RARE DISEASE
Noonan syndrome
Noonan syndrome
Noonan syndrome
Drug discovery
3
drugs
With orphan designations
Overview
Noonan syndrome is an autosomal dominant RASopathy caused by mutations in genes regulating the RAS/MAPK pathway (PTPN11, SOS1, RAF1). It features congenital heart defects (50-80%), short stature, distinctive facies, bleeding diathesis, and developmental delays. Management focuses on multisystem surveillance, growth hormone therapy, and surgical/cardiac interventions [1][2][6][12][16].
Burden
Medical complexity: 3.7 affected organ systems on average; frequent cardiac/GI/endocrine comorbidities [14][16].
Healthcare utilization: 3× higher hospitalization rates than peers; lifelong cardiac/developmental monitoring [4][14].
Psychosocial impact: 25% with learning disabilities, delayed milestones, caregiver stress, and reduced QoL [4][14][16].
Therapies
Cardiac: Surgical repair for pulmonary stenosis, septal defects; β-blockers for hypertrophic cardiomyopathy [1][3][13].
Growth: Recombinant growth hormone for short stature (initiated at 4–5 years) [3][12][13].
Multidisciplinary care: Hematology (bleeding disorders), endocrinology, developmental therapies, and genetic counseling [1][6][13].
Categories: rare bone diseases, rare cardiac diseases, rare cardiac malformations, rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare infertility disorders, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
549 drug discovery papers about Noonan syndrome, with 1 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
549 drug discovery papers about Noonan syndrome, with 1 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-09-21 | Generation of Valvular Interstitial Cells from Human Pluripotent Stem Cells
Abstract Heart valves are living structures whose sophisticated functions are mediated by a specialized population of mesenchymal cells known as valvular interstitial cells (VICs). Given their central role in valve homeostasis, VICs represent a promising cell population for studying heart valve diseases and developing novel therapies to treat them. Here, we describe a strategy for generating VICs from human pluripotent stem cells (hPSCs) by stage-specific manipulation of developmental signalling pathways. Our results demonstrate that hPSC-derived VICs show a high transcriptional similarity to primary human fetal VICs and can secrete key proteins of the valve extracellular matrix. We further investigate the heterogeneity of hPSC-derived VICs and identify two major subpopulations with distinct molecular and functional properties, mirroring the cellular diversity observed in vivo . Finally, we utilize an in vitro model of Noonan syndrome to demonstrate that hPSC-derived VICs can accurately recapitulate key aspects of valve disease. Collectively, these findings provide a reproducible method for the scaled generation of bona fide hPSC-derived VICs and establish their utility in disease modelling and tissue engineering applications. Clinical Perspective What is new? - We established a robust platform to generate bona fide valvular interstitial cells (VICs) from human pluripotent stem cells (hPSCs), recapitulating native VIC identity and function. - We delineated signaling pathways that promote the development of two distinct VIC subsets and identified a surface marker to distinguish between them. What are the clinical implications? - A renewable, human-specific source of VICs enables precise mechanistic studies of valve development and disease that are not possible with limited surgical specimens or animal models. - This platform creates opportunities for therapeutic applications, including drug discovery and tissue engineering approaches for valve repair.
2023-06-02 | Generation of a genetically-modified induced pluripotent stem cell line harboring a Noonan syndrome-associated gene variant MRAS p.G23V.
Patients harboring causative gene variants in RAS GTPase MRAS develop Noonan syndrome and early-onset hypertrophic cardiomyopathy. Here, we describe the generation of a human iPSC line harboring the Noonan syndrome-associated MRAS p.G23V variant by using CRISPR/Cas9 technology. The established MRASG23V iPSC line allows to study MRAS-specific pathomechanisms and to test novel therapeutic strategies in various disease-relevant cell types and tissues.
2022-06-09 | Noonan syndrome: cochlear implantation in the setting of cochlear nerve deficiency.
Noonan syndrome (NS) is a congenital disorder characterized by a wide heterogeneity in clinical and genetic features. Hearing loss can frequently occur in NS, although not always mentioned in its diagnostic criteria. We are reporting on a child with an established NS who underwent bilateral cochlear implantation (CI) in the setting of cochlear nerve deficiency. We present the case of a child-girl affected by NS. Newborn hearing screening and audiological evaluations reveled an asymmetric sensorineural hearing loss (SNHL), profound at left ear and severe at right ear. Hearing aids were fitted at the age of six months. Brain magnetic resonance imaging showed hypoplastic cochlear nerves. Due to progressive worsening of the hearing thresholds and inappropriate speech development, at the age of 2 years she underwent a left-sided cochlear implantation. Four years later, right ear was also implanted. Six years after the first surgery, a partial extrusion of the electrode array was noticed. Explantation and reimplantation of a new device was performed, adopting a subtotal petrosectomy approach. The patient reached a score of 95% in open-set speech perception tests. Hearing loss is a frequent finding in patients with NS; however, its nature and severity are very heterogenous. In consideration of the possible progression of SNHL, audiological follow-up in NS patients must be carefully and periodically performed so as to early detect worsening of hearing threshold. If indicated, cochlear implantation should be considered, taking account of audiological and systemic features of this syndrome.
2020-07-13 | Cardiac transplantation in children with Noonan syndrome.
NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS-specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post-discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.
2017-11-01 | Breast reconstruction in a patient with Noonan syndrome
Noonan syndrome (NS) is a relatively common genetic disorder with an autosomal dominant inheritance pattern affecting 1 in 1000–2500 births. Patients with this syndrome present with characteristic facial, musculoskeletal, cardiac and endocrine abnormalities. Lack of postpubertal breast development is a common manifestation of this syndrome and may result in severe hypomastia and a masculine appearance of the female chest. We report the first case of breast reconstruction in a 24-year-old woman with NS who lacked postpubertal breast development. Technical considerations for addressing the existing chest wall deformity, implant pocket selection as well as emphasis on the role of the plastic surgeon are presented.
small molecules
2026-08-11 | RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial
Background Noonan syndrome (NS) is a relatively common developmental disorder caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, leading to multisystem involvement including short stature, skeletal abnormalities, cardiac defects, and neurocognitive impairment. Preclinical studies suggest that statins attenuate RAS/MAPK pathway hyperactivation and improve neurocognitive deficits, growth impairment, and survival in experimental models. However, no randomised controlled trial has evaluated the efficacy and safety of statin therapy in children with NS. We aimed to evaluate the efficacy and safety of simvastatin in children with NS. Methods In this national, multicentre, double-blind, placebo-controlled phase 3 trial conducted across 13 French centres, children aged 6–15 years with genetically confirmed NS and growth impairment were randomly assigned (1:1) to receive oral simvastatin (10 mg/day during month 1, 20 mg/day during month 2, then 20 or 40 mg/day according to age) or matching placebo once daily for 12 months. The primary outcome was the change in serum insulin-like growth factor 1 (IGF-1) levels. Secondary outcomes included growth, bone, cardiac, metabolic, and behavioural parameters. Analyses followed the intention-to-treat principle using mixed-effects and adjusted regression models. The trial was prospectively registered at ClinicalTrials.gov (NCT02713945). Findings Fifty-three children were randomised (26 simvastatin, 27 placebo), and 49/53 (92.5%) completed the study. After 12 months, simvastatin did not significantly improve IGF-1 levels compared with placebo (between-group difference −0.08 log ng/mL, 95% CI −0.18 to 0.01; p=0.08). No differences were observed between groups for height, growth velocity, bone mineral density, metabolic measures, or behavioural outcomes. Simvastatin was associated with lower circulating Dickkopf-related protein 1 (DKK1) concentrations (−0.27, 95% CI −0.52 to −0.01; p=0.04), a biomarker of bone metabolism, and a higher ratio of early-to-late diastolic mitral annular velocity (Ea/Aa ratio) (0.27, 95% CI −0.004 to 0.55; p=0.05), an echocardiographic parameter related to left ventricular diastolic function. However, these isolated findings were of borderline statistical significance, and were not accompanied by corresponding clinical improvements. Treatment was generally well tolerated. One serious adverse event occurred in the simvastatin group and was considered doubtfully related to study treatment. Interpretation In children with NS, 12 months of simvastatin did not result in significant improvements in the primary endpoint or in major outcomes of clinical relevance under the conditions tested. Changes in DKK1 concentrations and the Ea/Aa ratio should be interpreted cautiously as exploratory secondary findings requiring confirmation in adequately powered studies. Further research is needed to explore alternative treatment strategies and more direct approaches to RAS/MAPK pathway modulation. Funding French Ministry of Health.
