RARE DISEASE
Cardiofaciocutaneous syndrome
Cardiofaciocutaneous syndrome
Cardiofaciocutaneous syndrome
Synonyms: CFC syndrome
Synonyms: CFC syndrome
Synonyms: CFC syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Cardiofaciocutaneous Syndrome (CFC) is a rare RASopathy caused by pathogenic variants in BRAF, MAP2K1/2, or KRAS, leading to dysregulated RAS/MAPK signaling. Key features include congenital heart defects (pulmonary stenosis, septal defects, cardiomyopathy), distinctive facies (high forehead, hypertelorism), cutaneous abnormalities (hyperkeratosis, keratosis pilaris), and neurodevelopmental delays. Most patients exhibit intellectual disability (moderate-severe) and refractory epilepsy. Unlike Costello syndrome, cancer risk is not elevated. Management requires multidisciplinary care targeting cardiac, neurological, and developmental comorbidities [1][2][6][18].
Burden
Morbidity: 75% with congenital heart disease, 54% with epilepsy (40% refractory), and universal developmental delays [2][4][12].
Functional impact: Severe activity limitations (mobility, socialization) and chronic pain in 50% [2][7].
Caregiver burden: High healthcare utilization, lifelong support needs, and reduced quality of life [2][7][12].
Therapies
Cardiac: Surgery/medications for structural defects (e.g., valve stenosis, cardiomyopathy) [1][5][20].
Neurological: Oxcarbazepine (first-line for seizures; superior to levetiracetam), early PT/OT/speech therapy [4][8][12].
Multidisciplinary care: Growth hormone for short stature, gastrostomy for dysphagia, and dermatological management (emollients, keratolytics) [3][13][15].
Categories: rare cardiac diseases, rare cardiac malformations, rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare skin diseases, rare transplant-related disorders
Research Papers
77 drug discovery papers about Cardiofaciocutaneous syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
77 drug discovery papers about Cardiofaciocutaneous syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-18 | 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.
2025-05-27 | Scarring Alopecia of Eyebrows with Comedonal Lesions in a Young Boy
A 12-year-old boy, known case of cryptorchidism, planned for orchidopexy, presented with comedonal lesions on the face [Figure 1a], predominantly involving cheeks, ear conchae, and temporal region. He also had erythematous keratotic papules on upper arms and complete loss of both eyebrows. Dermatoscopic evaluation of eyebrows confirmed the presence of scarring alopecia by loss of hair follicles and that of comedonal lesions revealed the presence of multiple discrete, homogenous, and blackish and few whitish keratotic comedonal plugs within dilated follicular openings [Figure 1b]. All relevant systemic workup was done to rule out a syndromic association (Noonan syndrome, Cornelia De Lange syndrome, Rubinstein Taybi syndrome, and cardiofaciocutaneous syndrome). This included a detailed investigative workup after neurological, cardiac, ophthalmological, audiological, renal, and genetic consultations. A diagnosis of ulerythema ophryogenes with comedonal lesions was established. The patient was started on oral isotretinoin 10 mg/day therapy. After receiving the therapy for 1 month, the patient showed significant improvement [Figure 2].Figure 1: (a) Multiple, discrete, black, comedonal lesions on the face, involving both cheeks with complete loss of both eyebrows; (b) Dermatoscopic evaluation revealed presence of multiple discrete, homogenous, blackish and few whitish keratotic comedonal plugs within dilated follicular openings (DermLite IV, ×10, polarized)Figure 2: Significant improvement after 1 month of oral isotretinoin therapyDeclaration of patient consent The authors certify that they have obtained all appropriate parent consent forms. In the form, the parent has given their consent for his images and other clinical information to be reported in the journal. The parent understands that his name and initials will not be published. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2025-04-03 | RASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments.
