and survival. The mechanism of action of Ras mutants in Costello syndrome and cancers has been identified, but the contribution of Ras mutants to Noonan syndrome, a genetic disorder that prevents normal development in various parts of the body, is unknown. Son of Sevenless (SOS) is a Ras guanine nucleotide exchange factor. In response to Ras-activating cell signaling, SOS autoinhibition is released and is followed by accelerative allosteric feedback autoactivation. Here, using mutagenesis-based kinetic and pulldown analyses, we show that Noonan syndrome Ras mutants I24N, T50I, V152G, and D153V deregulate the autoactivation of SOS to populate their active form. This previously unknown process has been linked so far only to the development of Noonan syndrome. In contrast, other Noonan syndrome Ras mutants--V14I, T58I, and G60E--populate their active form by deregulation of the previously documented Ras GTPase activities. We propose a novel mechanism responsible for the deregulation of SOS autoactivation, where I24N, T50I, V152G, and D153V Ras mutants evade SOS autoinhibition. Consequently, they are capable of forming a complex with the SOS allosteric site, thus aberrantly promoting SOS autoactivation, resulting in the population of active Ras mutants in cells. The results of this study elucidate the molecular mechanism of the Ras mutant- mediated development of Noonan syndrome. [ABSTRACT FROM AUTHOR]

Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer while also being implicated in a diverse group of developmental disorders named the 'RASopathies', including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and capillary malformation–arteriovenous syndrome (CM-AVM). It remains unclear why (i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and (ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is CS, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway. • RAS mutations have been associated with a range of malignancies and with developmental disorders called RASopathies. • Cancers associated with sporadic and germline RAS mutations are dissimilar in histological origins and mutational subtypes. • This disparity highlights our incomplete understanding of the relationship between the RAS–MAPK pathway and cancer. • Recent advances in targeting Ras G12C, HRAS and MEK have led to renewed interest in targeted therapies in this pathway. [ABSTRACT FROM AUTHOR]

RASopathies are a group of disorders characterized by mutations in the RAS-MAPK pathway. RAS-MAP signaling plays a critical role in cell differentiation, proliferation, and survival. Germline mutations can result in distinctive syndromes, including Noonan syndrome, Costello syndrome, and neurofibromatosis type 1. Mosaic RASopathies can present as localized cutaneous lesions like epidermal nevi and nevus sebaceous, or more extensive conditions such as encephalocraniocutaneous lipomatosis. We review the heterogenous presentation of RAS mutations, discuss new targeted therapies, and highlight areas of uncertainty, including carcinogenesis risk and appropriate screening. [ABSTRACT FROM AUTHOR]

• Noonan syndrome is the second most common syndromic cause of CHD. • We present a rare case of Noonan syndrome having a combination of ASD, PS and HCM. • Patient underwent balloon valvotomy for pulmonary stenosis. • The patient is under regular follow-up and awaiting heart transplant. Noonan syndrome is the second most common syndromic cause of congenital heart disease. Most patients have an autosomal dominant inheritance, but some cases may be sporadic. Pulmonary stenosis is the most common cardiac manifestation in Noonan syndrome, associated with the atrial septal defect and hypertrophic cardiomyopathy. A combination of these three is present only in 5% of patients. We report a case of a 21-year-old female who presented to our hospital concomitant cardiac lesions associated with pulmonary stenosis, atrial septal defect, and hypertrophic cardiomyopathy. This combination of cardiac defects is an infrequent manifestation of Noonan syndrome. The patient presented with complaints of exertion syncope over the past two years. 2D-Echocardiography showed biventricular hypertrophy, dysplastic pulmonary valve, severe pulmonary stenosis, asymmetric septal hypertrophy and large atrial septal defect. The genetic analysis report showed autosomal dominant inheritance with Ras/MAPK (mitogen-activated protein kinase) Positive. Due to the wide spectrum of symptoms and presentations in Noonan cases, accurate clinical and genetic diagnosis, and comprehensive management of the disorder are strongly recommended. We have described a case of rare combination of cardiovascular defects in Noonan Syndrome with a view to achieve better insight into the disease course and advantages of timely treatment and follow up. Our patient is currently in follow-up after treatment with percutaneous balloon pulmonary valvuloplasty, has improved symptoms, and is awaiting heart transplant. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a relatively common congenital multiple-anomaly syndrome, resembling Turner syndrome, but without chromosomal anomaly. Besides the unusual facies, the maxillofacial and dental features of patients with NS are not well-summarized in the literature. The aim of this study was to describe these features and propose specific treatment guidelines for practitioners involved in oral and maxillofacial care. A retrospective multicentric study was conducted of 14 patients who were referred for NS screening. In total, 10 patients were found to carry a mutation involved in NS or NS-related disorders. Fifty percent of the mutations affected PTPN11. All patients presented with the typical extraoral features, such as macrocephaly, hypertelorism, ptosis, triangular face shape and ear dystrophy. Intraoral manifestations, including malocclusion (maxillary transversal deficiency, crossbite, anterior open-bite and class II malocclusion), dental anomalies (delayed eruption, agenesis and dystrophy, odontoma) and radiologic jaw lesions were identified in five out of 10 patients. These findings were searched in a review of the literature to obtain a comprehensive description of oral and maxillofacial features in patients with NS. The proposed treatment guidelines emphasize frequent coagulation anomalies that need to be considered prior to surgery. Early dental assessment and yearly follow-up with oral prophylaxis are recommended. Orthodontics and orthognathic surgery are also of primary importance in the management of NS patients. [ABSTRACT FROM AUTHOR]

