Cardiofaciocutaneous Syndrome

Mendelian MONDO:0015280 Pathograph 11 Show in embeddings browser RASopathy

Cardiofaciocutaneous (CFC) syndrome is a RASopathy caused by heterozygous germline mutations in BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), or KRAS, characterized by distinctive craniofacial features, congenital heart defects, ectodermal abnormalities (sparse hair, keratosis pilaris, ichthyosis), failure to thrive, and developmental delay. CFC syndrome represents the most severe end of the RASopathy spectrum in terms of cognitive impairment.

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Inheritance

1
Autosomal Dominant HP:0000006
Autosomal dominant. Most affected individuals carry a de novo BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant, although familial recurrence has been reported; each child of an affected individual has a 50% chance of inheriting the variant. In a cohort of 43 cases, genotype distribution was BRAF (81%), MEK1 (14%), and MEK2 (5%).
Autosomal dominant inheritance
Show evidence (4 references)
PMID:20301365 SUPPORT REVIEW SYNTHESIS Human clinical
"CFC syndrome is inherited in an autosomal dominant manner. The majority of individuals with CFC syndrome reported to date have the disorder as the result of a de novo BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant."
The GeneReviews chapter states the mode of inheritance and that most cases arise de novo in one of the four causative genes.
PMID:20301365 SUPPORT REVIEW SYNTHESIS Human clinical
"However, instances of familial recurrence of CFC have been reported. Each child of an individual with CFC syndrome has a 50% chance of inheriting the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant."
Supports the familial-recurrence caveat and the 50% transmission risk stated in this inheritance block.
PMID:20301365 SUPPORT REVIEW SYNTHESIS Human clinical
"The diagnosis of CFC syndrome is established in a proband with suggestive clinical findings by the identification of a heterozygous pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing."
The GeneReviews diagnostic criterion: these four genes are the ones whose heterozygous pathogenic variants establish the diagnosis, which is the set this entry's four numbered subtype rows enumerate.
+ 1 more reference
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Subtypes

4
CFC1 (BRAF-related) MONDO:0007265
BRAF hgnc:1097 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The BRAF-related form, and the largest share of cardiofaciocutaneous syndrome at roughly three quarters of affected individuals. Not every CFC B-Raf mutant protein is kinase-activating: some are kinase-impaired and still phosphorylate the downstream effectors MEK and ERK, so a reduced in-vitro kinase measurement does not exclude the variant as causal.
Show evidence (3 references)
PMID:18413255 SUPPORT BACKGROUND Human clinical
"Approximately 75% of individuals with CFC have mutations in BRAF."
Quantifies the BRAF share of cardiofaciocutaneous syndrome cases that this subtype row carries.
PMID:18413255 SUPPORT PRIMARY RESULT In vitro / ex vivo
"However, as is seen cancer, some of the B-Raf mutant proteins are kinase impaired. Western blot analyses corroborate kinase assays as determined by mutant proteins phosphorylating downstream effectors MEK and ERK."
Biochemical characterisation showing that kinase-impaired CFC B-Raf mutants still phosphorylate MEK and ERK, which is why impaired kinase activity does not rule the variant out.
CGGV:assertion_a53e5a92-126f-4b00-a89b-af55d4f342ca-2018-07-24T160000.000Z SUPPORT Other
"BRAF | HGNC:1097 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
ClinGen classifies the BRAF-cardiofaciocutaneous syndrome relationship as definitive with autosomal dominant inheritance.
CFC2 (KRAS-related) MONDO:0014112
KRAS hgnc:6407 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRAS (hgnc:6407). hgnc:6407 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The KRAS-related form. Germline KRAS variants sit upstream of RAF in the RAS-RAF-ERK cascade whose dysregulation is the common molecular basis shared by cardiofaciocutaneous syndrome and the RASopathies it phenotypically overlaps.
Show evidence (2 references)
PMID:16474404 SUPPORT PRIMARY RESULT Human clinical
"In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders."
Original report of germline KRAS variants in cardiofaciocutaneous syndrome, in three of 43 affected individuals.
CGGV:assertion_248e0d6b-9300-4d17-a350-f742fa92c82c-2018-07-24T160000.000Z SUPPORT Other
"KRAS | HGNC:6407 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Strong"
ClinGen classifies the KRAS-cardiofaciocutaneous syndrome relationship as strong with autosomal dominant inheritance.
CFC3 (MAP2K1/MEK1-related) MONDO:0014113
MAP2K1 hgnc:6840 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MAP2K1 (hgnc:6840). hgnc:6840 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The MAP2K1-related form, encoding MEK1. MAP2K1 and MAP2K2 variants together account for about a quarter of cardiofaciocutaneous syndrome and raise MEK kinase activity, read out as increased phosphorylation of ERK. Seizure frequency and severity are higher in MAP2K1 than in MAP2K2 disease.
Show evidence (3 references)
PMID:18413255 SUPPORT PRIMARY RESULT In vitro / ex vivo
"Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK."
Gives the combined MEK1/MEK2 share of cases and the gain-of-activity mechanism shared by the CFC3 and CFC4 subtypes.
PMID:35524774 SUPPORT PRIMARY RESULT Human clinical
"The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants."
Multinational cohort establishing that MAP2K1 disease carries a heavier seizure burden than MAP2K2 disease, the clinical distinction between the CFC3 and CFC4 subtypes.
CGGV:assertion_f8c7a090-0a97-4653-bd51-702a9f9144b9-2018-05-29T160000.000Z SUPPORT Other
"MAP2K1 | HGNC:6840 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
ClinGen classifies the MAP2K1-cardiofaciocutaneous syndrome relationship as definitive with autosomal dominant inheritance.
CFC4 (MAP2K2/MEK2-related) MONDO:0014114
MAP2K2 hgnc:6842 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MAP2K2 (hgnc:6842). hgnc:6842 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The MAP2K2-related form, encoding MEK2. It shares the raised-MEK-activity mechanism with CFC3 but carries a lighter seizure burden than the BRAF- and MAP2K1-related forms.
Show evidence (3 references)
PMID:16439621 SUPPORT PRIMARY RESULT Human clinical
"three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf"
Original discovery that MEK1 and MEK2 variants cause cardiofaciocutaneous syndrome in individuals without a BRAF variant.
PMID:35524774 SUPPORT PRIMARY RESULT Human clinical
"The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants."
Places MAP2K2 disease at the lower end of the CFC seizure-burden gradient.
CGGV:assertion_7765e2a4-19e4-4b15-9233-4847606fc501-2018-07-24T160000.000Z SUPPORT Other
"MAP2K2 | HGNC:6842 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
ClinGen classifies the MAP2K2-cardiofaciocutaneous syndrome relationship as definitive with autosomal dominant inheritance.
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Pathophysiology

