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:
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.
2026-02-27 | 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.
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.
2026-02-27 | 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.
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