The nonreceptor protein-tyrosine phosphatase (PTP) SHP2 is encoded by the proto-oncogene PTPN11 and is a ubiquitously expressed key regulator of cell signaling, acting on a number of cellular processes and components, including the Ras/Raf/Erk, PI3K/Akt, and JAK/STAT pathways and immune checkpoint receptors. Aberrant SHP2 activity has been implicated in all phases of tumor initiation, progression, and metastasis. Gain-of-function PTPN11 mutations drive oncogenesis in several leukemias and cause developmental disorders with increased risk of malignancy such as Noonan syndrome. Until recently, small molecule-based targeting of SHP2 was hampered by the failure of orthosteric active-site inhibitors to achieve selectivity and potency within a useful therapeutic window. However, new SHP2 allosteric inhibitors with excellent potency and selectivity have sparked renewed interest in the selective targeting of SHP2 and other PTP family members. Crucially, drug discovery campaigns focusing on SHP2 would greatly benefit from the ability to validate the cellular target engagement of candidate inhibitors. Here, we report a cellular thermal shift assay that reliably detects target engagement of SHP2 inhibitors. Using this assay, based on the DiscoverX InCell Pulse enzyme complementation technology, we characterized the binding of several SHP2 allosteric inhibitors in intact cells. Moreover, we demonstrate the robustness and reliability of a 384-well miniaturized version of the assay for the screening of SHP2 inhibitors targeting either WT SHP2 or its oncogenic E76K variant. Finally, we provide an example of the assay's ability to identify and characterize novel compounds with specific cellular potency for either WT or mutant SHP2. [ABSTRACT FROM AUTHOR]

• Overlap between ophthalmic and psychiatric features has been described in a number of congenital and inherited disorders. • Recent studies using new technologies for ocular and brain imaging have identified novel potential links between the eye and the brain. • Prompt recognition of clinical features and co-morbidities by ophthalmologists and psychiatrists could facilitate diagnosis and treatment of the underlying issue and significantly improve prognosis. • Future studies can expand our understanding of the underlying pathophysiology and contribute to the development of useful biomarkers. A number of congenital and inherited diseases present with both ocular and psychiatric features. The genetic inheritance and phenotypic variants play a key role in disease severity. Early recognition of the signs and symptoms of those disorders is critical to earlier intervention and improved prognosis. Typically, the associations between these two medical subspecialties of ophthalmology and psychiatry are poorly understood by most practitioners so we hope to provide a narrative review to improve the identification and management of these disorders. We conducted a comprehensive review of the literature detailing the diseases with ophthalmic and psychiatric overlap that were more widely represented in the literature. Herein, we describe the clinical features, pathophysiology, molecular biology, diagnostic tests, and the most recent approaches for the treatment of these diseases. Recent studies have combined technologies for ocular and brain imaging such as optical coherence tomography (OCT) and functional imaging with genetic testing to identify the genetic basis for eye-brain connections. Additional work is needed to further explore these potential biomarkers. Overall, accurate, efficient, widely distributed and non-invasive tests that can help with early recognition of these diseases will improve the management of these patients using a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated. To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters. Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7–28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43–1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49–169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58–19.03, p < 0.007) were predictors of SCD on univariate analysis. Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further. [Display omitted] • Children with RASopathy associated hypertrophic cardiomyopathy (HCM) have a high risk for sudden cardiac death (SCD) • The HCM Risk-Kids risk prediction model used for children with non-syndromic HCM appears unsuitable for use in this cohort • Non-sustained ventricular tachycardia and unexplained syncope emerge as predictors of SCD • Larger collaborations are needed to validate these results and identify specific risk factors for SCD in this population [ABSTRACT FROM AUTHOR]