4
RAS GTPase Dysregulation by Germline KRAS Variants
Germline KRAS missense variants act at the most upstream step of the cascade, dysregulating RAS-RAF-ERK signal transduction before the RAF tier. This is the molecular entry point for the CFC2 subtype and the step shared with the RASopathies that cardiofaciocutaneous syndrome phenotypically overlaps.
KRAS hgnc:6407 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRAS (hgnc:6407). hgnc:6407 is a gene from the HUGO Gene Nomenclature Committee.
Ras protein signal transduction GO:0007265 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Ras protein signal transduction (GO:0007265). GO:0007265 is a biological process from the Gene Ontology.
GTPase activity GO:0003924 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated GTPase activity (GO:0003924). GO:0003924 is a molecular function from the Gene Ontology.
Downstream
RAS-MAPK Pathway Hyperactivation Dysregulated RAS signalling raises output through the downstream RAF-MEK-ERK tiers of the same cascade.
Show evidence (1 reference)
PMID:16474404 SUPPORT PRIMARY RESULT Human clinical
"In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders."
Identifies germline KRAS variants in cardiofaciocutaneous syndrome and attributes the disorder to dysregulated RAS-RAF-ERK signalling, the claim this node makes.
B-Raf Kinase Dysregulation by Germline BRAF Variants
Germline BRAF variants act at the RAF tier. They are biochemically heterogeneous: some raise B-Raf kinase activity outright, while others are kinase-impaired and yet still phosphorylate the downstream effectors MEK and ERK. Both classes therefore raise pathway output, which is why an impaired in-vitro kinase measurement does not exclude a variant as causal.
BRAF hgnc:1097 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee.
B-Raf MAP kinase kinase kinase activity GO:0004709 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated B-Raf MAP kinase kinase kinase activity, annotated with MAP kinase kinase kinase activity (GO:0004709). GO:0004709 is a molecular function from the Gene Ontology.
Downstream
MEK1 and MEK2 Kinase Hyperactivation Mutant B-Raf phosphorylates MEK1 and MEK2, the immediate downstream tier.
Seizures Epilepsy burden in cardiofaciocutaneous syndrome tracks the BRAF genotype, concentrating in variants of the catalytic protein kinase domain.
Show evidence (1 reference)
PMID:18413255 SUPPORT PRIMARY RESULT In vitro / ex vivo
"However, as is seen cancer, some of the B-Raf mutant proteins are kinase impaired. Western blot analyses corroborate kinase assays as determined by mutant proteins phosphorylating downstream effectors MEK and ERK."
Kinase assays and western blots showing that CFC B-Raf mutant proteins, including kinase-impaired ones, phosphorylate MEK and ERK - the MAP-kinase-kinase-kinase activity this node binds.
MEK1 and MEK2 Kinase Hyperactivation
MAP2K1 and MAP2K2 encode MEK1 and MEK2, the immediate downstream effectors of B-Raf. Germline CFC variants in either gene increase MEK kinase activity, measured as increased phosphorylation of ERK, and together account for about a quarter of cardiofaciocutaneous syndrome.
MAP2K1 hgnc:6840 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAP2K1 (hgnc:6840). hgnc:6840 is a gene from the HUGO Gene Nomenclature Committee. MAP2K2 hgnc:6842 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAP2K2 (hgnc:6842). hgnc:6842 is a gene from the HUGO Gene Nomenclature Committee.
MEK1 and MEK2 MAP kinase kinase activity GO:0004708 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased MEK1 and MEK2 MAP kinase kinase activity, annotated with MAP kinase kinase activity (GO:0004708). GO:0004708 is a molecular function from the Gene Ontology.
Downstream
RAS-MAPK Pathway Hyperactivation Raised MEK activity increases ERK1/2 phosphorylation, the pathway output measured in CFC models.
Seizures Epilepsy burden tracks the MEK genotype, concentrating at the recurrent MAP2K1 p.Tyr130 site and sparing MAP2K2 disease relative to BRAF and MAP2K1 disease.
Show evidence (1 reference)
PMID:18413255 SUPPORT PRIMARY RESULT In vitro / ex vivo
"Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK."
Reports the increased MEK kinase activity this node asserts and the share of cases carrying it.
RAS-MAPK Pathway Hyperactivation
Mutations in BRAF, MEK1, or MEK2 cause constitutive or enhanced activation of the RAS-MAPK signaling cascade, affecting cell proliferation and differentiation during development. BRAF mutations are most common (~75%), followed by MEK1/MEK2 mutations.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology. Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
MAPK Cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves MAPK Cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ERK1/2 Cascade GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves ERK1/2 Cascade, annotated with ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. Cell Proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cell Proliferation, annotated with cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Downstream
Congenital Heart Defects Germline RAS-MAPK pathway variants produce cardiac malformations detectable prenatally.
Polyhydramnios Germline RAS-MAPK pathway variants produce polyhydramnios as a prenatal consequence.
Show evidence (2 references)
PMID:16439621 SUPPORT Human clinical
"heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF"
Landmark Science paper establishing that CFC syndrome is caused by de novo mutations in MAPK pathway genes, with BRAF as the predominant causative gene.
PMID:22301711 SUPPORT BACKGROUND Human clinical
"Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2."
Names all four causative genes that converge on this node; the sentence states the human genetic cause, which the zebrafish study restates as its premise.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cardiofaciocutaneous Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Cardiovascular 2
Congenital Heart Defects FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Pulmonary Valve Stenosis FREQUENT Pulmonic stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary valve stenosis, annotated with Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Head and Neck 1
Distinctive Facies VERY_FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Integument 2
Sparse Hair VERY_FREQUENT HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Keratosis Pilaris FREQUENT HP:0032152 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratosis pilaris (HP:0032152). HP:0032152 is a phenotype from the Human Phenotype Ontology.
Musculoskeletal 1
Kyphoscoliosis FREQUENT HP:0002751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphoscoliosis (HP:0002751). HP:0002751 is a phenotype from the Human Phenotype Ontology.
Nervous System 2
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38136934 SUPPORT Human clinical
"Neurological involvement in CFC is more severe than in other RASopathies."
Review confirming that CFC syndrome has the most severe cognitive impairment among the RASopathy spectrum disorders.
PMID:35524774 SUPPORT Human clinical
"The overall frequency of intellectual disability and seizures was 82% and 55%, respectively."
Multinational CFC cohort (n=138) quantifying intellectual disability at 82%, supporting the very-frequent classification.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35524774 SUPPORT Human clinical
"The overall frequency of intellectual disability and seizures was 82% and 55%, respectively."
Multinational CFC cohort (n=138) quantifying the overall seizure frequency at 55%.
PMID:35524774 SUPPORT Human clinical
"The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants."
Establishes the genotype-associated gradient of seizure burden in CFC syndrome.
Prenatal and Birth 1
Polyhydramnios OCCASIONAL HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561). HP:0001561 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36308388 SUPPORT Human clinical
"Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities."
Study of 43 CFC cases documenting prenatal phenotype including polyhydramnios as a manifestation of germline RAS/MAPK dysregulation.
Growth 2
Failure to Thrive VERY_FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Short Stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
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Genetic Associations