RAS proteins are critical in cellular signal transduction, influencing cell proliferation, differentiation, and survival. While extensively studied for their role in cancer, RAS gene mutations also contribute significantly to cardiovascular diseases, such as hypertrophic cardiomyopathy, pulmonary valve stenosis, and atrial septal defects. Despite their similar primary structures, RAS proteins exhibit distinct functions in cardiac biology: H-RAS regulates cardiomyocyte size, K-RAS governs proliferation, and N-RAS, less associated with cardiac defects, is understudied in cardiac cells. Congenital RAS mutations, collectively known as RASopathies, include syndromes, like Noonan syndrome and cardio-facio-cutaneous syndrome, which often lead to severe cardiac complications, including heart failure. Genetic testing and imaging advances have improved the diagnosis and management of these conditions. Recent research has shown promise with MEK inhibitors and other targeted therapies, offering potential improvements in managing RAS-related cardiac conditions. This review explores the role of the RAS subfamily in heart disease, highlighting key concepts and potential therapeutic targets. PubMed database was searched using keywords, such as RASopathies, RAS gene mutations, cardiac hypertrophy, cardiovascular disease, RAS/MAPK pathway, congenital heart disease, and more. Relevant literature up to June 2024 was examined and summarized, consisting of data from various clinical trials, metaanalyses, retrospective/prospective cohort studies, and current guidelines.
2025-02-18 | Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models.
RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although B-Raf proto-oncogene (BRAF) mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific adeno-associated virus-BRAF KE (AAV-BRAF KE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca2+ fluctuations. Notably, reducing extracellular signal-regulated kinase (ERK) activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.
2024-11-01 | CSIG-06. BRAF GERMLINE MUTATIONS AND PREDISPOSITION TO BRAIN TUMORS
Abstract We report on two BRAF-mutated children and discuss genetic counseling regarding predisposition to brain tumors. Molecular analysis of the PTPN11 gene and twelve other genes in the RAS-MAPK pathway was carried out in a series of 54 dysmorphic patients with suspected Rasopathies. Two heterozygous BRAF germline mutations were detected in two 7-year-old girls, at exon 6 and 12 respectively. Both patients had the distinctive facial appearance of cardio-facio-cutaneous syndrome (CFC) type 1. Patients with CFC are rare and characterized by phenotypic and genetic heterogeneity, with overlaps with Noonan syndrome. While nearly 75% of CFC cases have germline BRAF mutations, the frequency of BRAF mutations is inferior in Noonan and LEOPARD syndromes. BRAF mutations in CFC are often found in the cysteine-rich domain of the BRAF protein (exons 6, 11, 12, 13, 14, 15 and 16). Conversely, somatic BRAF mutations are more common, grouped into classes according to their kinase activity level, and have been associated with a variety of malignancies, including pediatric and adult brain tumors (low- and high-grade gliomas, glioblastomas and low-grade astrocytomas). BRAF V600E is the most common somatic mutation, but other mutations are currently being identified. Many of these mutations are within the kinase domain, while others are located across the gene and have less well-understood functional consequences. Germinal V600E mutation has been described once, in a CFC patient having a severe phenotype. Nevertheless, it seems that patients with germline BRAF mutations and gliomas have not yet been reported. Given the rarity of CFC, it is unclear whether there is a high risk of brain tumors. Further molecular studies will enable us to refine recommendations for the prevention, monitoring and care of people with germline BRAF mutations, given the success of BRAF inhibitors in certain cancers, with encouraging results in gliomas.
proteins
2026-04-27 | A Novel MAP3K7 Variant Causing Loss of Function Identified in a Family With Cardiospondylocarpofacial Syndrome: Functional Validation and Molecular Insights.
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as transforming growth factor-β-activated kinase 1 (TAK1), is a widely expressed kinase that plays a crucial role in various cellular processes variants in the MAP3K7 gene have been implicated in two distinct genetic disorders: frontometaphyseal dysplasia Type 2 (FMD2) and cardiofaciocutaneous syndrome (CSCF). To elucidate the consequences of the MAP3K7 variant, we investigated a Chinese family with CSCF harboring a novel heterozygous MAP3K7 variant and examined the genotype-phenotype correlation. Functional validation was performed using clinical evaluations, whole-exome sequencing (WES), and biochemical assays, including western blotting to assess TAK1 phosphorylation levels and downstream signaling pathways. Clinical data and genomic DNA were collected from the proband and family members. WES identified a novel heterozygous variant in MAP3K7 (NM_145331.3: c.149 T > C, p.Val50Ala) inherited from the affected mother. Sequence conservation analysis revealed that the Val50 residue is highly conserved among vertebrates and is critical for ATP binding. Protein 3D modeling predicted that the Val50Ala variant disrupts the kinase domain structure, potentially impairing TAK1 function. In vitro overexpression experiments in human embryonic kidney 293T (HEK293T) cells demonstrated that the Val50Ala variant significantly reduced TAK1 phosphorylation levels. Furthermore, this variant differentially affected downstream signaling molecules (p38, p65, and JNK) compared with variants causing FMD2. Notably, stimulation with transforming growth factor-β (TGF-β) partially restored the altered phosphorylation patterns, suggesting a potential compensatory mechanism. Our study provides novel insights into the molecular pathogenesis of MAP3K7 variants associated with CSCF and FMD2. We demonstrate that the p.Val50Ala variant impairs TAK1 kinase activity and differentially affects downstream signaling pathways. These findings highlight the distinct molecular fingerprints of MAP3K7 variants causing CSCF versus FMD2 and underscore the importance of considering MAP3K7 variants in the differential diagnosis of syndromic congenital cardiac defects, recurrent infections, and global developmental delays. Our results also suggest that TGF-β signaling may offer a potential therapeutic target for modulating the effects of MAP3K7 variants.