RAS regulation and signaling are largely accomplished by direct protein-protein interactions, making RAS protein dynamics a critical determinant of RAS function. Here, we report a crystal structure of GDP-bound KRASV14I, a mutated KRAS variant associated with the developmental RASopathy disorder Noonan syndrome (NS), at 1.5-1.6 Å resolution. The structure is notable for revealing a marked extension of switch 1 away from the G-domain and nucleotide-binding site of the KRAS protein. We found that this extension is associated with a loss of the magnesium ion and a tilt in the position of the guanine base because of the additional carbon introduced by the isoleucine substitution. Hydrogen-deuterium exchange MS analysis confirmed that this conformation occurs in solution, but also disclosed a difference in kinetics when compared with KRASA146T, another RAS mutant that displays a nearly identical conformation in previously reported crystal structures. This conformational change contributed to a high rate of guanine nucleotide-exchange factor (GEF)-dependent and -independent nucleotide exchange and to an increase in affinity for SOS Ras/Rac GEF 1 (SOS1), which appears to be the major mode of activation for this RAS variant. These results highlight a mechanistic connection between KRASA146T and KRASV14I that may have implications for the regulation of these variants and for the development of therapeutic strategies to manage KRAS variant-associated disorders. [ABSTRACT FROM AUTHOR]

Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. "RASopathies" is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a "RASopathy" to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS. [ABSTRACT FROM AUTHOR]

There is a paucity of cardiac surgery outcomes data for patients with Noonan syndrome (NS). Our objective was to evaluate early results in these patients. Between January 1999 and December 2015, 29 patients (18 males, 62%) with NS underwent cardiac surgery at our institution. Mean age was 23 ± 17.9 years; 12 (41%) were under 18 years of age. Fourteen patients (48%) had prior sternotomies. The primary operations for the main diagnosis were pulmonary valve/conduit replacement/repair (n = 14, 48%), septal myectomy for obstructive hypertrophic cardiomyopathy (n = 7, 24%), aortic valve replacement/repair (n = 4, 14%), atrial septal defect (ASD) repair (n = 2, 7%), and cardiac transplantation (n = 2, 7%). Concomitant procedures were performed in 24 patients (83%), most commonly right ventricular outflow tract reconstruction (n = 13, 45%), mitral valve repair/replacement (n = 7, 24%), and ASD repair (n = 6, 21%). Mean bypass and cross-clamp times were 88.8 ± 51 minutes and 54.7 ± 67 minutes, respectively. There was 1 early death (3%). Postoperative morbidity occurred in 18 patients (62%), most commonly arrhythmias (n = 14, 48%) or respiratory insufficiency/pneumonia (n = 6, 21%). There were 2 early reoperations and 4 early readmissions. Univariate factors associated with morbidity included male gender (P = 0.03) and longer cross-clamp time (P = 0.02). Median length of hospital stay was 6 days (interquartile range 5-10.5 days). Patients with NS frequently have multiple cardiac lesions requiring a broad spectrum of operations. Early mortality is low despite procedure complexity. Although early postoperative morbidity is common, patients overall do well with reasonable hospital lengths of stay. Additional studies are needed to evaluate long-term outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Highlights • This is the first report of embryonal rhabdomyosarcoma in a patient with a germline pathogenic variant in CBL , further broadening the CBL cancer predisposition spectrum. • This case report highlights the importance of germline testing for patients with cancer and constitutional features suggestive of an underlying syndrome, as well as the need to be able to pursue germline testing when an oncology assay is suggestive of a constitutional variant. • While cancer risk associated with a germline CBL mutation has not been precisely defined, systematic surveillance for both hematologic and solid malignancies is warranted. We believe that this is important information for the oncology and genetics community who evaluate and treat these patients. Abstract Germline pathogenic variants in CBL are associated with an autosomal dominant RASopathy and an increased risk for malignancies, particularly juvenile myelomonocytic leukemia. Herein, we describe a patient with clinical features of a Noonan-spectrum disorder who developed embryonal rhabdomyosarcoma of the bladder at age two years. Tumor analysis using the OncoKids® cancer panel revealed a CBL pathogenic variant: NM_005188.3:c.1100A>C (p.Gln367Pro). Sanger sequencing of peripheral blood DNA confirmed a de novo heterozygous germline variant. This is the first report of embryonal rhabdomyosarcoma in association with a germline CBL pathogenic variant, further broadening the CBL cancer predisposition spectrum. [ABSTRACT FROM AUTHOR]