5
BRAF (Pathogenic Variants)
Gene: BRAF hgnc:1097 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BRAF (hgnc:1097). hgnc:1097 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:16439621 SUPPORT PRIMARY RESULT Human clinical
"The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation."
Establishes BRAF as the major causative gene and supports the note that most CFC BRAF variants are not the recurrent tumour substitutions.
CGGV:assertion_a53e5a92-126f-4b00-a89b-af55d4f342ca-2018-07-24T160000.000Z SUPPORT Other
"BRAF | HGNC:1097 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
ClinGen classifies the BRAF-cardiofaciocutaneous syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
KRAS (Pathogenic Variants)
Gene: KRAS hgnc:6407 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRAS (hgnc:6407). hgnc:6407 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:16474404 SUPPORT PRIMARY RESULT Human clinical
"In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders."
Original report of germline KRAS variants in cardiofaciocutaneous syndrome and the source of the case count in this entry's frequency band.
CGGV:assertion_248e0d6b-9300-4d17-a350-f742fa92c82c-2018-07-24T160000.000Z SUPPORT Other
"KRAS | HGNC:6407 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Strong"
ClinGen classifies the KRAS-cardiofaciocutaneous syndrome gene-disease relationship as strong with autosomal dominant inheritance.
MAP2K1 (Pathogenic Variants)
Gene: MAP2K1 hgnc:6840 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAP2K1 (hgnc:6840). hgnc:6840 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:16439621 SUPPORT PRIMARY RESULT Human clinical
"three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf"
Original discovery that MEK1 and MEK2 variants cause cardiofaciocutaneous syndrome in individuals without a BRAF variant.
CGGV:assertion_f8c7a090-0a97-4653-bd51-702a9f9144b9-2018-05-29T160000.000Z SUPPORT Other
"MAP2K1 | HGNC:6840 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
ClinGen classifies the MAP2K1-cardiofaciocutaneous syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
MAP2K2 (Pathogenic Variants)
Gene: MAP2K2 hgnc:6842 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAP2K2 (hgnc:6842). hgnc:6842 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:35524774 SUPPORT PRIMARY RESULT Human clinical
"The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants."
Supports the note that MAP2K2 disease carries a lighter seizure burden than BRAF- or MAP2K1-related disease.
CGGV:assertion_7765e2a4-19e4-4b15-9233-4847606fc501-2018-07-24T160000.000Z SUPPORT Other
"MAP2K2 | HGNC:6842 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
ClinGen classifies the MAP2K2-cardiofaciocutaneous syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
NRAS (Pathogenic Variants)
Gene: NRAS hgnc:7989 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NRAS (hgnc:7989). hgnc:7989 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
CGGV:assertion_d466df2a-8e3d-4d4a-bb96-8e483d4c56e7-2018-07-24T160000.000Z SUPPORT Other
"NRAS | HGNC:7989 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Limited"
ClinGen classifies the NRAS-cardiofaciocutaneous syndrome gene-disease relationship as limited with autosomal dominant inheritance.
💊

