RARE DISEASE
Costello syndrome
Costello syndrome
Costello syndrome
Synonyms: FCS syndrome, Faciocutaneoskeletal syndrome
Synonyms: FCS syndrome, Faciocutaneoskeletal syndrome
Synonyms: FCS syndrome, Faciocutaneoskeletal syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Costello syndrome is a rare RASopathy caused by germline HRAS mutations, leading to constitutive RAS/MAPK pathway activation [1][11][17]. Key features include developmental delay, intellectual disability, hypertrophic cardiomyopathy (60-75% prevalence), distinctive facies (full lips, macrocephaly), musculoskeletal abnormalities (kyphoscoliosis, ulnar deviation), and tumor predisposition (15% lifetime malignancy risk) [1][7][15]. Diagnosis combines clinical evaluation with HRAS sequencing. Management requires multidisciplinary care addressing cardiac, oncologic, and developmental complications [8][10][15].
Therapies
Categories: rare cardiac diseases, rare cardiac malformations, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare skin diseases, rare transplant-related disorders
Research Papers
107 drug discovery papers about Costello syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
107 drug discovery papers about Costello syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-04 | Targeting Nitric Oxide Synthase 2 Reverses Learning Deficits in an Oligodendrocyte-Focused Model of Costello Syndrome
ABSTRACT Myelination of axons by oligodendrocytes (OLs) greatly improves information processing in the brain; consequently, compromised myelin negatively impacts brain function. Young-adult Costello Syndrome (CS) patients present with learning disabilities and regression of psychomotor skills in correlation with abnormal brain white matter, delayed myelination, and dysmyelination. This suggests the involvement of OLs and myelin in abnormal brain physiology during and beyond development; however, the neuropathophysiology of CS remains poorly understood. Replacing the endogenous HRas gene with the CS-causing HRasG12V mutant gene in adult OLs (pHRasG/+ mice) induces ultrastructural myelin abnormalities; nonetheless, any functional impact is unknown. Here we show robust learning - but not memory - deficits in pHRasG/+ males and modest, delayed learning issues in females. Learning phenotypes are transient, likely involving compensatory responses from the OL lineage and microglia. Diffusion-weighted magnetic resonance imaging reveals region- and sex-dependent compromised myelin microstructure, coinciding with the peak of learning issues. Remarkably, pharmacological control of nitric oxide synthase 2 restores learning in male pHRasG/+ mice. Our study supports the notion that abnormal nitric oxide signaling in mature OLs affects learning, suggests a chronic impact of myelin-driven mechanisms in CS neuropathology, and proposes molecular targets with therapeutic potential for CS.
2026-05-18 | RAS/MAPK Pathway and RASopathies
The RAS/Mitogen-Activated Protein Kinase (MAPK) pathway is a core developmental signaling cascade that regulates proliferation, differentiation, survival, and tissue growth across multiple organ systems. Germline dysregulation of this pathway results in RASopathies. Although the causal variants affect different components of the pathway, they converge on abnormal downstream signaling. This explains why these disorders share a recognizable clinical core despite clear syndrome-specific differences. The most prevalent and well-known entity is Noonan syndrome, while other major subtypes include cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines. RASopathies are characterized by distinctive craniofacial features and multisystem involvement. Congenital heart disease is a significant cause of morbidity. Neurodevelopmental difficulties are common across the spectrum and may be particularly pronounced in Cardiofaciocutaneous and Costello syndromes. Short stature, pectus anomalies, scoliosis, and other musculoskeletal findings are also recurrent features. Another important concern is the malignancy risk, which varies significantly by genotype. Although these disorders share a common pathway, genotype-phenotype correlations are increasingly relevant in daily practice. Molecular findings now directly inform risk assessment and long-term follow-up. In parallel, early experience with pathway-directed therapies is beginning to influence the management of selected complications. MEK inhibitors have shown promising results in selected manifestations, particularly hypertrophic cardiomyopathy and refractory lymphatic complications. In this review, we discuss the biological organization of the RAS/MAPK pathway and relate it to the clinical spectrum of RASopathies. We focus on shared and distinguishing phenotypic features, clinically relevant genotype-phenotype correlations, and the emerging role of targeted therapies.
2026-04-27 | Resolution of Refractory Multifocal Atrial Tachycardia in Costello Syndrome Using Trametinib: A Case Supporting MEK Inhibitors as Targeted, Specific Antiarrhythmic.