2026-07-30 | Effects of MEK-inhibitor treatment in infants with lymphatic abnormalities in noonan syndrome.
Noonan syndrome (NS) is a genetic disorder associated with dysregulation of the RAS/MAPK signaling pathway and is frequently accompanied by lymphatic abnormalities. These lymphatic complications can lead to severe clinical manifestations, including chylous effusions and respiratory compromise, particularly in infants. Management of such complications is often challenging, and conventional therapies may be insufficient in severe cases. Recently, targeted therapies affecting the RAS/MAPK pathway, such as MEK inhibitors, have emerged as a potential treatment option for patients with refractory lymphatic disease. In this context, the present study describes our initial clinical experience with MEK inhibitor therapy using Trametinib in infants with Noonan syndrome and lymphatic abnormalities. Six infants with genetically confirmed NS (3 female, 3 male; mean age 0.5 ± 0.72 years) presenting with lymphatic abnormalities and intractable chylous effusions were treated with Trametinib. Clinical presentation was assessed at baseline as well as at 6-week and 1-year follow-up. Dedicated MR lymphangiography was performed at baseline and after one year, and lymphatic abnormalities were rated using a 6-point Likert scale. Possible adverse events were documented. After one year of therapy, considerable clinical improvement was observed in all patients. None of the patients required chest drainage and no clinical signs of chylothorax were present. Follow-up MR lymphangiography demonstrated a decrease in pleural effusions in all cases, with no residual fluid in three patients and only minimal residual fluid in the remaining three. Pathologic pulmonary and pleural lymphatic perfusion decreased in all cases (median 3 vs. 1). However, lymphatic imaging did not demonstrate normalization of lymphatic anatomy or flow in any patient. Overall, in this exploratory analysis Trametinib therapy resulted in considerable clinical improvement in infants with lymphatic abnormalities associated with Noonan syndrome, while MR lymphangiography showed only limited remodeling of the central lymphatic system over one year of treatment without normalization of lymphatic anatomy or lymphatic flow.
2026-06-16 | Lymphatics in Noonan Syndrome
In this thesis we describe the use of zebrafish (Danio rerio), to study lymphangiogenesis in health and in the presence of patient associated Noonan syndrome mutations. In chapter 1 we give a general overview of the subjects discussed in this thesis, namely the function of the lymphatic vasculature, lymphangiogenesis in the zebrafish and the congenital disorder Noonan syndrome. In chapter 2 we review the current knowledge of the role of SHP2 variants in rare diseases and advances in the understanding of its pathogenesis using model systems. These two chapters provide the background for the scientific questions we pursue in the subsequent experimental chapters. In chapter 3 we describe the consequences of the absence of the ptpn11a and ptpn11b genes in zebrafish embryos. We show that all double mutant zebrafish embryos completely lack their lymphatic vasculature including the lymphatics in the head. In addition, we show that the absence of ptpn11a and ptpn11b targets the lymphatic vasculature, but not the venous connections established by the same cell population. In chapter 4 we describe how we generated zebrafish knockouts for both sos1 and sos2. We show that loss of sos1 is viable but knockout of sos2 is embryonically lethal. We show that all double mutant zebrafish embryos lack an intact lymphatic vasculature including the lymphatics in the head. Additionally, sos double mutants also displayed defects in the establishment of venous connections in the zebrafish trunk. In chapter 5 we describe the establishment of a zebrafish line with a patient-associated Noonan syndrome mutation in Sos2 and compare this line with a previously characterized zebrafish model for Noonan Syndrome. We show a lymphatic phenotype, including vasodilation of the thoracic duct (TD), whereas lymphangiogenesis was normal in ptpn11a+/D61G embryos. We demonstrate that treatment with the MEK inhibitor trametinib, which is currently being used in the clinic, effectively rescued the dilated TD associated with the Sos2+/M264R mutation, highlighting the potential of our model to study treatment options in zebrafish. In chapter 6 the clinical outcomes of trametinib therapy in eight patients with Noonan syndrome-like RASopathies and central conducting lymphatic anomaly was assessed, each offering unique insights into the therapeutic efficacy of MEK inhibition. Finally, chapter 7 provides a summarizing discussion of the observations and findings of the previous chapters in the context of implications for further research. To conclude, the hope is that an integrated understanding of Noonan syndrome and lymphangiogenesis will not only elucidate fundamental developmental biological questions, but also pave the way for better management of lymphatic diseases in patients with Noonan syndrome.
2026-06-08 | Trametinib Therapy for Hypertrophic Cardiomyopathy and Pulmonary Hypertension in a Child With RAF1-Related Noonan Syndrome (p.Ser257Leu): A Case Report.
This case describes a female infant with RAF1-related Noonan syndrome who developed severe hypertrophic obstructive cardiomyopathy, pulmonary hypertension, and cardiorespiratory failure that responded to trametinib treatment but ultimately progressed to death following dose tapering and discontinuation of therapy. To the best of our knowledge, this is the first case with detailed respiratory information in a trametinib-treated patient with RASopathy-related pulmonary disease.
2026-05-29 | Long-term clinical benefit of mavacamten for hypertrophic cardiomyopathy in a patient with RAF1-associated Noonan syndrome-case report.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is frequently complicated by left ventricular outflow tract (LVOT) obstruction. While most cases are caused by sarcomeric mutations, up to 10% represent non-sarcomeric or syndromic phenocopies, including Noonan syndrome (NS). Noonan syndrome is a RASopathy in which mutations in genes such as RAF1 predispose to HCM through dysregulation of the Ras/MAPK pathway and are often associated with severe LVOT obstruction. Cardiac myosin inhibitors have demonstrated efficacy in sarcomeric obstructive HCM, but patients with syndromic HCM were excluded from pivotal clinical trials. We report a 29-year-old woman with long-standing obstructive HCM and NYHA class III symptoms, angina, and dizziness. Multimodality imaging demonstrated asymmetric septal hypertrophy (maximal wall thickness 20 mm), focal intramural late gadolinium enhancement, and dynamic LVOT obstruction reaching 55 mmHg during exercise. Owing to progressive obstruction, the patient was enrolled in the EXPLORER-HCM trial. During follow-up exceeding 5 years, treatment resulted in sustained reduction of LVOT gradients, improvement in functional status to NYHA class II, and complete resolution of angina and presyncope, without adverse effects. Genetic testing performed during trial participation identified a heterozygous likely pathogenic RAF1 variant, confirming Noonan syndrome-associated HCM. This case report demonstrates durable clinical and haemodynamic benefit of myosin inhibition in RAF1-associated Noonan syndrome HCM. This finding suggests that possible downstream hypercontractility may represent a shared and therapeutically targetable mechanism across sarcomeric HCM and selected syndromic phenocopies.
gene therapies
2026-06-03 | A Rras2-BMPR2 feedback loop sustains osteogenesis and represents a therapeutic target for osteoporosis.