2025-05-03 | Quantitative T1 Mapping Indicates Elevated White Matter Myelin in Children With RASopathies.
Evidence suggests a pathological role of myelination in neurodevelopmental disorders with links to cognitive difficulties, but in vivo assessment remains challenging. Quantitative T1 mapping (QT1) has been used in previous clinical studies (e.g., of multiple sclerosis) and shows promise for reliable measurement of myelin alterations. We investigated QT1 for measuring myelination in children with neurodevelopmental disorders of the Ras/mitogen-activated protein kinase (RAS-MAPK) signaling pathway (RASopathies). We collected QT1, diffusion-weighted, and structural magnetic resonance imaging scans from 72 children (49 with RASopathies, 23 typically developing [TD]). QT1 myelin content measures included white matter macromolecular tissue volume (MTV) and cortical R1 (1/T1 relaxation). Group differences were assessed across 39 white matter tracts. Principal component analysis captured cortical myelination patterns across 360 regions, followed by a multivariate analysis of variance (MANOVA). A support vector machine (SVM) identified the most discriminative features between groups. Of 39 tracts, 34 were higher in MTV in children with RASopathies relative to TD children (false discovery rate-corrected p < .05), indicating widespread elevation in myelination. MANOVA revealed a group effect on cortical R1 (p = .002, η2 = 0.028), suggesting cortical myelination differences between the groups. The SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between groups. We found widespread elevated white matter tract myelin and region-dependent cortical myelination patterns in children with RASopathies. Leveraging preclinical models that have shown oligodendrocyte dysfunction, QT1 revealed precocious myelination. Further work is needed to explore relationships with cognition. QT1 is a promising tool for identification and monitoring of myelin as a treatment target in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.
2018-09-17 | C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.
2013-10-01 | Management of rasopathies
Noonan syndrome (NS) and NS-related disorders (Cardio-Facio-Cutaneous (CFC) syndrome, Costello syndrome, LEOPARD (Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth and sensory neural Deafness) syndrome) share common clinical features characterized by unique facial features, postnatal growth failure, psychomotor retardation, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During last decade, strident progress has been made in molecular understanding of NS. The functional alterations of the Ras-mitogen-activated protein kinase (MAPK) pathway are caused by the mutation in more than 10 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2). Thus, NS and NS-related disorders are called RASopathies as a disease group. PTPN11 (40-50%), SOS1 (10%–20%), and RAF1 (3%-17%) mutations are common in NS patients. Noonan syndrome and its related disorders are not rare as a whole. Since their disease natural course and management are different, it is important to recognize RASopathies and differentiate them primarily based on typical clinical feature. By utilizing DNA testing, the confirmatory diagnosis can be made. Multi-systemic involvement in RASopathies requires multidisciplinary evaluation and regular monitoring for each special clinical issue. It involves whole spectra of clinical issues of cardiovascular, growth & endocrine, neuro-cognitive, developmental, skeletal & orthopedic, opthalmo-otolaryngological, GI-nutritional, dental, hemato-oncological and ectodermal systems. For instances, surgical intervention is required for congenital heart defects and cryptoorchidism. Before the surgery, bleeding diathesis should be excluded. Also the risk for malignant hyperthermia has to be considered in choosing anesthetics. Special education might be required in 10-40% of NS patients. However, NS patients carrying the mutation in the SOS1 gene and N380D or N380S mutation in the PTPN11 gene tend to show normal cognitive function. Many NS infants have feeding difficulties with poor suck and prolonged feeding time and may require tube feeding in 24% of NS infants. Most NS patients show normal levels of IGF-1 and IGF-BP3, indicating growth hormone (GH) deficiency is not culpable for postnatal growth failure. However, some studies have demonstrated subnormal overnight mean growth hormone concentration, suggestive of impaired GH secretion. The rhGH therapy in NS has been reported to be effective to improve both the height velocity and the final adult height. In this review, the constellation of overlapping clinical features of RASopathies will be described based on genotype as well as their differential diagnostic points and management.