Arrhythmias affect approximately half of patients with Costello syndrome (CS, OMIM # 218040), with non-reentrant atrial tachycardia being the most common. This case describes an infant with Costello syndrome carrying the pathogenic HRAS c.34G>A (p.G12S) variant who developed early-onset, drug-refractory multifocal atrial tachycardia (MAT). Despite multiple antiarrhythmic therapies, rhythm control remained inadequate until trametinib was initiated, resulting in rapid resolution of MAT and allowing stepwise discontinuation of adjunct antiarrhythmics. Although MAT did not recur after the MEK inhibitor was stopped, the patient subsequently developed hypertrophic cardiomyopathy only after trametinib was discontinued, suggesting a potential disease-modifying cardioprotective effect during active treatment. This case supports MEK inhibition as a targeted antiarrhythmic strategy in Costello syndrome, with benefits that may extend beyond acute rhythm stabilization to include prevention of cardiac hypertrophy. While spontaneous resolution of MAT can occur in Costello syndrome, the rapid and sustained response in this patient strengthens the hypothesis that trametinib exerts a direct antiarrhythmic effect.
2026-01-01 | Genetic research progress on Costello syndrome
Costello syndrome (CS) is a rare autosomal dominant genetic disorder characterized by cardiac anomalies, distinctive craniofacial features, growth and developmental delays, as well as cutaneous abnormalities. Given the complexity of its clinical presentation and underlying pathogenic mechanisms, advances in genetic and molecular research are essential for deepening our understanding of CS and improving patient outcomes. This review systematically synthesizes recent progress on the genetics of CS from four interconnected perspectives: clinical manifestations, molecular pathogenesis, current diagnostic and therapeutic strategies, and future research directions. By critically integrating existing evidence, we aim to elucidate the core molecular mechanisms driven by dysregulated HRAS signaling and to consolidate both established and emerging genotype-phenotype correlations, which are critical for prognosis and clinical management. The HRAS gene, which encodes a pivotal GTPase in cellular signal transduction, lies at the heart of CS pathogenesis. Through a comprehensive analysis of published HRAS mutation data from CS cases worldwide, this review delineates the mutational spectrum, with emphasis on the predominant p.Gly12Ser variant, its functional consequences, and the associated range of clinical phenotypes. We describe how specific germline missense mutations, predominantly affecting codons 12 or 13, impair GTPase activity or accelerate GDP/GTP exchange, leading to constitutive activation of the HRAS protein. This persistent activation results in hyperactivation of the downstream RAS/MAPK signaling pathway, disrupting fundamental cellular processes such as proliferation, differentiation, and apoptosis, ultimately giving rise to the multisystem features of CS, particularly its hallmark cardiac, neurological, and dermatological manifestations. Beyond cataloging genetic variants, this review critically evaluates the translational implications of these findings for clinical practice. It examines how molecular confirmation through HRAS sequencing has refined diagnostic criteria, underscores the necessity of proactive, multidisciplinary management involving cardiology, neurology, and oncology, and highlights the importance of individualized genetic counseling for affected families. In conclusion, HRAS mutations represent the central molecular drivers of CS, with disease pathogenesis primarily mediated by sustained RAS/MAPK pathway activation. A clear understanding of this genetic basis not only facilitates accurate diagnosis, informed reproductive decision-making, and personalized surveillance but also establishes a robust scientific foundation for advancing prenatal diagnostics and developing targeted therapeutic interventions, including MEK inhibitors, for this complex and heterogeneous disorder.
2025-06-16 | RASopathies. Part I: Genetics and therapeutic considerations.
RASopathies are common developmental disorders caused by variants in RAS and RAS-related proteins that affect a biological signaling pathway regulating cell growth and development. Considering the genetic and biochemical basis, part I will discuss the RASopathies divided into germline and mosaic patterns. The germline RASopathies include neurofibromatosis type 1 (not discussed in detail in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. Mosaic RASopathies encompass a broad category including nevus sebaceus syndrome, neurocutaneous melanosis, melanocytic nevi, McCune-Albright syndrome, phacomatosis spilosebacea, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Due to the RAS pathway's downstream impact on cell growth, many RASopathies predispose to malignancy. Conversely, the RAS pathway is overactive in many cancers, and some oncologic therapies also benefit patients with RASopathies. Although RAS ubiquity and homology complicate the efficacy of direct inhibition, several candidate drugs carry potential for decreasing RAS activity. Continued investigation into RAS biochemistry and genetics may elucidate strategies for pharmacological targets and pathways in both RASopathies and cancers.