Ras-related protein 2 (Rras2) mutations are linked to Noonan syndrome, a disorder characterized by skeletal dysplasia and growth deficits. However, the role of Rras2 in bone homeostasis remains poorly defined, hindering the development of clinical interventions. Here, we show that Rras2 deficiency in mice leads to osteopenia, reduced bone strength, and impaired osteogenesis, recapitulating the clinical features of human patients. Mechanistically, Rras2 promotes osteogenic differentiation of bone marrow mesenchymal stem cells and supports bone regeneration. At the molecular level, Rras2 sustains BMP signaling by blocking Smurf1-dependent ubiquitination and degradation of BMPR2; in turn, BMP signaling enhances Rras2 transcription. Osteoporotic mice exhibit marked reduction in Rras2 expression in bone, and adeno-associated virus 9 (AAV9)-mediated restoration of Rras2 rescues bone loss. Our findings identify a Rras2-BMPR2 positive feedback loop that is critical for bone homeostasis and provide a therapeutic avenue for osteoporosis and Noonan syndrome.
2026-01-01 | Assessment of CRISPR-based disruption of a cryptic splice site in LZTR1 causing Noonan syndrome
Noonan syndrome is a relatively common congenital multisystemic disorder characterised by a broad spectrum of coexisting phenotypic features. It most frequently affects the heart, rendering it the second most common congenital heart disease after trisomy 21. Cardiac involvement, particularly the presence of hypertrophic cardiomyopathy, significantly increases mortality and morbidity of affected patients. Noonan syndrome is the most common representative of the disease group of RASopathies, because it is caused by mutations in genes encoding proteins involved in the RAS/MAPK pathway leading to RAS/MAPK signalling hyperactivity. More recently, loss-of-function mutations in leucine zipper like transregulator 1 (LZTR1) have been introduced as causes for Noonan syndrome due to its pivotal role in the ubiquitination and degradation of RAS proteins. Insufficient degradation of RAS proteins culminates in RAS/MAPK signalling hyperactivity. Previously, our laboratory presented a case of two patients with NS caused by loss-offunction mutations in LZTR1. The mutation in intron 16 is a point mutation that is recognised as an additional splice site leading to the incorporation of a cryptic exon in the mRNA transcript. The cryptic exon contains a stop codon, so no functional LZTR1 protein is translated leading to the expression of NS. This study presents an efficient and safe single-cut CRISPR/Cas9-based genetic editing approach aiming at the destruction of an intronic mutation in a model of the common LZTR1-associated RASopathy NS. High reproducibility and predictability of induced insertions and deletions by DNA repair mechanisms were discovered presenting a clinically translatable CRISPR/Cas9-mediated genome editing approach, that featured low off-target editing and is highly efficient in rehabilitating LZTR1 function and thereby reducing RAS protein levels. However, additional research is needed to translate the genome editing strategy explored in this study into non-dividing cardiomyocytes.
2025-05-28 | Advancing CRISPR gene therapy for Noonan syndrome: Targeting recurrent LZTR1 variants with all-in-one Cas9 and base editors in patient-derived iPSC-cardiomyocytes
Pathogenic variants in LZTR1 are causative for Noonan syndrome with early onset of a severe hypertrophic cardiomyopathy. Despite high clinical relevance, therapeutic options are highly limited, and no curative treatment exists. In this thesis, different CRISPR-based gene editing approaches were evaluated in a preclinical model of Noonan syndrome-associated hypertrophic cardiomyopathy based on patient-derived induced pluripotent stem cells differentiated into ventricular cardiomyocytes. The findings revealed that classical CRISPR-Cas9 gene editing was not able to rescue the disease pathology in vitro. In contrast, base editing efficiently corrected the pathogenic variant and rescued LZTR1 function in patient-specific cardiomyocytes, demonstrating a suitable strategy for a curative therapy for Noonan syndrome caused by recessive LZTR1 variants.
2024-07-29 | Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
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 LZTR1L580P 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 LZTR1L580P-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 LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.
2024-05-17 | Functional CRISPR repair of induced pluripotent stem cells from patients with Noonan syndrome-associated cardiac hypertrophy
Noonan syndrome (NS) is a multisystemic disorder and characterised by its vast clinical variety including craniofacial dysmorphism, short stature and congenital heart defects resulting in severe pulmonary stenosis, hypertrophic cardiomyopathy (HCM), and other cardiac anomalies. With an estimated prevalence of one in 1000 to 2500 live births and a common autosomal-dominant inheritance, NS is the second most frequent congenital heart disease after trisomy 21. Caused by mutations encoding the RAS/MAPK signaling pathway and its components, NS is classified as a RASopathy (Roberts et al. 2013). Exploration of biallelic autosomal-recessive loss-of-function mutations within Leucine Zipper Like Transcription Regulator 1 (LZTR1) in cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) allowed identification of the underlying pathomechanism causing severe-onset NS-associated HCM (Hanses et al. 2020). LZTR1 is known to attenuate RAS activity through ubiquitination and is hypothesised to act as a 'RAS-killer', inhibiting RAS-hyperactivity, with cellular processes disinhibited upon loss-of-function (Abe et al. 2020). In-depth molecular and functional studies of patient-specific iPSC-CMs recapitulated the hypertrophic disease phenotype showing severely elevated RAS/MAPK signaling levels and impaired calcium handling (Hanses et al. 2020). This project was able to correct, reverse and thus repair the disease-causing deep-intronic mutation c.1943-256C>T in LZTR1 in patient-specific iPSCs utilizing CRISPR/Cas9 as a precise genome editing tool. The intronic editing approach chosen to disrupt the disease-causative additional donor splice site, thereby preventing installation of a cryptic exon, restored the expression of functional LZTR1. Furthermore, the isogenic-CRISPR-controls confirmed the families' mutations as disease-causing. The extensive in vitro exploration of the CRISPR-corrected-iPSC-CMs demonstrated a reversal of hypertrophy by normalised cell size compared to hypertrophic NS-iPSC-CMs, as well as attenuation of RAS protein to WT levels (Hanses et al. 2020). By combining molecular approaches with structural and functional investigations, this study ultimately led to a better understanding of the underlying disease pathomechanisms of this severe phenotype of NS. This improved understanding may pave the way for more effective diagnostic and therapeutic approaches in patient-specific precision medicine. In conclusion, this study presented an efficient, safe, and clinically translatable CRISPR-based gene therapy targeting a deep-intronic mutation in LZTR1 to cure the NS-associated pathology in a preclinical iPSC-CM screening platform. Translation of this CRISPR-based strategy could lead to the development of a promising therapeutic approach for the clinic (Knauer et al. 2024).
proteins
2026-06-29 | Model-based somapacitan dosing and IGF-I response in children born SGA or with ISS, Noonan or Turner syndromes.