2010-02-01 | Impact of Feedback Phosphorylation and Raf Heterodimerization on Normal and Mutant B-Raf Signaling
The B-Raf kinase is a Ras pathway effector activated by mutation in numerous human cancers and certain developmental disorders. Here we report that normal and oncogenic B-Raf proteins are subject to a regulatory cycle of extracellular signal-regulated kinase (ERK)-dependent feedback phosphorylation, followed by PP2A- and Pin1-dependent dephosphorylation/recycling. We identify four S/TP sites of B-Raf phosphorylated by activated ERK and find that feedback phosphorylation of B-Raf inhibits binding to activated Ras and disrupts heterodimerization with C-Raf, which is dependent on the B-Raf pS729/14-3-3 binding site. Moreover, we find that events influencing Raf heterodimerization can alter the transforming potential of oncogenic B-Raf proteins possessing intermediate or impaired kinase activity but have no significant effect on proteins with high kinase activity, such as V600E B-Raf. Mutation of the feedback sites or overexpression of the Pin1 prolyl-isomerase, which facilitates B-Raf dephosphorylation/recycling, resulted in increased transformation, whereas mutation of the S729/14-3-3 binding site or expression of dominant negative Pin1 reduced transformation. Mutation of each feedback site caused increased transformation and correlated with enhanced heterodimerization and activation of C-Raf. Finally, we find that B-Raf and C-Raf proteins containing mutations identified in certain developmental disorders constitutively heterodimerize and that their signaling activity can also be modulated by feedback phosphorylation.
antibodies
2026-02-19 | Combined Immunodeficiency Associated With MAP2K1 p.Tyr130His Variant in Cardiofaciocutaneous Syndrome: A Case Report With Literature-Based Phenotypic Comparison.
Cardiofaciocutaneous syndrome (CFCS) is a RASopathy involving craniofacial, cardiac, cutaneous, and neurologic features. MAP2K1 mutations, particularly in the kinase domain, are linked to CFCS type 3. Immune dysfunction has not previously been reported with the p.Tyr130His variant. To describe the case of combined immunodeficiency (CID) associated with the MAP2K1 p.Tyr130His variant. A 4-month-old female with CFCS presented with recurrent infections, growth failure, and ectodermal findings. Immunologic workup revealed hypogammaglobulinemia, low T cell subsets, and absent vaccine responses. Genetic analysis identified the MAP2K1 p.Tyr130His variant. She was started on intravenous immunoglobulin and prophylaxis, with clinical improvement. We describe a case of CID associated with the MAP2K1 p.Tyr130His variant adding to the growing evidence of immune dysregulation in CFCS.
small molecules
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.
2025-05-27 | Scarring Alopecia of Eyebrows with Comedonal Lesions in a Young Boy
A 12-year-old boy, known case of cryptorchidism, planned for orchidopexy, presented with comedonal lesions on the face [Figure 1a], predominantly involving cheeks, ear conchae, and temporal region. He also had erythematous keratotic papules on upper arms and complete loss of both eyebrows. Dermatoscopic evaluation of eyebrows confirmed the presence of scarring alopecia by loss of hair follicles and that of comedonal lesions revealed the presence of multiple discrete, homogenous, and blackish and few whitish keratotic comedonal plugs within dilated follicular openings [Figure 1b]. All relevant systemic workup was done to rule out a syndromic association (Noonan syndrome, Cornelia De Lange syndrome, Rubinstein Taybi syndrome, and cardiofaciocutaneous syndrome). This included a detailed investigative workup after neurological, cardiac, ophthalmological, audiological, renal, and genetic consultations. A diagnosis of ulerythema ophryogenes with comedonal lesions was established. The patient was started on oral isotretinoin 10 mg/day therapy. After receiving the therapy for 1 month, the patient showed significant improvement [Figure 2].Figure 1: (a) Multiple, discrete, black, comedonal lesions on the face, involving both cheeks with complete loss of both eyebrows; (b) Dermatoscopic evaluation revealed presence of multiple discrete, homogenous, blackish and few whitish keratotic comedonal plugs within dilated follicular openings (DermLite IV, ×10, polarized)Figure 2: Significant improvement after 1 month of oral isotretinoin therapyDeclaration of patient consent The authors certify that they have obtained all appropriate parent consent forms. In the form, the parent has given their consent for his images and other clinical information to be reported in the journal. The parent understands that his name and initials will not be published. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2025-04-03 | RASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments.