Objective: This retrospective study aims to evaluate the incidence, presence of chromosomal anomalies and outcome of fetuses diagnosed with cystic hygroma colli in the first trimester in a single tertiary center.Study Design: A retrospective study was performed over a ten-years period from 2007 to 2017 of all fetuses with a first-trimester diagnosis of cystic hygroma. Maternal and fetal parameters were assessed with descriptive statistics.Results: A total of 185 singleton pregnancies were included. Chromosomal anomalies were present in 122 cases (65.9%). Sixty-three fetuses (34.1%) had a normal karyotype. Noonan syndrome was diagnosed in 6 cases using additional testing for RASopathies. In euploid fetuses, a major congenital anomaly was detected in 35 of 63 cases (56%) and if present, 91.4% had an abnormal fetal outcome compared to 32.1% if no structural anomaly was found (p < 0.01). Fetuses with a nuchal translucency thickness more than 10 mm and hydropic fetuses had a worse outcome.Discussion: Associated structural anomalies or hydrops fetalis are significant predictors for an abnormal outcome in pregnancies with first-trimester cystic hygroma and a normal karyotype. Cytogenetic evaluation and detailed sonographic evaluation are of great importance in the determination of the prognosis of pregnancies complicated by first-trimester cystic hygroma. [ABSTRACT FROM AUTHOR]

Abstract Congenital heart disease affects around 0.7% of liveborn infants and is the most frequent cause of death from congenital malformations. This review will consider some of the commoner genetic syndromes associated with congenital heart disease, the spectrum of cardiac defects observed in them and the associated features and comorbidities that may impact on the outcomes of cardiac surgery. [ABSTRACT FROM AUTHOR]

Vascular anomalies and some overgrowth disorders are typically caused by mosaic variants. Due to the frequent selection against these variants in blood, sensitive assays are required to detect them in affected tissues. The Vascular Anomalies and Mosaic Disorders (VMD4Kids) panel was developed using a Twist custom capture design with Unique Molecular Indexes (UMIs) targeting the coding sequence and intron/exon junctions of 218 genes. These genes are associated with capillary/lymphatic/ venous/arteriovenous malformations, lymphedema, vascular tumors, generalized body overgrowth, Noonan syndrome, skin pigmentary mosaicism and dermal hypoplasia, focal sclerotic bone lesions, and focal cortical dysplasia. Forty-five samples, previously clinically tested for single nucleotide variants (SNVs) and insertion/deletions (INDELs) were used to determine clinical accuracy (100%) and sensitivity (100%). The specimen types included formalin-fixed, paraffin-embedded (FFPE) and fresh-frozen tissue, skin fibroblasts and blood. Using a compressed average read depth of 1000X coverage; the limit of detection was determined to be 1% for both SNVs and INDELs at a minimum depth of coverage of 200X. Initial clinical testing has identified clinically relevant variants in the genes PIK3CA, KRAS, KDR, RHOA and TEK in a variety of vascular and overgrowth phenotypes. Variant allele frequencies ranged from 4.9%-32.6%. In conclusion, this test addresses the need for detection of low-level mosaic variants in an overlapping set of disorders and provides necessary molecular diagnoses for gene and variant specific therapies, including MEK, MTOR and PIK3CA inhibitors. [ABSTRACT FROM AUTHOR]