The weekly insulin-like growth factor I (IGF-I) profile for children and adolescents treated with long-acting growth hormone differs from that of daily growth hormone (GH). The objective of this study is to provide guidance on the use of once-weekly somapacitan and IGF-I monitoring in prepubertal short children and adolescents born small for gestational age (SGA) or with idiopathic short stature (ISS), Noonan syndrome (NS), or Turner syndrome (TS). Modeling, including population pharmacokinetic/pharmacodynamic (PK/PD) modeling, were utilized, analyzing IGF-I data from 4 clinical studies, including 2 phase 3 trials (REAL8: NCT05330325; REAL9: NCT05723835) involving children and adolescents born SGA (N = 80), ISS (N = 69), NS (N = 62), and TS (N = 79), along with additional data from phase 2 (REAL5: NCT03878446, N = 59) and phase 1 trials (NCT01973244, N = 24). Relationships between somapacitan dose, exposure, baseline IGF-I SD score (SDS), and height velocity (HV) were established in children born SGA, with similar responses anticipated for those with ISS, NS, or TS. A linear model enabled the estimation of average weekly IGF-I exposure from a single sample collected during the somapacitan dosing interval. IGF-I SDS simulations support flexible dosing changes while maintaining a minimum of 4 days between doses. Somapacitan 0.24 mg/kg/week produced similar IGF-I SDS changes and height velocity increases as daily GH in prepubertal short children and adolescents born SGA or with ISS, NS, or TS. The results support that the guidance already established for GHD regarding somapacitan initiation, dosing flexibility, and IGF-I monitoring remain appropriate for prepubertal short children and adolescents born SGA or with ISS, NS, or TS.
2026-06-01 | From case reports to a cohort: illuminating the spectrum of pulmonary hypertension in Noonan syndrome
Noonan syndrome is an autosomal dominant genetic condition with multisystem involvement and an estimated prevalence of one in 1000 to 2500 live births [1]. Its unifying biological feature is dysregulation of the RAS/MAP kinase signalling pathway with pathogenic variants most commonly found in PTPN11 (∼50%), SOS1 (10%), RAF1 (5–15%) and RIT1 (10%) [2, 3]. Cardiovascular manifestations are among the most clinically significant features, including pulmonary stenosis in 50–60% of individuals, hypertrophic cardiomyopathy in 20%, and secundum-type atrial septal defects in 6–10% [3].
2026-04-13 | A Phase II Basket Trial of Vosoritide in Children with RASopathies, ACAN and NPR2 Deficiency.
Genetic defects in many biological pathways, including activation of the Ras-MAPK pathway, cause short stature. Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia. To determine whether vosoritide improves growth in children with disorders of the Ras-MAPK pathway including RASopathies, ACAN and NPR2 deficiency. Prospective phase 2 basket trial. Academic medical center. Thirty pre-pubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height <-2.25 SD. 6-month observation period followed by 12-month treatment with vosoritide subcutaneously 15 micrograms/kg/day. Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV) and height standard deviation scores. The AGV increased from 4.53+1.61 cm/yr to 8.09+1.58 cm/yr with treatment (p<0.0001). This corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (p<0.0001). The increase in AGV was seen in all genetic subgroups. There was a height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment versus observation period (p<0.0001).Short-term safety was reassuring with mild injection site reactions being the most common adverse events. However, with longer use, five subjects discontinued medication due to adverse events including three slipped capital femoral epiphyses and four cases of genu valgum. Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN and NPR2 deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway.
2026-04-10 | Sleep disorders in genetic syndromes associated with congenital heart disease: A comprehensive review.
Children with genetic syndromes frequently have congenital heart disease (CHD) and are at an increased risk of sleep disorders due to overlapping anatomical, neurological, and cardiopulmonary vulnerabilities. Despite growing recognition, sleep disorders remain underdiagnosed in this high-risk population, with potential consequences for cardiovascular health, neurodevelopmental health, and quality of life. To comprehensively review the prevalence, patterns, pathophysiological mechanisms, diagnostic challenges, and management strategies of sleep disorders in children with genetic syndromes associated with CHD. A comprehensive systematic literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and the Cochrane Library for studies published between January 2010 and December 2022. Eligible studies included children and adolescents (0-18 years) with genetic syndromes in which the CHD prevalence exceeded 30% and reported sleep-related outcomes. Forty-two studies met the inclusion criteria and were narratively synthesized. Sleep-disordered breathing, particularly obstructive sleep apnea, was the most prevalent sleep disorder across syndromes, with the highest rates reported in Down syndrome, Noonan syndrome, and CHARGE syndrome. Central sleep apnea, hypoventilation, insomnia, and circadian rhythm disturbances were observed in syndromes with neurological or hypothalamic involvement. Sleep disorders are consistently associated with adverse cardiovascular, neurodevelopmental, and metabolic outcomes. Sleep disorders are common, clinically significant, and under-recognized in children with genetic syndromes and CHD. Routine screening and multidisciplinary management are essential for improving long-term outcomes. Future prospective studies are needed to clarify the causal relationships and treatment efficacy.
2026-03-13 | Plain language summary for "Once-weekly Somapacitan in Children with Noonan Syndrome: Randomised Controlled Phase 3 Trial"
Plain language summary for "Once-weekly Somapacitan in Children with Noonan Syndrome: Randomised Controlled Phase 3 Trial"
other
2024-02-05 | Central giant cell granuloma: Off-label treatment with Denosumab in a patient with Noonan syndrome.
This study aims to describe the utilization of Denosumabࣨ, a human monoclonal antibody against the RANK-L receptor, in a mandibular giant cell granuloma (GCG) with a significant local aggressiveness component that was unresponsive to surgical treatment. We present a case of a 19-year-old male patient diagnosed with Noonan syndrome, who presented a multifocal giant cell granuloma with aggressive behaviour resistant to surgical treatment. Due to the functional and aesthetic implications associated with a surgical procedure, a decision was made to initiate medical treatment using Denosumabࣨ. Throughout the treatment, the patient presented excellent clinical and analytical tolerance, with no reported adverse effects. Surgical intervention remains the preferred approach for GCG. Denosumabࣨ emerges as an alternative, either as neoadjuvant treatment or as definitive therapy for unresectable or resectable tumors associated with significant morbidity. It leads to size stabilization and regression of the tumour stage.
2022-03-04 | Psychopathology and Adaptive Functioning in Children, Adolescents, and Young Adults with Noonan Syndrome.
The objective of this study was to examine psychopathology and its impact on adaptive functioning in a sample of patients affected by Noonan syndrome (NS), a genetically heterogeneous condition with systemic manifestations. Forty-two subjects affected by NS (23 males and 19 females), aged 5 to 21 years (mean 12.6 ± SD 5.1), were assessed for nonverbal cognitive abilities, with dimensional measures of psychopathology, adaptive functioning, and family quality of life. The nonverbal intelligence quotient (IQ) mean was 99.4 ± SD 22.2, with 3 subjects (8%, 95% confidence interval [CI], 1.6%-20.9%) showing cognitive impairment (IQ<70). The Parent Child Behavior Checklist (CBCL) total psychopathology score was in the clinical range in 10% of sample and borderline in another 10%. On the Conners' Parent Rating Scales, scores suggestive of attention-deficit/hyperactivity disorder (ADHD) were in the clinical range in 20%. On the autism quotient, autism spectrum disorder symptoms were reported in 10%. Higher scores on the Adaptive Behavioral Assessment System-Second Edition and on the World Health Organization Quality of Life (26 items) were associated with lower problems on the CBCL (r = -0.63, 95% CI, -0.78 to -0.40 and r = -0.48, 95% CI, -0.69 to -0.20, respectively). Psychopathology was common in patients with NS and negatively correlated with global functioning and family quality of life. Treatable psychopathology, such as ADHD, may constitute a treatment target for improving adaptive functioning.