Medical Actions

3
Cardiac Management
Action: Cardiac surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cardiac surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Management of congenital heart defects, including surgical correction of pulmonary stenosis when indicated.
Nutritional Support
Action: Nutritional supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Nutritional interventions for failure to thrive, including tube feeding when necessary.
MEK Inhibitor Therapy
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
MEK inhibitors are under investigation for treatment of RASopathies, with potential to ameliorate some features. Zebrafish model studies suggest MEK inhibitors could treat progressive phenotypes.
Show evidence (1 reference)
PMID:38136934 SUPPORT Model organism
"Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children."
Review summarizing preclinical evidence supporting MEK inhibitor therapy for CFC syndrome based on zebrafish model studies.
📊

Prevalence

1
Japanese nationwide survey
Point prevalence 0.123457 per 100,000 1–9 per 1,000,000
A nationwide Japanese epidemiological survey estimated a minimum prevalence of about 1 in 810,000 individuals. A recent review continues to describe cardiofaciocutaneous syndrome as one of the rarest RASopathies, so this survey-based figure is best interpreted as a lower-bound clinically ascertained prevalence rather than a definitive global estimate.
Show evidence (2 references)
PMID:22495831 SUPPORT Human clinical
"The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively."
This nationwide epidemiological survey directly reports the estimated prevalence of cardiofaciocutaneous syndrome in Japan.
PMID:38136934 SUPPORT Human clinical
"Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies"
This contemporary review supports interpreting CFC syndrome as an ultra-rare disorder and contextualizes the survey-based prevalence estimate.
{ }