Summary Hyperactivating mutations in the non-receptor tyrosine phosphatase SHP2 cause Noonan syndrome (NS). NS is associated with cognitive deficits, but how hyperactivation of SHP2 in NS changes neuron function is not well understood. We find that mice bearing an NS-associated SHP2 allele (NS mice) have selectively impaired Schaffer collateral-CA1 NMDA (N-methyl-D-aspartate) receptor (NMDAR)-mediated neurotransmission and that residual NMDAR-mediated currents decay faster in NS mice because of reduced contribution of GluN1:GluN2B diheteromers. Consistent with altered GluN2B function, we identify GluN2B Y1252 as an NS-associated SHP2 substrate both in vitro and in vivo . Mutation of Y1252 does not alter recombinant GluN1:GluN2B receptor kinetics. Instead, phospho-Y1252 binds the actin-regulatory adaptor protein Nck2, and this interaction is required for proper NMDAR function. These results establish SHP2 and Nck2 as NMDAR regulatory proteins and strongly suggest that NMDAR dysfunction contributes to NS cognitive deficits. [ABSTRACT FROM AUTHOR]

Purpose Noonan Syndrome (NS) is an autosomal dominant disorder with many variable and heterogeneous conditions. The genetic basis for 20–30% of cases is still unknown. This study evaluates Iranian Noonan patients both clinically and genetically for the first time. Materials/methods Mutational analysis of PTPN11 gene was performed in 15 Iranian patients, using PCR and Sanger sequencing at phase one. Then, as phase two, Next Generation Sequencing (NGS) in the form of targeted resequencing was utilized for analysis of exons from other related genes. Homology modelling for the novel founded mutations was performed as well. The genotype, phenotype correlation was done according to the molecular findings and clinical features. Results Previously reported mutation (p.N308D) in some patients and a novel mutation (p.D155N) in one of the patients were identified in phase one. After applying NGS methods, known and new variants were found in four patients in other genes, including: CBL (p. V904I), KRAS (p. L53W), SOS1 (p. I1302V), and SOS1 (p. R552G). Structural studies of two deduced novel mutations in related genes revealed deficiencies in the mutated proteins. Following genotype, phenotype correlation, a new pattern of the presence of intellectual disability in two patients was registered. Conclusions NS shows strong variable expressivity along the high genetic heterogeneity especially in distinct populations and ethnic groups. Also possibly unknown other causative genes may be exist. Obviously, more comprehensive and new technologies like NGS methods are the best choice for detection of molecular defects in patients for genotype, phenotype correlation and disease management. [ABSTRACT FROM AUTHOR]

Introduction Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. Methods The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. Results The study included 27 individuals (67% males) with an average age of 10.4 years (range 6–18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11 , five in SOS1 and two in SHOC2 . The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52–85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19–56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. Conclusion Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS. [ABSTRACT FROM AUTHOR]

The following is a case report of 6 patients with Noonan syndrome (NS) and/or a related RASsopathy that also have evidence of left ventricular noncompaction cardiomyopathy (LVNC). Noonan syndrome,a type of RASopathy, is an autosomal dominant disorder that is typically associated with congenital heart defects and hypertrophic cardiomyopathy. There have been minimal reports of Noonan syndrome or other RASopathy and the association of LVNC. This report promulgates 6 nonrelated cases of Noonan syndrome or unspecified RASopathy and LVNC. [ABSTRACT FROM AUTHOR]

• An objective approach is proposed for speech characterization of genetic syndromes. • The innovative approach concerns the number listing task of the SIFEL protocol. • The speech phenotype is assessed with acoustical analysis and entropy measures. • Objective acoustical features are estimated with the BioVoice software tool. • The proposed approach could be helpful in syndrome diagnosis and long-term monitoring. For several disorders and diseases, quantitative acoustical analysis represents a non-invasive approach for assessing voice pathologies. Recently, methods were proposed to characterize the speech phenotype of some genetic syndromes, but the analysis was often limited to sustained vowels. Thus, more evidence is needed to confirm the usefulness of acoustical analysis in such cases. In this work, we evaluated if the acoustical analysis of a number listing task (numbers in ascending order from 1 to 10) may add helpful information for characterizing the speech phenotype related to the Italian language for three genetic syndromes: Down, Noonan, and Smith-Magenis. For each syndrome, 24 subjects were analysed, along with 15 control subjects. Several acoustical features and entropy indexes were estimated using the BioVoice software and MATLAB routines. Differences between pathological and control cases and possible inter-syndromes differences were evaluated. Statistical results suggest that overall differences might exist between controls and subjects with genetic syndromes. Moreover, entropy indexes gave significant results also when the acoustical features did not detect differences. Preliminary results confirmed the usefulness of both acoustical analysis and entropy techniques for the analyzed syndromes: for some syndromes, a specific speech phenotype exists that might support the clinician, highlighting the syndrome's characteristics not yet exploited. An innovative approach is proposed to characterize the speech phenotype of some genetic syndromes based on both quantitative acoustical analysis and entropy measures of a speech task. The proposed non-invasive approach might be helpful for diagnosis, long-term monitoring, and follow-up of such syndromes. [ABSTRACT FROM AUTHOR]