2017-05-26 | Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome
Abstract Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1 L613V/+ knock-in mice. Here, using inducible Raf1 L613V expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1 L613V enhances Ca 2+ sensitivity and cardiac contractility without causing hypertrophy. Raf1 L613V expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) Raf1 L613V causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine (TNF/IL6) hierarchy in Raf1 L613V -expressing ECs that drives cardiomyocyte hypertrophy in vitro . Furthermore, postnatal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo . We conclude that NS-cardiomyopathy involves cardiomyocytes, ECs and fibroblasts, TNF/IL6 signalling components represent potential therapeutic targets, and abnormal EC signalling might contribute to other forms of LVH.
cell therapies
2025-09-21 | Generation of Valvular Interstitial Cells from Human Pluripotent Stem Cells
Abstract Heart valves are living structures whose sophisticated functions are mediated by a specialized population of mesenchymal cells known as valvular interstitial cells (VICs). Given their central role in valve homeostasis, VICs represent a promising cell population for studying heart valve diseases and developing novel therapies to treat them. Here, we describe a strategy for generating VICs from human pluripotent stem cells (hPSCs) by stage-specific manipulation of developmental signalling pathways. Our results demonstrate that hPSC-derived VICs show a high transcriptional similarity to primary human fetal VICs and can secrete key proteins of the valve extracellular matrix. We further investigate the heterogeneity of hPSC-derived VICs and identify two major subpopulations with distinct molecular and functional properties, mirroring the cellular diversity observed in vivo . Finally, we utilize an in vitro model of Noonan syndrome to demonstrate that hPSC-derived VICs can accurately recapitulate key aspects of valve disease. Collectively, these findings provide a reproducible method for the scaled generation of bona fide hPSC-derived VICs and establish their utility in disease modelling and tissue engineering applications. Clinical Perspective What is new? - We established a robust platform to generate bona fide valvular interstitial cells (VICs) from human pluripotent stem cells (hPSCs), recapitulating native VIC identity and function. - We delineated signaling pathways that promote the development of two distinct VIC subsets and identified a surface marker to distinguish between them. What are the clinical implications? - A renewable, human-specific source of VICs enables precise mechanistic studies of valve development and disease that are not possible with limited surgical specimens or animal models. - This platform creates opportunities for therapeutic applications, including drug discovery and tissue engineering approaches for valve repair.
2023-06-02 | Generation of a genetically-modified induced pluripotent stem cell line harboring a Noonan syndrome-associated gene variant MRAS p.G23V.
Patients harboring causative gene variants in RAS GTPase MRAS develop Noonan syndrome and early-onset hypertrophic cardiomyopathy. Here, we describe the generation of a human iPSC line harboring the Noonan syndrome-associated MRAS p.G23V variant by using CRISPR/Cas9 technology. The established MRASG23V iPSC line allows to study MRAS-specific pathomechanisms and to test novel therapeutic strategies in various disease-relevant cell types and tissues.
2022-06-09 | Noonan syndrome: cochlear implantation in the setting of cochlear nerve deficiency.
Noonan syndrome (NS) is a congenital disorder characterized by a wide heterogeneity in clinical and genetic features. Hearing loss can frequently occur in NS, although not always mentioned in its diagnostic criteria. We are reporting on a child with an established NS who underwent bilateral cochlear implantation (CI) in the setting of cochlear nerve deficiency. We present the case of a child-girl affected by NS. Newborn hearing screening and audiological evaluations reveled an asymmetric sensorineural hearing loss (SNHL), profound at left ear and severe at right ear. Hearing aids were fitted at the age of six months. Brain magnetic resonance imaging showed hypoplastic cochlear nerves. Due to progressive worsening of the hearing thresholds and inappropriate speech development, at the age of 2 years she underwent a left-sided cochlear implantation. Four years later, right ear was also implanted. Six years after the first surgery, a partial extrusion of the electrode array was noticed. Explantation and reimplantation of a new device was performed, adopting a subtotal petrosectomy approach. The patient reached a score of 95% in open-set speech perception tests. Hearing loss is a frequent finding in patients with NS; however, its nature and severity are very heterogenous. In consideration of the possible progression of SNHL, audiological follow-up in NS patients must be carefully and periodically performed so as to early detect worsening of hearing threshold. If indicated, cochlear implantation should be considered, taking account of audiological and systemic features of this syndrome.
2020-07-13 | Cardiac transplantation in children with Noonan syndrome.
NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS-specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post-discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.
2017-11-01 | Breast reconstruction in a patient with Noonan syndrome
Noonan syndrome (NS) is a relatively common genetic disorder with an autosomal dominant inheritance pattern affecting 1 in 1000–2500 births. Patients with this syndrome present with characteristic facial, musculoskeletal, cardiac and endocrine abnormalities. Lack of postpubertal breast development is a common manifestation of this syndrome and may result in severe hypomastia and a masculine appearance of the female chest. We report the first case of breast reconstruction in a 24-year-old woman with NS who lacked postpubertal breast development. Technical considerations for addressing the existing chest wall deformity, implant pocket selection as well as emphasis on the role of the plastic surgeon are presented.
small molecules
2026-08-11 | RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial
Background Noonan syndrome (NS) is a relatively common developmental disorder caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, leading to multisystem involvement including short stature, skeletal abnormalities, cardiac defects, and neurocognitive impairment. Preclinical studies suggest that statins attenuate RAS/MAPK pathway hyperactivation and improve neurocognitive deficits, growth impairment, and survival in experimental models. However, no randomised controlled trial has evaluated the efficacy and safety of statin therapy in children with NS. We aimed to evaluate the efficacy and safety of simvastatin in children with NS. Methods In this national, multicentre, double-blind, placebo-controlled phase 3 trial conducted across 13 French centres, children aged 6–15 years with genetically confirmed NS and growth impairment were randomly assigned (1:1) to receive oral simvastatin (10 mg/day during month 1, 20 mg/day during month 2, then 20 or 40 mg/day according to age) or matching placebo once daily for 12 months. The primary outcome was the change in serum insulin-like growth factor 1 (IGF-1) levels. Secondary outcomes included growth, bone, cardiac, metabolic, and behavioural parameters. Analyses followed the intention-to-treat principle using mixed-effects and adjusted regression models. The trial was prospectively registered at ClinicalTrials.gov (NCT02713945). Findings Fifty-three children were randomised (26 simvastatin, 27 placebo), and 49/53 (92.5%) completed the study. After 12 months, simvastatin did not significantly improve IGF-1 levels compared with placebo (between-group difference −0.08 log ng/mL, 95% CI −0.18 to 0.01; p=0.08). No differences were observed between groups for height, growth velocity, bone mineral density, metabolic measures, or behavioural outcomes. Simvastatin was associated with lower circulating Dickkopf-related protein 1 (DKK1) concentrations (−0.27, 95% CI −0.52 to −0.01; p=0.04), a biomarker of bone metabolism, and a higher ratio of early-to-late diastolic mitral annular velocity (Ea/Aa ratio) (0.27, 95% CI −0.004 to 0.55; p=0.05), an echocardiographic parameter related to left ventricular diastolic function. However, these isolated findings were of borderline statistical significance, and were not accompanied by corresponding clinical improvements. Treatment was generally well tolerated. One serious adverse event occurred in the simvastatin group and was considered doubtfully related to study treatment. Interpretation In children with NS, 12 months of simvastatin did not result in significant improvements in the primary endpoint or in major outcomes of clinical relevance under the conditions tested. Changes in DKK1 concentrations and the Ea/Aa ratio should be interpreted cautiously as exploratory secondary findings requiring confirmation in adequately powered studies. Further research is needed to explore alternative treatment strategies and more direct approaches to RAS/MAPK pathway modulation. Funding French Ministry of Health.