gene therapies
2026-02-27 | HRAS GENE MUTATION AND SEVERE NEUROLOGICAL DEFICIT: A CASE OF COSTELLO SYNDROME WITH CEREBRAL PALSY MANIFESTATIONS
Costello syndrome (CS) is a rare inherited disorder from the group of RASopathies, caused by a mutation in the HRAS gene. The disease is characterized by multiple systemic abnormalities, including craniofacial anomalies, cardiomyopathy, skin changes, severe developmental delays, and an increased risk of malignancies. This article presents a clinical case of a boy with molecularly confirmed Costello syndrome, who was also diagnosed with cerebral palsy (CP) — spastic tetraparesis with profound psychomotor developmental delay. The report provides a detailed analysis of perinatal history, clinical manifestations, neuroimaging findings, and genetic testing. This case highlights the importance of a multidisciplinary approach in diagnosing and managing patients with combined central nervous system pathologies. Синдром Костелло (СК) — редкое наследственное заболевание из группы RASопатий, обусловленное мутацией в гене HRAS. Заболевание характеризуется множественными системными нарушениями, включая краниофациальные аномалии, кардиомиопатию, кожные изменения, тяжелые задержки развития и повышенный онкологический риск. В данной статье представлен клинический случай мальчика с молекулярно подтверждённым синдромом Костелло, у которого также диагностирован детский церебральный паралич (ДЦП) — спастический тетрапарез с грубой задержкой психомоторного развития. Подробно рассмотрены перинатальный анамнез, клинические проявления, данные нейровизуализации и генетического анализа. Случай подчёркивает необходимость междисциплинарного подхода при диагностике и ведении пациентов с сочетанными патологиями центральной нервной системы. Костелло синдромы (КС) — сирек кездесетін, HRAS геніндегі мутациямен байланысты RASопатиялартобына жататын тұқым қуалайтын ауру. Бұл ауру әртүрлі жүйелік бұзылыстармен сипатталады: краниофациалдық ақаулар, кардиомиопатия, тері өзгерістері, дамуының ауыр кешеуілдеуі және онкологиялық ауруларға бейімділік. Бұл мақалада молекулалық-генетикалық тұрғыдан дәлелденген Костелло синдромы диагнозы қойылған, сонымен қатар балалар церебральды параличі (БЦП) — спастикалық тетрапарезбен және психомоторлық дамудың айқын кешеуілдеуімен жүрген ұл баланың клиникалық жағдайы баяндалған. Мақалада перинаталдық анамнез, клиникалық белгілер, нейровизуализацияжәне генетикалық зерттеу нәтижелері егжей-тегжейлі талданады. Бұл клиникалық жағдай Костелло синдромының ауыр неврологиялық бұзылыстармен қатар жүретін сирек жағдайларын сипаттап, орталық жүйке жүйесінің аралас патологиялары бар науқастарды диагностикалау және бақылау кезінде мультидисциплинарлық тәсілдің маңыздылығын көрсетеді.
2026-02-12 | Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.
RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk. This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques. Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS, besides one with variants in both LZTR1 and SOS1), two with Noonan syndrome with multiple lentigines (both with variants in PTPN11), two with Neurofibromatosis-Noonan (NF1), two with cardiofaciocutaneous syndrome (BRAF), and one each with Noonan syndrome-like with loose anagen hair (PPP1CB), Noonan syndrome-like (CBL), and Costello syndrome (HRAS); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes. Three pairs of unrelated patients presented recurrent variants in the PTPN11 gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.