Our pediatric, tertiary care institution developed a translational protocol to evaluate the genomic landscape of hematologic disease, solid tumors, and somatic disease among pediatric and adolescent patients. We aim to provide results that refine diagnosis, identify targeted therapeutics, determine eligibility for clinical trials, inform prognosis, and identify germline cancer predisposition. Translational research findings are discussed at multidisciplinary conferences, involving clinicians, pathologists, surgeons, radiologists, radiation oncologists, and genomic medicine. Findings that may impact patient care are confirmed in our CAP-accredited, CLIA-certified clinical lab and reported in the patient medical record. Over four years, 448 patients were nominated onto this protocol, 380 (85%) consented, and 346 (77%) sequenced using paired disease-involved/germline comparator exome sequencing and RNA-sequencing. DNA-based methylation was performed on a subset of solid tumor cases (n=188). Germline findings were identified in 99 (22%) patients, including 9 with Li-Fraumeni syndrome, 6 with neurofibromatosis type 1 (NF1), 5 with rhabdoid tumor predisposition syndrome (RTPS), and 3 with Noonan syndrome. Notably, a diagnosis was established from this translational testing with follow up clinical confirmation and appropriate genetic counseling for 11 (2.5%) individuals (Li-Fraumeni syndrome n=5, Lynch syndrome n=2, schwannomatosis n=2, Noonan syndrome n=2, RTPS n=1, NF1 n=1). Outcome data was captured on 251 (56%) individuals thus far, with refinement/reclassification of diagnosis for 82 (33%) individuals, refinement of treatment for 32 (13%) individuals, and refined prognostication for 66 (26%) individuals. Through multidisciplinary collaboration with a team of clinician colleagues, we demonstrated clinical utility in identifying germline disease and characterization of medically meaningful somatic findings. [ABSTRACT FROM AUTHOR]

Background RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. Methods A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CA rdiac R asopathy NET work (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. Results Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20 years, respectively. Restricted estimated mean survival at 20 years follow-up was 19.6 years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age < 2 years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. Conclusions The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death. [ABSTRACT FROM AUTHOR]

Existing literature only reports a few patients with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) who underwent cochlear implantation (CI). The present study describes four NS patients and one NSML patient with a PTPN11 mutation. They all had severe to profound hearing loss, and they received a CI. The age at which the CI surgery occurred ranged from 1 to 13 years old, and the audiological results in all five patients improved after the CI. Otological and audiological examinations in NS and NSML are important, and for those with severe hearing loss, the CI surgery improved the audiological outcome regardless of age. [ABSTRACT FROM AUTHOR]

Noonan syndrome is a well-known genetic condition associating congenital heart defects, short stature, and distinctive facial features. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most frequent cardiac abnormalities, the latter being associated with a higher mortality. Here we report for the first time, a case of congenital left main coronary artery atresia in a Noonan syndrome associated with RIT1 variant, leading to unrescued sudden death. This case-report supports the already-suspected severity of the RIT1 -related Noonan syndrome compared to average Noonan syndrome, and should encourage clinicians to be very cautious with these patients. [ABSTRACT FROM AUTHOR]