2026-07-30 | Effects of MEK-inhibitor treatment in infants with lymphatic abnormalities in noonan syndrome.
Noonan syndrome (NS) is a genetic disorder associated with dysregulation of the RAS/MAPK signaling pathway and is frequently accompanied by lymphatic abnormalities. These lymphatic complications can lead to severe clinical manifestations, including chylous effusions and respiratory compromise, particularly in infants. Management of such complications is often challenging, and conventional therapies may be insufficient in severe cases. Recently, targeted therapies affecting the RAS/MAPK pathway, such as MEK inhibitors, have emerged as a potential treatment option for patients with refractory lymphatic disease. In this context, the present study describes our initial clinical experience with MEK inhibitor therapy using Trametinib in infants with Noonan syndrome and lymphatic abnormalities. Six infants with genetically confirmed NS (3 female, 3 male; mean age 0.5 ± 0.72 years) presenting with lymphatic abnormalities and intractable chylous effusions were treated with Trametinib. Clinical presentation was assessed at baseline as well as at 6-week and 1-year follow-up. Dedicated MR lymphangiography was performed at baseline and after one year, and lymphatic abnormalities were rated using a 6-point Likert scale. Possible adverse events were documented. After one year of therapy, considerable clinical improvement was observed in all patients. None of the patients required chest drainage and no clinical signs of chylothorax were present. Follow-up MR lymphangiography demonstrated a decrease in pleural effusions in all cases, with no residual fluid in three patients and only minimal residual fluid in the remaining three. Pathologic pulmonary and pleural lymphatic perfusion decreased in all cases (median 3 vs. 1). However, lymphatic imaging did not demonstrate normalization of lymphatic anatomy or flow in any patient. Overall, in this exploratory analysis Trametinib therapy resulted in considerable clinical improvement in infants with lymphatic abnormalities associated with Noonan syndrome, while MR lymphangiography showed only limited remodeling of the central lymphatic system over one year of treatment without normalization of lymphatic anatomy or lymphatic flow.
2026-06-16 | Lymphatics in Noonan Syndrome
In this thesis we describe the use of zebrafish (Danio rerio), to study lymphangiogenesis in health and in the presence of patient associated Noonan syndrome mutations. In chapter 1 we give a general overview of the subjects discussed in this thesis, namely the function of the lymphatic vasculature, lymphangiogenesis in the zebrafish and the congenital disorder Noonan syndrome. In chapter 2 we review the current knowledge of the role of SHP2 variants in rare diseases and advances in the understanding of its pathogenesis using model systems. These two chapters provide the background for the scientific questions we pursue in the subsequent experimental chapters. In chapter 3 we describe the consequences of the absence of the ptpn11a and ptpn11b genes in zebrafish embryos. We show that all double mutant zebrafish embryos completely lack their lymphatic vasculature including the lymphatics in the head. In addition, we show that the absence of ptpn11a and ptpn11b targets the lymphatic vasculature, but not the venous connections established by the same cell population. In chapter 4 we describe how we generated zebrafish knockouts for both sos1 and sos2. We show that loss of sos1 is viable but knockout of sos2 is embryonically lethal. We show that all double mutant zebrafish embryos lack an intact lymphatic vasculature including the lymphatics in the head. Additionally, sos double mutants also displayed defects in the establishment of venous connections in the zebrafish trunk. In chapter 5 we describe the establishment of a zebrafish line with a patient-associated Noonan syndrome mutation in Sos2 and compare this line with a previously characterized zebrafish model for Noonan Syndrome. We show a lymphatic phenotype, including vasodilation of the thoracic duct (TD), whereas lymphangiogenesis was normal in ptpn11a+/D61G embryos. We demonstrate that treatment with the MEK inhibitor trametinib, which is currently being used in the clinic, effectively rescued the dilated TD associated with the Sos2+/M264R mutation, highlighting the potential of our model to study treatment options in zebrafish. In chapter 6 the clinical outcomes of trametinib therapy in eight patients with Noonan syndrome-like RASopathies and central conducting lymphatic anomaly was assessed, each offering unique insights into the therapeutic efficacy of MEK inhibition. Finally, chapter 7 provides a summarizing discussion of the observations and findings of the previous chapters in the context of implications for further research. To conclude, the hope is that an integrated understanding of Noonan syndrome and lymphangiogenesis will not only elucidate fundamental developmental biological questions, but also pave the way for better management of lymphatic diseases in patients with Noonan syndrome.
2026-06-08 | Trametinib Therapy for Hypertrophic Cardiomyopathy and Pulmonary Hypertension in a Child With RAF1-Related Noonan Syndrome (p.Ser257Leu): A Case Report.
This case describes a female infant with RAF1-related Noonan syndrome who developed severe hypertrophic obstructive cardiomyopathy, pulmonary hypertension, and cardiorespiratory failure that responded to trametinib treatment but ultimately progressed to death following dose tapering and discontinuation of therapy. To the best of our knowledge, this is the first case with detailed respiratory information in a trametinib-treated patient with RASopathy-related pulmonary disease.
2026-05-29 | Long-term clinical benefit of mavacamten for hypertrophic cardiomyopathy in a patient with RAF1-associated Noonan syndrome-case report.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is frequently complicated by left ventricular outflow tract (LVOT) obstruction. While most cases are caused by sarcomeric mutations, up to 10% represent non-sarcomeric or syndromic phenocopies, including Noonan syndrome (NS). Noonan syndrome is a RASopathy in which mutations in genes such as RAF1 predispose to HCM through dysregulation of the Ras/MAPK pathway and are often associated with severe LVOT obstruction. Cardiac myosin inhibitors have demonstrated efficacy in sarcomeric obstructive HCM, but patients with syndromic HCM were excluded from pivotal clinical trials. We report a 29-year-old woman with long-standing obstructive HCM and NYHA class III symptoms, angina, and dizziness. Multimodality imaging demonstrated asymmetric septal hypertrophy (maximal wall thickness 20 mm), focal intramural late gadolinium enhancement, and dynamic LVOT obstruction reaching 55 mmHg during exercise. Owing to progressive obstruction, the patient was enrolled in the EXPLORER-HCM trial. During follow-up exceeding 5 years, treatment resulted in sustained reduction of LVOT gradients, improvement in functional status to NYHA class II, and complete resolution of angina and presyncope, without adverse effects. Genetic testing performed during trial participation identified a heterozygous likely pathogenic RAF1 variant, confirming Noonan syndrome-associated HCM. This case report demonstrates durable clinical and haemodynamic benefit of myosin inhibition in RAF1-associated Noonan syndrome HCM. This finding suggests that possible downstream hypercontractility may represent a shared and therapeutically targetable mechanism across sarcomeric HCM and selected syndromic phenocopies.
gene therapies
2026-06-03 | A Rras2-BMPR2 feedback loop sustains osteogenesis and represents a therapeutic target for osteoporosis.
Ras-related protein 2 (Rras2) mutations are linked to Noonan syndrome, a disorder characterized by skeletal dysplasia and growth deficits. However, the role of Rras2 in bone homeostasis remains poorly defined, hindering the development of clinical interventions. Here, we show that Rras2 deficiency in mice leads to osteopenia, reduced bone strength, and impaired osteogenesis, recapitulating the clinical features of human patients. Mechanistically, Rras2 promotes osteogenic differentiation of bone marrow mesenchymal stem cells and supports bone regeneration. At the molecular level, Rras2 sustains BMP signaling by blocking Smurf1-dependent ubiquitination and degradation of BMPR2; in turn, BMP signaling enhances Rras2 transcription. Osteoporotic mice exhibit marked reduction in Rras2 expression in bone, and adeno-associated virus 9 (AAV9)-mediated restoration of Rras2 rescues bone loss. Our findings identify a Rras2-BMPR2 positive feedback loop that is critical for bone homeostasis and provide a therapeutic avenue for osteoporosis and Noonan syndrome.
