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:
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.
2026-06-29 | 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.
2026-06-16 | 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.
2026-08-11 | 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.
2026-06-29 | 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.
2026-06-16 | 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.
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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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