Glutamate is the major excitatory neurotransmitter in the central nervous system, and related signaling involves both AMPA and NMDA subtype receptors. The expression of glutamate receptors is dynamically regulated during development. Recent studies showed that the dysregulation of glutamate receptor expression and function is associated with neurodevelopmental disorders including intellectual disability. Previously, a Noonan syndrome (NS)-associated SHP2 mutation (SHP2 D61G ) was shown to increase the synaptic delivery of AMPA receptor, subsequently impairing synaptic plasticity and learning in adult mice. However, how the mutant SHP2 affects glutamate receptor expression during development is not known. Here, we found that the SHP2 D61G differentially regulates the expression of AMPA and NMDA receptors depending on the stage of neuronal maturation. In cultured neurons (immature stage; DIV 6), overexpression of SHP2 D61G significantly increased the average size and the number of NMDA receptor-containing particles, but not those with AMPA receptors. In early matured neurons (DIV 12), SHP2 D61G significantly increased only the average size of AMPA receptor particles, and subsequently increased their number in matured neurons (DIV 18). Importantly, all the changes described above for SHP2 D61G neurons were reversed by inhibiting MAPK. These data demonstrate that the increased activation of MAPK signaling pathway by SHP2 D61G could deregulate the surface expression of synaptic receptors during neuronal development, which likely contributes to cognitive impairments in NS patients. [ABSTRACT FROM AUTHOR]

Shp2 is a classical non-receptor protein tyrosine phosphatase (PTP) involved in many human diseases such as Noonan syndrome and tumors, and identified as a potential therapeutic target. In order to find a potent and selective Shp2 inhibitor, we screened a diverse collection of the secondary metabolites from endophyte fungi using an in vitro enzyme assay, and finally identified a potent Shp2 inhibitor, HLP46 (demethylincisterol A 3 ) from Pestalotiopsis sp . HLP46 was reported to have anti-tumor and anti-inflammation activity previously. We provide the first evidence that HLP46 is an inhibitor of the Shp2. HLP46 shows high selective inhibition of Shp2 over Shp1, PTP1B, Lyp, STEP, PTPRA and Cdc25b. Enzymatic kinetic analyses showed that HLP46 is a non-competitive inhibitor of Shp2. HLP46 interrupts Gab1-Shp2 association and blocked Shp2-dependent activation of the Ras/ERK signal pathway induced by EGF. Furthermore, HLP46 decreased Src activation and inhibit tumor cell migration and invasion. As expected, HLP46 has no effect on the Shp2-independent activation of ERK induced by PMA or on the activation of the PI3K/Akt pathway. We testified therapeutic efficacy targeting both Shp2 and PI3K in MCF7 cells. HLP46 does not show any synergistic inhibition with PI3K inhibitor in suppressing cell growth. Collectively, these results suggest that HLP46 is a selective Shp2 inhibitor and could inhibit Shp2-dependent cell signaling in human cells. [ABSTRACT FROM AUTHOR]

Noonan Syndrome (NS) is a genetic disorder with a predisposition for cardiac anomalies that can lead to heart transplantation (HT) secondary to end stage failure. Few reports exist on outcomes of patients with NS who undergo HT. This report describes the medium- and long-term outcomes following HT in patients with NS at a single center. Four patients out of 77 HT recipients over 12 years had NS. Three patients underwent HT at our center. Three patients (75%) were female and 3 patients (75%) had a RAF1 mutation. Median age at HT was 7 months (IQR 6.5-7.8) and post-HT survival was 100% with a median age of 4.7 years (IQR 3.8-6.2). Three patients (75%) had outflow tract obstruction and only 1 (25%) had documented arrhythmias pre-HT. UNOS status at HT was variable with 2 patients (50%) as 1A, 1 patient (25%) as 1B, and 1 patient (25%) as status 2. Complications post-HT included severe acute cellular rejection (25%), lymphatic disease (25%), Posterior Reversible Encephalopathy Syndrome (PRES) (25%), recurrent infections (50%), and pleural and/or pericardial effusions (50%) (Table 1). One patient (25%) had multiple cardiac arrests and seizures post-HT, but not PRES. This study contributes important data on outcomes and complications post-HT in patients with NS. This information may inform evaluation and listing of patients with NS to better foresee complications and their management. [ABSTRACT FROM AUTHOR]