2026-01-01 | Assessment of CRISPR-based disruption of a cryptic splice site in LZTR1 causing Noonan syndrome
Noonan syndrome is a relatively common congenital multisystemic disorder characterised by a broad spectrum of coexisting phenotypic features. It most frequently affects the heart, rendering it the second most common congenital heart disease after trisomy 21. Cardiac involvement, particularly the presence of hypertrophic cardiomyopathy, significantly increases mortality and morbidity of affected patients. Noonan syndrome is the most common representative of the disease group of RASopathies, because it is caused by mutations in genes encoding proteins involved in the RAS/MAPK pathway leading to RAS/MAPK signalling hyperactivity. More recently, loss-of-function mutations in leucine zipper like transregulator 1 (LZTR1) have been introduced as causes for Noonan syndrome due to its pivotal role in the ubiquitination and degradation of RAS proteins. Insufficient degradation of RAS proteins culminates in RAS/MAPK signalling hyperactivity. Previously, our laboratory presented a case of two patients with NS caused by loss-offunction mutations in LZTR1. The mutation in intron 16 is a point mutation that is recognised as an additional splice site leading to the incorporation of a cryptic exon in the mRNA transcript. The cryptic exon contains a stop codon, so no functional LZTR1 protein is translated leading to the expression of NS. This study presents an efficient and safe single-cut CRISPR/Cas9-based genetic editing approach aiming at the destruction of an intronic mutation in a model of the common LZTR1-associated RASopathy NS. High reproducibility and predictability of induced insertions and deletions by DNA repair mechanisms were discovered presenting a clinically translatable CRISPR/Cas9-mediated genome editing approach, that featured low off-target editing and is highly efficient in rehabilitating LZTR1 function and thereby reducing RAS protein levels. However, additional research is needed to translate the genome editing strategy explored in this study into non-dividing cardiomyocytes.
2025-05-28 | Advancing CRISPR gene therapy for Noonan syndrome: Targeting recurrent LZTR1 variants with all-in-one Cas9 and base editors in patient-derived iPSC-cardiomyocytes
Pathogenic variants in LZTR1 are causative for Noonan syndrome with early onset of a severe hypertrophic cardiomyopathy. Despite high clinical relevance, therapeutic options are highly limited, and no curative treatment exists. In this thesis, different CRISPR-based gene editing approaches were evaluated in a preclinical model of Noonan syndrome-associated hypertrophic cardiomyopathy based on patient-derived induced pluripotent stem cells differentiated into ventricular cardiomyocytes. The findings revealed that classical CRISPR-Cas9 gene editing was not able to rescue the disease pathology in vitro. In contrast, base editing efficiently corrected the pathogenic variant and rescued LZTR1 function in patient-specific cardiomyocytes, demonstrating a suitable strategy for a curative therapy for Noonan syndrome caused by recessive LZTR1 variants.
2024-07-29 | Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
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 LZTR1L580P 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 LZTR1L580P-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 LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.
2024-05-17 | Functional CRISPR repair of induced pluripotent stem cells from patients with Noonan syndrome-associated cardiac hypertrophy
Noonan syndrome (NS) is a multisystemic disorder and characterised by its vast clinical variety including craniofacial dysmorphism, short stature and congenital heart defects resulting in severe pulmonary stenosis, hypertrophic cardiomyopathy (HCM), and other cardiac anomalies. With an estimated prevalence of one in 1000 to 2500 live births and a common autosomal-dominant inheritance, NS is the second most frequent congenital heart disease after trisomy 21. Caused by mutations encoding the RAS/MAPK signaling pathway and its components, NS is classified as a RASopathy (Roberts et al. 2013). Exploration of biallelic autosomal-recessive loss-of-function mutations within Leucine Zipper Like Transcription Regulator 1 (LZTR1) in cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) allowed identification of the underlying pathomechanism causing severe-onset NS-associated HCM (Hanses et al. 2020). LZTR1 is known to attenuate RAS activity through ubiquitination and is hypothesised to act as a 'RAS-killer', inhibiting RAS-hyperactivity, with cellular processes disinhibited upon loss-of-function (Abe et al. 2020). In-depth molecular and functional studies of patient-specific iPSC-CMs recapitulated the hypertrophic disease phenotype showing severely elevated RAS/MAPK signaling levels and impaired calcium handling (Hanses et al. 2020). This project was able to correct, reverse and thus repair the disease-causing deep-intronic mutation c.1943-256C>T in LZTR1 in patient-specific iPSCs utilizing CRISPR/Cas9 as a precise genome editing tool. The intronic editing approach chosen to disrupt the disease-causative additional donor splice site, thereby preventing installation of a cryptic exon, restored the expression of functional LZTR1. Furthermore, the isogenic-CRISPR-controls confirmed the families' mutations as disease-causing. The extensive in vitro exploration of the CRISPR-corrected-iPSC-CMs demonstrated a reversal of hypertrophy by normalised cell size compared to hypertrophic NS-iPSC-CMs, as well as attenuation of RAS protein to WT levels (Hanses et al. 2020). By combining molecular approaches with structural and functional investigations, this study ultimately led to a better understanding of the underlying disease pathomechanisms of this severe phenotype of NS. This improved understanding may pave the way for more effective diagnostic and therapeutic approaches in patient-specific precision medicine. In conclusion, this study presented an efficient, safe, and clinically translatable CRISPR-based gene therapy targeting a deep-intronic mutation in LZTR1 to cure the NS-associated pathology in a preclinical iPSC-CM screening platform. Translation of this CRISPR-based strategy could lead to the development of a promising therapeutic approach for the clinic (Knauer et al. 2024).
proteins
2026-06-29 | Model-based somapacitan dosing and IGF-I response in children born SGA or with ISS, Noonan or Turner syndromes.
The weekly insulin-like growth factor I (IGF-I) profile for children and adolescents treated with long-acting growth hormone differs from that of daily growth hormone (GH). The objective of this study is to provide guidance on the use of once-weekly somapacitan and IGF-I monitoring in prepubertal short children and adolescents born small for gestational age (SGA) or with idiopathic short stature (ISS), Noonan syndrome (NS), or Turner syndrome (TS). Modeling, including population pharmacokinetic/pharmacodynamic (PK/PD) modeling, were utilized, analyzing IGF-I data from 4 clinical studies, including 2 phase 3 trials (REAL8: NCT05330325; REAL9: NCT05723835) involving children and adolescents born SGA (N = 80), ISS (N = 69), NS (N = 62), and TS (N = 79), along with additional data from phase 2 (REAL5: NCT03878446, N = 59) and phase 1 trials (NCT01973244, N = 24). Relationships between somapacitan dose, exposure, baseline IGF-I SD score (SDS), and height velocity (HV) were established in children born SGA, with similar responses anticipated for those with ISS, NS, or TS. A linear model enabled the estimation of average weekly IGF-I exposure from a single sample collected during the somapacitan dosing interval. IGF-I SDS simulations support flexible dosing changes while maintaining a minimum of 4 days between doses. Somapacitan 0.24 mg/kg/week produced similar IGF-I SDS changes and height velocity increases as daily GH in prepubertal short children and adolescents born SGA or with ISS, NS, or TS. The results support that the guidance already established for GHD regarding somapacitan initiation, dosing flexibility, and IGF-I monitoring remain appropriate for prepubertal short children and adolescents born SGA or with ISS, NS, or TS.