2025-11-03 | Abstract 4370295: Single dose of a novel CRISPR-CasX editor potently reduces triglycerides in preclinical models and efficiently edits APOC3 in non-human primates
Background: Severe hypertriglyceridemia (SHTG) and familial chylomicronemia syndrome (FCS) are marked by extreme triglyceride (TG) elevations, raising the risk for acute pancreatitis and cardiovascular complications. Apolipoprotein C-III (APOC3) impairs TG catabolism and clearance. Loss-of-function APOC3 mutations are linked to lower TGs and reduced atherosclerotic risk, highlighting APOC3 as a promising therapeutic target. CRISPR-CasXE (XE) is an engineered gene editing platform with improved potency and specificity over natural systems. Here, we report the development of STX-1400, the first liver-targeted XE gene editing therapy designed to disrupt APOC3 expression and reduce circulating TGs. Approach: STX-1400 consists of an mRNA encoding an engineered XE editor and a single APOC3-targeting gRNA delivered via lipid nanoparticles. We evaluated the efficacy of a STX-1400 prototype in multiple in vitro and in vivo models. Specificity was assessed using a comprehensive off-target strategy to nominate potential off-target sites, followed by deep sequencing evaluation in primary human hepatocytes (PHHs) treated at 10xEC90. A non-human primate (NHP) surrogate was also tested in cynomolgus monkeys at escalating doses, with APOC3 editing measured in liver biopsies 18 days post-dose. Results: In PHHs, a STX-1400 prototype showed dose-dependent APOC3 editing (up to 90%) with >70% decrease in secreted APOC3 protein. In human APOC3 transgenic mice, hepatic editing at the APOC3 locus exceeded >70%, reducing circulating APOC3 by 80%. In hypertriglyceridemic mice, the STX-1400 prototype reduced APOC3 mRNA by >90% and protein by >95%, which corresponded with decreasing plasma TGs by >95% and total cholesterol by >80%. No off-target editing was observed in PHHs treated at 10xEC90. Notably, a single administration of the NHP analog of the STX-1400 prototype in cynomolgus monkeys achieved saturated editing levels (>70%) in the liver at 1mg/kg, with liver enzyme profiles comparable to controls. Conclusions: Our findings demonstrate that the STX-1400 prototype potently and specifically edits APOC3 across human cells, mouse models, and non-human primates. This study is the first demonstration that a CRISPR-based therapy has achieved saturated in vivo editing of the APOC3 locus in NHP liver. These results provide strong preclinical evidence supporting the potential of STX-1400 as a first-in class genome editing therapy for hypertriglyceridemia in patients with SHTG and FCS.
2024-11-30 | Noonan and RAS/MAPK Syndromes in Pediatric Cardiology: A Review
Noonan症候群（Noonan syndrome: NS）は，特徴的顔貌，心疾患，低身長を特徴とする常染色体顕性（優性）遺伝形式の先天性異常症候群で，1963年にJacqueline Noonan博士によって報告された．多彩な全身症状に対して，包括的な診療が必要となる．近年，NSと臨床的に類似点が多いCostello 症候群（Costello syndrome: CS），心臓・顔・皮膚（cardio-facio-cutaneous: CFC）症候群などが，遺伝子解析によりNSと共通のRAS/MAPK細胞内シグナル伝達系の分子の異常により発症することが解明され，これらの症候群を含むNSの類縁疾患がRAS/MAPK症候群または“RASopathies”と総称されるようになった．本稿では，小児循環器専門医が知っておくべきNoonan・RAS/MAPK症候群の基本知識を紹介する．
2008-09-24 | Germline expression of H-Ras(G12V) causes neurological deficits associated to Costello syndrome.
Costello syndrome (CS) is a rare congenital disorder caused by germline activation of H‐ Ras oncogenes. A mouse model of CS generated by introduction of an oncogenic Gly12Val mutation in the mouse H‐ Ras locus using homologous recombination in embryonic stem (ES) cells has been recently described. These mice phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. We investigated here their neurological and behavioral phenotype. The analysis of H‐ Ras G12V mice revealed phenotypes that resembled the hyperemotivity, hypersensibility and cognitive impairments observed in children with CS. Stronger neurological deficits were found in the analysis of mice homozygous for this mutation than in the analysis of heterozygous mice, suggesting the existence of a gene dose effect. These mice represent the first mouse model for CS, offering an experimental tool to study the molecular and physiological alterations underlying the neurological manifestations of CS and to test new therapies aimed at preventing or ameliorating the cognitive and emotional impairments associated to this condition.
oligonucleotides
2022-03-14 | Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs.
Costello syndrome (CS) is an autosomal dominant disorder caused by mutations in HRAS. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we use CS induced pluripotent stem cells (iPSCs) undergoing osteogenic differentiation to investigate how dysregulation of extracellular matrix (ECM) remodeling proteins contributes to impaired osteogenesis. Although CS patient-derived iPSCs develop normally to produce mesenchymal stem cells (MSCs), the resulting CS MSCs show defective osteogenesis with reduced alkaline phosphatase activity and lower levels of bone mineralization. We found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of CS MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. CS MSCs undergoing osteogenic differentiation also show reduced β-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances β-catenin signaling in a RUNX2-independent manner. Thus, this study demonstrates that enhanced TIMP expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via an inactivation of β-catenin signaling.