Patients with Noonan syndrome typically have a target height <2 standard deviations compared to the general population, and half of the affected adults remain permanently below the 3rd centile for height, though their short stature might result from a multifactorial etiology, not-yet fully understood. The secretion of growth hormone (GH) following the classic GH stimulation tests is often normal, with baseline insulin-like growth factor-1 (IGF-1) levels at the lower normal limits, but patients with Noonan syndrome have also a possible moderate response to GH therapy, leading to a final increased height and substantial improvement in growth rate. Aim of this review was to evaluate both safety and efficacy of GH therapy in children and adolescents with Noonan syndrome, also evaluating as a secondary aim the possible correlations between the underlying genetic mutations and GH responses. • Noonan syndrome is a multisystem autosomal dominantly inherited disorder caused by dysregulation of the RAS-MAPK signal pathway. • Patients typically have a target height <2 standard deviations compared to the general population, and half of affected adults remain permanently below the 3rd centile for height, though their short stature might display a multifactorial etiology. • The present review discusses on available data dealing with growth hormone efficacy and safety in children and adolescents with Noonan syndrome. [ABSTRACT FROM AUTHOR]

Noonan syndrome and related conditions (RASopathies) are known to be associated with abnormalities in many organ systems. It is our impression that few otolaryngologists are familiar with the manifestations of these syndromes and we therefore reviewed our hospital's patient cohort to identify the prevalence of ear, nose and throat disorders in these children. We cross-referenced various hospital department databases (otolaryngology, audiology, cardiology, haematology and genetics) to try to identify as many children with Noonan and other RASopathies as possible. We then performed a retrospective review of electronic patient records. We identified 67 children with Noonan, Costello, LEOPARD and other RASopathy syndromes. Around half have been seen in otolaryngology and audiology clinics. Otitis media with effusion requiring ventilation tubes occurred in 4% of children. 10% have suffered recurrent acute otitis media. 9% have a sensorineural hearing loss. 7% have undergone adenotonsillectomy for obstructive sleep apnoea. Airway anomalies and head and neck malformations occur but are rare. Children with Noonan and other RASopathies present commonly to otolaryngology and audiology clinics. The prevalence of sensorineural hearing loss is high and audiological screening is likely to be worthwhile. Surgeons should be aware that complications of surgery are common and can be very severe, especially in those with cardiac anomalies. [ABSTRACT FROM AUTHOR]

We present an unusual association between Noonan syndrome and tetraventricular hydrocephalus, caused by fourth ventricle outlet obstruction, in a 5-year-old boy. Magnetic resonance imaging showed a diverticular enlargement of the left foramen of Luschka, with compression of the facial nerve that resolved following treatment of hydrocephalus by endoscopic third ventriculostomy. [ABSTRACT FROM AUTHOR]

Noonan syndrome is characterized by variable phenotypic expressivity with characteristic dysmorphic facial features, varying degrees of intellectual disability, developmental delay, short stature, and congenital heart defects in 50–80%. Other findings include a webbed neck, cryptorchidism, coagulation defects and eye abnormalities. Thus far, Noonan syndrome has mainly been attributed to heterozygous pathogenic variants in 10+ different genes, with the rare exception of cases due to biallelic pathogenic variants in LZTR1. Recently, homozygous loss-of-function variants in SPRED2 have been identified as a cause of a recessive Noonan syndrome-like phenotype. We present the phenotypes of two additional patients with homozygosity for a previously unreported loss-of-function variant in SPRED2 , thereby adding relevant clinical information about the recently described Noonan syndrome-like SPRED2 -related phenotype. [ABSTRACT FROM AUTHOR]

Noonan syndrome is a common developmental disorder characterized by distinctive facial dysmorphism, short stature, congenital heart defects, pectus deformity, and developmental delay. It is related to the abnormal activation of genes involved in the RAS-MAPK signaling pathway, more than a dozen of which can be affected. However, mutations of the RRAS2 gene are rare, with only 6 different RRAS2 variants in 13 patients reported to date. In this case report, whole-exome sequencing revealed a novel heterozygous variant in the RRAS2 gene NM_012250: c.212G > A, p.(Gly71Glu). Phenotypically, our patient had typical Noonan syndrome-related clinical manifestations consistent with published reports, such as short stature, facial dysmorphism, short neck, patent foramen ovale, moderate global developmental delay, and hearing impairment. In addition, our patient also had a distal middle finger deformity and hair defect, which have not been reported in previous cases. We analyzed the clinical characteristics of all patients with Noonan syndrome caused by RRAS2 variants and reviewed the literature. This discovery expands the genetic and phenotypic spectrum of Noonan syndrome. [ABSTRACT FROM AUTHOR]