2026-06-01 | From case reports to a cohort: illuminating the spectrum of pulmonary hypertension in Noonan syndrome
Noonan syndrome is an autosomal dominant genetic condition with multisystem involvement and an estimated prevalence of one in 1000 to 2500 live births [1]. Its unifying biological feature is dysregulation of the RAS/MAP kinase signalling pathway with pathogenic variants most commonly found in PTPN11 (∼50%), SOS1 (10%), RAF1 (5–15%) and RIT1 (10%) [2, 3]. Cardiovascular manifestations are among the most clinically significant features, including pulmonary stenosis in 50–60% of individuals, hypertrophic cardiomyopathy in 20%, and secundum-type atrial septal defects in 6–10% [3].
2026-04-13 | A Phase II Basket Trial of Vosoritide in Children with RASopathies, ACAN and NPR2 Deficiency.
Genetic defects in many biological pathways, including activation of the Ras-MAPK pathway, cause short stature. Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia. To determine whether vosoritide improves growth in children with disorders of the Ras-MAPK pathway including RASopathies, ACAN and NPR2 deficiency. Prospective phase 2 basket trial. Academic medical center. Thirty pre-pubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height <-2.25 SD. 6-month observation period followed by 12-month treatment with vosoritide subcutaneously 15 micrograms/kg/day. Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV) and height standard deviation scores. The AGV increased from 4.53+1.61 cm/yr to 8.09+1.58 cm/yr with treatment (p<0.0001). This corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (p<0.0001). The increase in AGV was seen in all genetic subgroups. There was a height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment versus observation period (p<0.0001).Short-term safety was reassuring with mild injection site reactions being the most common adverse events. However, with longer use, five subjects discontinued medication due to adverse events including three slipped capital femoral epiphyses and four cases of genu valgum. Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN and NPR2 deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway.
2026-04-10 | Sleep disorders in genetic syndromes associated with congenital heart disease: A comprehensive review.
Children with genetic syndromes frequently have congenital heart disease (CHD) and are at an increased risk of sleep disorders due to overlapping anatomical, neurological, and cardiopulmonary vulnerabilities. Despite growing recognition, sleep disorders remain underdiagnosed in this high-risk population, with potential consequences for cardiovascular health, neurodevelopmental health, and quality of life. To comprehensively review the prevalence, patterns, pathophysiological mechanisms, diagnostic challenges, and management strategies of sleep disorders in children with genetic syndromes associated with CHD. A comprehensive systematic literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and the Cochrane Library for studies published between January 2010 and December 2022. Eligible studies included children and adolescents (0-18 years) with genetic syndromes in which the CHD prevalence exceeded 30% and reported sleep-related outcomes. Forty-two studies met the inclusion criteria and were narratively synthesized. Sleep-disordered breathing, particularly obstructive sleep apnea, was the most prevalent sleep disorder across syndromes, with the highest rates reported in Down syndrome, Noonan syndrome, and CHARGE syndrome. Central sleep apnea, hypoventilation, insomnia, and circadian rhythm disturbances were observed in syndromes with neurological or hypothalamic involvement. Sleep disorders are consistently associated with adverse cardiovascular, neurodevelopmental, and metabolic outcomes. Sleep disorders are common, clinically significant, and under-recognized in children with genetic syndromes and CHD. Routine screening and multidisciplinary management are essential for improving long-term outcomes. Future prospective studies are needed to clarify the causal relationships and treatment efficacy.
2026-03-13 | Plain language summary for "Once-weekly Somapacitan in Children with Noonan Syndrome: Randomised Controlled Phase 3 Trial"
Plain language summary for "Once-weekly Somapacitan in Children with Noonan Syndrome: Randomised Controlled Phase 3 Trial"
other
2024-02-05 | Central giant cell granuloma: Off-label treatment with Denosumab in a patient with Noonan syndrome.
This study aims to describe the utilization of Denosumabࣨ, a human monoclonal antibody against the RANK-L receptor, in a mandibular giant cell granuloma (GCG) with a significant local aggressiveness component that was unresponsive to surgical treatment. We present a case of a 19-year-old male patient diagnosed with Noonan syndrome, who presented a multifocal giant cell granuloma with aggressive behaviour resistant to surgical treatment. Due to the functional and aesthetic implications associated with a surgical procedure, a decision was made to initiate medical treatment using Denosumabࣨ. Throughout the treatment, the patient presented excellent clinical and analytical tolerance, with no reported adverse effects. Surgical intervention remains the preferred approach for GCG. Denosumabࣨ emerges as an alternative, either as neoadjuvant treatment or as definitive therapy for unresectable or resectable tumors associated with significant morbidity. It leads to size stabilization and regression of the tumour stage.
2022-03-04 | Psychopathology and Adaptive Functioning in Children, Adolescents, and Young Adults with Noonan Syndrome.
The objective of this study was to examine psychopathology and its impact on adaptive functioning in a sample of patients affected by Noonan syndrome (NS), a genetically heterogeneous condition with systemic manifestations. Forty-two subjects affected by NS (23 males and 19 females), aged 5 to 21 years (mean 12.6 ± SD 5.1), were assessed for nonverbal cognitive abilities, with dimensional measures of psychopathology, adaptive functioning, and family quality of life. The nonverbal intelligence quotient (IQ) mean was 99.4 ± SD 22.2, with 3 subjects (8%, 95% confidence interval [CI], 1.6%-20.9%) showing cognitive impairment (IQ<70). The Parent Child Behavior Checklist (CBCL) total psychopathology score was in the clinical range in 10% of sample and borderline in another 10%. On the Conners' Parent Rating Scales, scores suggestive of attention-deficit/hyperactivity disorder (ADHD) were in the clinical range in 20%. On the autism quotient, autism spectrum disorder symptoms were reported in 10%. Higher scores on the Adaptive Behavioral Assessment System-Second Edition and on the World Health Organization Quality of Life (26 items) were associated with lower problems on the CBCL (r = -0.63, 95% CI, -0.78 to -0.40 and r = -0.48, 95% CI, -0.69 to -0.20, respectively). Psychopathology was common in patients with NS and negatively correlated with global functioning and family quality of life. Treatable psychopathology, such as ADHD, may constitute a treatment target for improving adaptive functioning.
2017-05-26 | Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome
Abstract Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1 L613V/+ knock-in mice. Here, using inducible Raf1 L613V expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1 L613V enhances Ca 2+ sensitivity and cardiac contractility without causing hypertrophy. Raf1 L613V expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) Raf1 L613V causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine (TNF/IL6) hierarchy in Raf1 L613V -expressing ECs that drives cardiomyocyte hypertrophy in vitro . Furthermore, postnatal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo . We conclude that NS-cardiomyopathy involves cardiomyocytes, ECs and fibroblasts, TNF/IL6 signalling components represent potential therapeutic targets, and abnormal EC signalling might contribute to other forms of LVH.
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Drug Discovery Landscape
3 orphan drug designations for Noonan syndrome, including 1 approved therapy.
3 orphan drug designations for Noonan syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
vosoritide | peptides | FDA | 2024-10-11 | — | BioMarin Pharmaceutical Inc. |
Dasatinib | small molecules | FDA | 2020-10-26 | — | IGIA Pharmaceuticals, Inc. |
Somatropin [Norditropin] | proteins | FDA | 2006-08-09 | 2007-05-31 | Novo Nordisk Inc. |
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