2015-07-02 | The role of p19 and p21 H-Ras proteins and mutants in miRNA expression in cancer and a Costello syndrome cell model
P19 H-Ras, a second product derived from the H-Ras gene by alternative splicing, induces a G1/S phase delay, thereby maintaining cells in a reversible quiescence state. When P21 H-Ras is mutated in tumour cells, the alternative protein P19 H-Ras is also mutated. The H-Ras mutation Q61L is frequently detected in different tumours, which acts as constitutive activator of Ras functions and is considered to be a strong activating mutant. Additionally, a rare congenital disorder named Costello Syndrome, is described as a H-Ras disorder in children, mainly due to mutation G12S in p19 and p21 H-Ras proteins, which is present in 90 % of the Costello Syndrome patients. Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression. Total miRNAs expression regulated by H-Ras proteins were first analyzed in human miRNA microarrays assays. Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers. This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. Furthermore, they suggest that oncogenes may have a sufficiently important impact on miRNA expression to promote the development of numerous cancers.
small molecules
2026-06-04 | Targeting Nitric Oxide Synthase 2 Reverses Learning Deficits in an Oligodendrocyte-Focused Model of Costello Syndrome
ABSTRACT Myelination of axons by oligodendrocytes (OLs) greatly improves information processing in the brain; consequently, compromised myelin negatively impacts brain function. Young-adult Costello Syndrome (CS) patients present with learning disabilities and regression of psychomotor skills in correlation with abnormal brain white matter, delayed myelination, and dysmyelination. This suggests the involvement of OLs and myelin in abnormal brain physiology during and beyond development; however, the neuropathophysiology of CS remains poorly understood. Replacing the endogenous HRas gene with the CS-causing HRasG12V mutant gene in adult OLs (pHRasG/+ mice) induces ultrastructural myelin abnormalities; nonetheless, any functional impact is unknown. Here we show robust learning - but not memory - deficits in pHRasG/+ males and modest, delayed learning issues in females. Learning phenotypes are transient, likely involving compensatory responses from the OL lineage and microglia. Diffusion-weighted magnetic resonance imaging reveals region- and sex-dependent compromised myelin microstructure, coinciding with the peak of learning issues. Remarkably, pharmacological control of nitric oxide synthase 2 restores learning in male pHRasG/+ mice. Our study supports the notion that abnormal nitric oxide signaling in mature OLs affects learning, suggests a chronic impact of myelin-driven mechanisms in CS neuropathology, and proposes molecular targets with therapeutic potential for CS.
2026-05-18 | RAS/MAPK Pathway and RASopathies
The RAS/Mitogen-Activated Protein Kinase (MAPK) pathway is a core developmental signaling cascade that regulates proliferation, differentiation, survival, and tissue growth across multiple organ systems. Germline dysregulation of this pathway results in RASopathies. Although the causal variants affect different components of the pathway, they converge on abnormal downstream signaling. This explains why these disorders share a recognizable clinical core despite clear syndrome-specific differences. The most prevalent and well-known entity is Noonan syndrome, while other major subtypes include cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines. RASopathies are characterized by distinctive craniofacial features and multisystem involvement. Congenital heart disease is a significant cause of morbidity. Neurodevelopmental difficulties are common across the spectrum and may be particularly pronounced in Cardiofaciocutaneous and Costello syndromes. Short stature, pectus anomalies, scoliosis, and other musculoskeletal findings are also recurrent features. Another important concern is the malignancy risk, which varies significantly by genotype. Although these disorders share a common pathway, genotype-phenotype correlations are increasingly relevant in daily practice. Molecular findings now directly inform risk assessment and long-term follow-up. In parallel, early experience with pathway-directed therapies is beginning to influence the management of selected complications. MEK inhibitors have shown promising results in selected manifestations, particularly hypertrophic cardiomyopathy and refractory lymphatic complications. In this review, we discuss the biological organization of the RAS/MAPK pathway and relate it to the clinical spectrum of RASopathies. We focus on shared and distinguishing phenotypic features, clinically relevant genotype-phenotype correlations, and the emerging role of targeted therapies.
2026-04-27 | Resolution of Refractory Multifocal Atrial Tachycardia in Costello Syndrome Using Trametinib: A Case Supporting MEK Inhibitors as Targeted, Specific Antiarrhythmic.
Arrhythmias affect approximately half of patients with Costello syndrome (CS, OMIM # 218040), with non-reentrant atrial tachycardia being the most common. This case describes an infant with Costello syndrome carrying the pathogenic HRAS c.34G>A (p.G12S) variant who developed early-onset, drug-refractory multifocal atrial tachycardia (MAT). Despite multiple antiarrhythmic therapies, rhythm control remained inadequate until trametinib was initiated, resulting in rapid resolution of MAT and allowing stepwise discontinuation of adjunct antiarrhythmics. Although MAT did not recur after the MEK inhibitor was stopped, the patient subsequently developed hypertrophic cardiomyopathy only after trametinib was discontinued, suggesting a potential disease-modifying cardioprotective effect during active treatment. This case supports MEK inhibition as a targeted antiarrhythmic strategy in Costello syndrome, with benefits that may extend beyond acute rhythm stabilization to include prevention of cardiac hypertrophy. While spontaneous resolution of MAT can occur in Costello syndrome, the rapid and sustained response in this patient strengthens the hypothesis that trametinib exerts a direct antiarrhythmic effect.