RAS proteins are critical in cellular signal transduction, influencing cell proliferation, differentiation, and survival. While extensively studied for their role in cancer, RAS gene mutations also contribute significantly to cardiovascular diseases, such as hypertrophic cardiomyopathy, pulmonary valve stenosis, and atrial septal defects. Despite their similar primary structures, RAS proteins exhibit distinct functions in cardiac biology: H-RAS regulates cardiomyocyte size, K-RAS governs proliferation, and N-RAS, less associated with cardiac defects, is understudied in cardiac cells. Congenital RAS mutations, collectively known as RASopathies, include syndromes, like Noonan syndrome and cardio-facio-cutaneous syndrome, which often lead to severe cardiac complications, including heart failure. Genetic testing and imaging advances have improved the diagnosis and management of these conditions. Recent research has shown promise with MEK inhibitors and other targeted therapies, offering potential improvements in managing RAS-related cardiac conditions. This review explores the role of the RAS subfamily in heart disease, highlighting key concepts and potential therapeutic targets. PubMed database was searched using keywords, such as RASopathies, RAS gene mutations, cardiac hypertrophy, cardiovascular disease, RAS/MAPK pathway, congenital heart disease, and more. Relevant literature up to June 2024 was examined and summarized, consisting of data from various clinical trials, metaanalyses, retrospective/prospective cohort studies, and current guidelines.
2025-02-18 | Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models.
RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although B-Raf proto-oncogene (BRAF) mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific adeno-associated virus-BRAF KE (AAV-BRAF KE) delivery induced memory deficits and reactive astrogliosis and increased astrocytic Ca2+ fluctuations. Notably, reducing extracellular signal-regulated kinase (ERK) activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.
2024-11-01 | CSIG-06. BRAF GERMLINE MUTATIONS AND PREDISPOSITION TO BRAIN TUMORS
Abstract We report on two BRAF-mutated children and discuss genetic counseling regarding predisposition to brain tumors. Molecular analysis of the PTPN11 gene and twelve other genes in the RAS-MAPK pathway was carried out in a series of 54 dysmorphic patients with suspected Rasopathies. Two heterozygous BRAF germline mutations were detected in two 7-year-old girls, at exon 6 and 12 respectively. Both patients had the distinctive facial appearance of cardio-facio-cutaneous syndrome (CFC) type 1. Patients with CFC are rare and characterized by phenotypic and genetic heterogeneity, with overlaps with Noonan syndrome. While nearly 75% of CFC cases have germline BRAF mutations, the frequency of BRAF mutations is inferior in Noonan and LEOPARD syndromes. BRAF mutations in CFC are often found in the cysteine-rich domain of the BRAF protein (exons 6, 11, 12, 13, 14, 15 and 16). Conversely, somatic BRAF mutations are more common, grouped into classes according to their kinase activity level, and have been associated with a variety of malignancies, including pediatric and adult brain tumors (low- and high-grade gliomas, glioblastomas and low-grade astrocytomas). BRAF V600E is the most common somatic mutation, but other mutations are currently being identified. Many of these mutations are within the kinase domain, while others are located across the gene and have less well-understood functional consequences. Germinal V600E mutation has been described once, in a CFC patient having a severe phenotype. Nevertheless, it seems that patients with germline BRAF mutations and gliomas have not yet been reported. Given the rarity of CFC, it is unclear whether there is a high risk of brain tumors. Further molecular studies will enable us to refine recommendations for the prevention, monitoring and care of people with germline BRAF mutations, given the success of BRAF inhibitors in certain cancers, with encouraging results in gliomas.
proteins
2026-04-27 | A Novel MAP3K7 Variant Causing Loss of Function Identified in a Family With Cardiospondylocarpofacial Syndrome: Functional Validation and Molecular Insights.