2026-01-01 | Genetic research progress on Costello syndrome
Costello syndrome (CS) is a rare autosomal dominant genetic disorder characterized by cardiac anomalies, distinctive craniofacial features, growth and developmental delays, as well as cutaneous abnormalities. Given the complexity of its clinical presentation and underlying pathogenic mechanisms, advances in genetic and molecular research are essential for deepening our understanding of CS and improving patient outcomes. This review systematically synthesizes recent progress on the genetics of CS from four interconnected perspectives: clinical manifestations, molecular pathogenesis, current diagnostic and therapeutic strategies, and future research directions. By critically integrating existing evidence, we aim to elucidate the core molecular mechanisms driven by dysregulated HRAS signaling and to consolidate both established and emerging genotype-phenotype correlations, which are critical for prognosis and clinical management. The HRAS gene, which encodes a pivotal GTPase in cellular signal transduction, lies at the heart of CS pathogenesis. Through a comprehensive analysis of published HRAS mutation data from CS cases worldwide, this review delineates the mutational spectrum, with emphasis on the predominant p.Gly12Ser variant, its functional consequences, and the associated range of clinical phenotypes. We describe how specific germline missense mutations, predominantly affecting codons 12 or 13, impair GTPase activity or accelerate GDP/GTP exchange, leading to constitutive activation of the HRAS protein. This persistent activation results in hyperactivation of the downstream RAS/MAPK signaling pathway, disrupting fundamental cellular processes such as proliferation, differentiation, and apoptosis, ultimately giving rise to the multisystem features of CS, particularly its hallmark cardiac, neurological, and dermatological manifestations. Beyond cataloging genetic variants, this review critically evaluates the translational implications of these findings for clinical practice. It examines how molecular confirmation through HRAS sequencing has refined diagnostic criteria, underscores the necessity of proactive, multidisciplinary management involving cardiology, neurology, and oncology, and highlights the importance of individualized genetic counseling for affected families. In conclusion, HRAS mutations represent the central molecular drivers of CS, with disease pathogenesis primarily mediated by sustained RAS/MAPK pathway activation. A clear understanding of this genetic basis not only facilitates accurate diagnosis, informed reproductive decision-making, and personalized surveillance but also establishes a robust scientific foundation for advancing prenatal diagnostics and developing targeted therapeutic interventions, including MEK inhibitors, for this complex and heterogeneous disorder.
2025-06-16 | RASopathies. Part I: Genetics and therapeutic considerations.
RASopathies are common developmental disorders caused by variants in RAS and RAS-related proteins that affect a biological signaling pathway regulating cell growth and development. Considering the genetic and biochemical basis, part I will discuss the RASopathies divided into germline and mosaic patterns. The germline RASopathies include neurofibromatosis type 1 (not discussed in detail in this review), Noonan syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. Mosaic RASopathies encompass a broad category including nevus sebaceus syndrome, neurocutaneous melanosis, melanocytic nevi, McCune-Albright syndrome, phacomatosis spilosebacea, epidermal nevus syndrome, and encephalocraniocutaneous lipomatosis. Due to the RAS pathway's downstream impact on cell growth, many RASopathies predispose to malignancy. Conversely, the RAS pathway is overactive in many cancers, and some oncologic therapies also benefit patients with RASopathies. Although RAS ubiquity and homology complicate the efficacy of direct inhibition, several candidate drugs carry potential for decreasing RAS activity. Continued investigation into RAS biochemistry and genetics may elucidate strategies for pharmacological targets and pathways in both RASopathies and cancers.
gene therapies
2026-02-27 | HRAS GENE MUTATION AND SEVERE NEUROLOGICAL DEFICIT: A CASE OF COSTELLO SYNDROME WITH CEREBRAL PALSY MANIFESTATIONS
Costello syndrome (CS) is a rare inherited disorder from the group of RASopathies, caused by a mutation in the HRAS gene. The disease is characterized by multiple systemic abnormalities, including craniofacial anomalies, cardiomyopathy, skin changes, severe developmental delays, and an increased risk of malignancies. This article presents a clinical case of a boy with molecularly confirmed Costello syndrome, who was also diagnosed with cerebral palsy (CP) — spastic tetraparesis with profound psychomotor developmental delay. The report provides a detailed analysis of perinatal history, clinical manifestations, neuroimaging findings, and genetic testing. This case highlights the importance of a multidisciplinary approach in diagnosing and managing patients with combined central nervous system pathologies. Синдром Костелло (СК) — редкое наследственное заболевание из группы RASопатий, обусловленное мутацией в гене HRAS. Заболевание характеризуется множественными системными нарушениями, включая краниофациальные аномалии, кардиомиопатию, кожные изменения, тяжелые задержки развития и повышенный онкологический риск. В данной статье представлен клинический случай мальчика с молекулярно подтверждённым синдромом Костелло, у которого также диагностирован детский церебральный паралич (ДЦП) — спастический тетрапарез с грубой задержкой психомоторного развития. Подробно рассмотрены перинатальный анамнез, клинические проявления, данные нейровизуализации и генетического анализа. Случай подчёркивает необходимость междисциплинарного подхода при диагностике и ведении пациентов с сочетанными патологиями центральной нервной системы. Костелло синдромы (КС) — сирек кездесетін, HRAS геніндегі мутациямен байланысты RASопатиялартобына жататын тұқым қуалайтын ауру. Бұл ауру әртүрлі жүйелік бұзылыстармен сипатталады: краниофациалдық ақаулар, кардиомиопатия, тері өзгерістері, дамуының ауыр кешеуілдеуі және онкологиялық ауруларға бейімділік. Бұл мақалада молекулалық-генетикалық тұрғыдан дәлелденген Костелло синдромы диагнозы қойылған, сонымен қатар балалар церебральды параличі (БЦП) — спастикалық тетрапарезбен және психомоторлық дамудың айқын кешеуілдеуімен жүрген ұл баланың клиникалық жағдайы баяндалған. Мақалада перинаталдық анамнез, клиникалық белгілер, нейровизуализацияжәне генетикалық зерттеу нәтижелері егжей-тегжейлі талданады. Бұл клиникалық жағдай Костелло синдромының ауыр неврологиялық бұзылыстармен қатар жүретін сирек жағдайларын сипаттап, орталық жүйке жүйесінің аралас патологиялары бар науқастарды диагностикалау және бақылау кезінде мультидисциплинарлық тәсілдің маңыздылығын көрсетеді.
2026-02-12 | Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.
RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk. This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques. Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS, besides one with variants in both LZTR1 and SOS1), two with Noonan syndrome with multiple lentigines (both with variants in PTPN11), two with Neurofibromatosis-Noonan (NF1), two with cardiofaciocutaneous syndrome (BRAF), and one each with Noonan syndrome-like with loose anagen hair (PPP1CB), Noonan syndrome-like (CBL), and Costello syndrome (HRAS); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes. Three pairs of unrelated patients presented recurrent variants in the PTPN11 gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.
2025-11-03 | Abstract 4370295: Single dose of a novel CRISPR-CasX editor potently reduces triglycerides in preclinical models and efficiently edits APOC3 in non-human primates
Background: Severe hypertriglyceridemia (SHTG) and familial chylomicronemia syndrome (FCS) are marked by extreme triglyceride (TG) elevations, raising the risk for acute pancreatitis and cardiovascular complications. Apolipoprotein C-III (APOC3) impairs TG catabolism and clearance. Loss-of-function APOC3 mutations are linked to lower TGs and reduced atherosclerotic risk, highlighting APOC3 as a promising therapeutic target. CRISPR-CasXE (XE) is an engineered gene editing platform with improved potency and specificity over natural systems. Here, we report the development of STX-1400, the first liver-targeted XE gene editing therapy designed to disrupt APOC3 expression and reduce circulating TGs. Approach: STX-1400 consists of an mRNA encoding an engineered XE editor and a single APOC3-targeting gRNA delivered via lipid nanoparticles. We evaluated the efficacy of a STX-1400 prototype in multiple in vitro and in vivo models. Specificity was assessed using a comprehensive off-target strategy to nominate potential off-target sites, followed by deep sequencing evaluation in primary human hepatocytes (PHHs) treated at 10xEC90. A non-human primate (NHP) surrogate was also tested in cynomolgus monkeys at escalating doses, with APOC3 editing measured in liver biopsies 18 days post-dose. Results: In PHHs, a STX-1400 prototype showed dose-dependent APOC3 editing (up to 90%) with >70% decrease in secreted APOC3 protein. In human APOC3 transgenic mice, hepatic editing at the APOC3 locus exceeded >70%, reducing circulating APOC3 by 80%. In hypertriglyceridemic mice, the STX-1400 prototype reduced APOC3 mRNA by >90% and protein by >95%, which corresponded with decreasing plasma TGs by >95% and total cholesterol by >80%. No off-target editing was observed in PHHs treated at 10xEC90. Notably, a single administration of the NHP analog of the STX-1400 prototype in cynomolgus monkeys achieved saturated editing levels (>70%) in the liver at 1mg/kg, with liver enzyme profiles comparable to controls. Conclusions: Our findings demonstrate that the STX-1400 prototype potently and specifically edits APOC3 across human cells, mouse models, and non-human primates. This study is the first demonstration that a CRISPR-based therapy has achieved saturated in vivo editing of the APOC3 locus in NHP liver. These results provide strong preclinical evidence supporting the potential of STX-1400 as a first-in class genome editing therapy for hypertriglyceridemia in patients with SHTG and FCS.