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as transforming growth factor-β-activated kinase 1 (TAK1), is a widely expressed kinase that plays a crucial role in various cellular processes variants in the MAP3K7 gene have been implicated in two distinct genetic disorders: frontometaphyseal dysplasia Type 2 (FMD2) and cardiofaciocutaneous syndrome (CSCF). To elucidate the consequences of the MAP3K7 variant, we investigated a Chinese family with CSCF harboring a novel heterozygous MAP3K7 variant and examined the genotype-phenotype correlation. Functional validation was performed using clinical evaluations, whole-exome sequencing (WES), and biochemical assays, including western blotting to assess TAK1 phosphorylation levels and downstream signaling pathways. Clinical data and genomic DNA were collected from the proband and family members. WES identified a novel heterozygous variant in MAP3K7 (NM_145331.3: c.149 T > C, p.Val50Ala) inherited from the affected mother. Sequence conservation analysis revealed that the Val50 residue is highly conserved among vertebrates and is critical for ATP binding. Protein 3D modeling predicted that the Val50Ala variant disrupts the kinase domain structure, potentially impairing TAK1 function. In vitro overexpression experiments in human embryonic kidney 293T (HEK293T) cells demonstrated that the Val50Ala variant significantly reduced TAK1 phosphorylation levels. Furthermore, this variant differentially affected downstream signaling molecules (p38, p65, and JNK) compared with variants causing FMD2. Notably, stimulation with transforming growth factor-β (TGF-β) partially restored the altered phosphorylation patterns, suggesting a potential compensatory mechanism. Our study provides novel insights into the molecular pathogenesis of MAP3K7 variants associated with CSCF and FMD2. We demonstrate that the p.Val50Ala variant impairs TAK1 kinase activity and differentially affects downstream signaling pathways. These findings highlight the distinct molecular fingerprints of MAP3K7 variants causing CSCF versus FMD2 and underscore the importance of considering MAP3K7 variants in the differential diagnosis of syndromic congenital cardiac defects, recurrent infections, and global developmental delays. Our results also suggest that TGF-β signaling may offer a potential therapeutic target for modulating the effects of MAP3K7 variants.
2025-05-03 | Quantitative T1 Mapping Indicates Elevated White Matter Myelin in Children With RASopathies.
Evidence suggests a pathological role of myelination in neurodevelopmental disorders with links to cognitive difficulties, but in vivo assessment remains challenging. Quantitative T1 mapping (QT1) has been used in previous clinical studies (e.g., of multiple sclerosis) and shows promise for reliable measurement of myelin alterations. We investigated QT1 for measuring myelination in children with neurodevelopmental disorders of the Ras/mitogen-activated protein kinase (RAS-MAPK) signaling pathway (RASopathies). We collected QT1, diffusion-weighted, and structural magnetic resonance imaging scans from 72 children (49 with RASopathies, 23 typically developing [TD]). QT1 myelin content measures included white matter macromolecular tissue volume (MTV) and cortical R1 (1/T1 relaxation). Group differences were assessed across 39 white matter tracts. Principal component analysis captured cortical myelination patterns across 360 regions, followed by a multivariate analysis of variance (MANOVA). A support vector machine (SVM) identified the most discriminative features between groups. Of 39 tracts, 34 were higher in MTV in children with RASopathies relative to TD children (false discovery rate-corrected p < .05), indicating widespread elevation in myelination. MANOVA revealed a group effect on cortical R1 (p = .002, η2 = 0.028), suggesting cortical myelination differences between the groups. The SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between groups. We found widespread elevated white matter tract myelin and region-dependent cortical myelination patterns in children with RASopathies. Leveraging preclinical models that have shown oligodendrocyte dysfunction, QT1 revealed precocious myelination. Further work is needed to explore relationships with cognition. QT1 is a promising tool for identification and monitoring of myelin as a treatment target in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.
2018-09-17 | C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.