2024-11-30 | Noonan and RAS/MAPK Syndromes in Pediatric Cardiology: A Review
Noonan症候群（Noonan syndrome: NS）は，特徴的顔貌，心疾患，低身長を特徴とする常染色体顕性（優性）遺伝形式の先天性異常症候群で，1963年にJacqueline Noonan博士によって報告された．多彩な全身症状に対して，包括的な診療が必要となる．近年，NSと臨床的に類似点が多いCostello 症候群（Costello syndrome: CS），心臓・顔・皮膚（cardio-facio-cutaneous: CFC）症候群などが，遺伝子解析によりNSと共通のRAS/MAPK細胞内シグナル伝達系の分子の異常により発症することが解明され，これらの症候群を含むNSの類縁疾患がRAS/MAPK症候群または“RASopathies”と総称されるようになった．本稿では，小児循環器専門医が知っておくべきNoonan・RAS/MAPK症候群の基本知識を紹介する．
2008-09-24 | Germline expression of H-Ras(G12V) causes neurological deficits associated to Costello syndrome.
Costello syndrome (CS) is a rare congenital disorder caused by germline activation of H‐ Ras oncogenes. A mouse model of CS generated by introduction of an oncogenic Gly12Val mutation in the mouse H‐ Ras locus using homologous recombination in embryonic stem (ES) cells has been recently described. These mice phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. We investigated here their neurological and behavioral phenotype. The analysis of H‐ Ras G12V mice revealed phenotypes that resembled the hyperemotivity, hypersensibility and cognitive impairments observed in children with CS. Stronger neurological deficits were found in the analysis of mice homozygous for this mutation than in the analysis of heterozygous mice, suggesting the existence of a gene dose effect. These mice represent the first mouse model for CS, offering an experimental tool to study the molecular and physiological alterations underlying the neurological manifestations of CS and to test new therapies aimed at preventing or ameliorating the cognitive and emotional impairments associated to this condition.
oligonucleotides
2022-03-14 | Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs.
Costello syndrome (CS) is an autosomal dominant disorder caused by mutations in HRAS. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we use CS induced pluripotent stem cells (iPSCs) undergoing osteogenic differentiation to investigate how dysregulation of extracellular matrix (ECM) remodeling proteins contributes to impaired osteogenesis. Although CS patient-derived iPSCs develop normally to produce mesenchymal stem cells (MSCs), the resulting CS MSCs show defective osteogenesis with reduced alkaline phosphatase activity and lower levels of bone mineralization. We found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of CS MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. CS MSCs undergoing osteogenic differentiation also show reduced β-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances β-catenin signaling in a RUNX2-independent manner. Thus, this study demonstrates that enhanced TIMP expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via an inactivation of β-catenin signaling.
2015-07-02 | The role of p19 and p21 H-Ras proteins and mutants in miRNA expression in cancer and a Costello syndrome cell model
P19 H-Ras, a second product derived from the H-Ras gene by alternative splicing, induces a G1/S phase delay, thereby maintaining cells in a reversible quiescence state. When P21 H-Ras is mutated in tumour cells, the alternative protein P19 H-Ras is also mutated. The H-Ras mutation Q61L is frequently detected in different tumours, which acts as constitutive activator of Ras functions and is considered to be a strong activating mutant. Additionally, a rare congenital disorder named Costello Syndrome, is described as a H-Ras disorder in children, mainly due to mutation G12S in p19 and p21 H-Ras proteins, which is present in 90 % of the Costello Syndrome patients. Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression. Total miRNAs expression regulated by H-Ras proteins were first analyzed in human miRNA microarrays assays. Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers. This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. Furthermore, they suggest that oncogenes may have a sufficiently important impact on miRNA expression to promote the development of numerous cancers.
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