2013-10-01 | Management of rasopathies
Noonan syndrome (NS) and NS-related disorders (Cardio-Facio-Cutaneous (CFC) syndrome, Costello syndrome, LEOPARD (Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth and sensory neural Deafness) syndrome) share common clinical features characterized by unique facial features, postnatal growth failure, psychomotor retardation, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During last decade, strident progress has been made in molecular understanding of NS. The functional alterations of the Ras-mitogen-activated protein kinase (MAPK) pathway are caused by the mutation in more than 10 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2). Thus, NS and NS-related disorders are called RASopathies as a disease group. PTPN11 (40-50%), SOS1 (10%–20%), and RAF1 (3%-17%) mutations are common in NS patients. Noonan syndrome and its related disorders are not rare as a whole. Since their disease natural course and management are different, it is important to recognize RASopathies and differentiate them primarily based on typical clinical feature. By utilizing DNA testing, the confirmatory diagnosis can be made. Multi-systemic involvement in RASopathies requires multidisciplinary evaluation and regular monitoring for each special clinical issue. It involves whole spectra of clinical issues of cardiovascular, growth & endocrine, neuro-cognitive, developmental, skeletal & orthopedic, opthalmo-otolaryngological, GI-nutritional, dental, hemato-oncological and ectodermal systems. For instances, surgical intervention is required for congenital heart defects and cryptoorchidism. Before the surgery, bleeding diathesis should be excluded. Also the risk for malignant hyperthermia has to be considered in choosing anesthetics. Special education might be required in 10-40% of NS patients. However, NS patients carrying the mutation in the SOS1 gene and N380D or N380S mutation in the PTPN11 gene tend to show normal cognitive function. Many NS infants have feeding difficulties with poor suck and prolonged feeding time and may require tube feeding in 24% of NS infants. Most NS patients show normal levels of IGF-1 and IGF-BP3, indicating growth hormone (GH) deficiency is not culpable for postnatal growth failure. However, some studies have demonstrated subnormal overnight mean growth hormone concentration, suggestive of impaired GH secretion. The rhGH therapy in NS has been reported to be effective to improve both the height velocity and the final adult height. In this review, the constellation of overlapping clinical features of RASopathies will be described based on genotype as well as their differential diagnostic points and management.
2010-02-01 | Impact of Feedback Phosphorylation and Raf Heterodimerization on Normal and Mutant B-Raf Signaling
The B-Raf kinase is a Ras pathway effector activated by mutation in numerous human cancers and certain developmental disorders. Here we report that normal and oncogenic B-Raf proteins are subject to a regulatory cycle of extracellular signal-regulated kinase (ERK)-dependent feedback phosphorylation, followed by PP2A- and Pin1-dependent dephosphorylation/recycling. We identify four S/TP sites of B-Raf phosphorylated by activated ERK and find that feedback phosphorylation of B-Raf inhibits binding to activated Ras and disrupts heterodimerization with C-Raf, which is dependent on the B-Raf pS729/14-3-3 binding site. Moreover, we find that events influencing Raf heterodimerization can alter the transforming potential of oncogenic B-Raf proteins possessing intermediate or impaired kinase activity but have no significant effect on proteins with high kinase activity, such as V600E B-Raf. Mutation of the feedback sites or overexpression of the Pin1 prolyl-isomerase, which facilitates B-Raf dephosphorylation/recycling, resulted in increased transformation, whereas mutation of the S729/14-3-3 binding site or expression of dominant negative Pin1 reduced transformation. Mutation of each feedback site caused increased transformation and correlated with enhanced heterodimerization and activation of C-Raf. Finally, we find that B-Raf and C-Raf proteins containing mutations identified in certain developmental disorders constitutively heterodimerize and that their signaling activity can also be modulated by feedback phosphorylation.
antibodies
2026-02-19 | Combined Immunodeficiency Associated With MAP2K1 p.Tyr130His Variant in Cardiofaciocutaneous Syndrome: A Case Report With Literature-Based Phenotypic Comparison.
Cardiofaciocutaneous syndrome (CFCS) is a RASopathy involving craniofacial, cardiac, cutaneous, and neurologic features. MAP2K1 mutations, particularly in the kinase domain, are linked to CFCS type 3. Immune dysfunction has not previously been reported with the p.Tyr130His variant. To describe the case of combined immunodeficiency (CID) associated with the MAP2K1 p.Tyr130His variant. A 4-month-old female with CFCS presented with recurrent infections, growth failure, and ectodermal findings. Immunologic workup revealed hypogammaglobulinemia, low T cell subsets, and absent vaccine responses. Genetic analysis identified the MAP2K1 p.Tyr130His variant. She was started on intravenous immunoglobulin and prophylaxis, with clinical improvement. We describe a case of CID associated with the MAP2K1 p.Tyr130His variant adding to the growing evidence of immune dysregulation in CFCS.
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