Source YAML

click to show 
name: Cardiofaciocutaneous Syndrome
creation_date: '2026-02-06T03:39:54Z'
category: Mendelian
description: >
  Cardiofaciocutaneous (CFC) syndrome is a RASopathy caused by heterozygous
  germline mutations in BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), or KRAS, characterized
  by distinctive craniofacial features, congenital heart defects, ectodermal
  abnormalities (sparse hair, keratosis pilaris, ichthyosis), failure to thrive,
  and developmental delay. CFC syndrome represents the most severe end of the
  RASopathy spectrum in terms of cognitive impairment.
disease_term:
  preferred_term: Cardiofaciocutaneous syndrome
  term:
    id: MONDO:0015280
    label: cardiofaciocutaneous syndrome
parents:
- RASopathy
has_subtypes:
- name: CFC1
  display_name: CFC1 (BRAF-related)
  subtype_term:
    preferred_term: BRAF-related cardiofaciocutaneous syndrome
    term:
      id: MONDO:0007265
      label: cardiofaciocutaneous syndrome 1
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The BRAF-related form, and the largest share of cardiofaciocutaneous
    syndrome at roughly three quarters of affected individuals. Not every CFC
    B-Raf mutant protein is kinase-activating: some are kinase-impaired and
    still phosphorylate the downstream effectors MEK and ERK, so a reduced
    in-vitro kinase measurement does not exclude the variant as causal.
  evidence:
  - reference: PMID:18413255
    reference_title: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Approximately 75% of individuals with CFC have mutations in BRAF.
    explanation: >-
      Quantifies the BRAF share of cardiofaciocutaneous syndrome cases that this
      subtype row carries.
  - reference: PMID:18413255
    reference_title: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, as is seen cancer, some of the B-Raf mutant proteins are kinase
      impaired. Western blot analyses corroborate kinase assays as determined by
      mutant proteins phosphorylating downstream effectors MEK and ERK.
    explanation: >-
      Biochemical characterisation showing that kinase-impaired CFC B-Raf mutants
      still phosphorylate MEK and ERK, which is why impaired kinase activity does
      not rule the variant out.
  - reference: CGGV:assertion_a53e5a92-126f-4b00-a89b-af55d4f342ca-2018-07-24T160000.000Z
    reference_title: "BRAF / cardiofaciocutaneous syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BRAF | HGNC:1097 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
    explanation: >-
      ClinGen classifies the BRAF-cardiofaciocutaneous syndrome relationship as
      definitive with autosomal dominant inheritance.
- name: CFC2
  display_name: CFC2 (KRAS-related)
  subtype_term:
    preferred_term: KRAS-related cardiofaciocutaneous syndrome
    term:
      id: MONDO:0014112
      label: cardiofaciocutaneous syndrome 2
  genes:
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The KRAS-related form. Germline KRAS variants sit upstream of RAF in the
    RAS-RAF-ERK cascade whose dysregulation is the common molecular basis shared
    by cardiofaciocutaneous syndrome and the RASopathies it phenotypically
    overlaps.
  evidence:
  - reference: PMID:16474404
    reference_title: Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In 43 individuals with CFC, we identified two heterozygous KRAS mutations
      in three individuals and eight BRAF mutations in 16 individuals, suggesting
      that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis
      for the three related disorders.
    explanation: >-
      Original report of germline KRAS variants in cardiofaciocutaneous syndrome,
      in three of 43 affected individuals.
  - reference: CGGV:assertion_248e0d6b-9300-4d17-a350-f742fa92c82c-2018-07-24T160000.000Z
    reference_title: "KRAS / cardiofaciocutaneous syndrome (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRAS | HGNC:6407 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Strong"
    explanation: >-
      ClinGen classifies the KRAS-cardiofaciocutaneous syndrome relationship as
      strong with autosomal dominant inheritance.
- name: CFC3
  display_name: CFC3 (MAP2K1/MEK1-related)
  subtype_term:
    preferred_term: MAP2K1-related cardiofaciocutaneous syndrome
    term:
      id: MONDO:0014113
      label: cardiofaciocutaneous syndrome 3
  genes:
  - preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The MAP2K1-related form, encoding MEK1. MAP2K1 and MAP2K2 variants together
    account for about a quarter of cardiofaciocutaneous syndrome and raise MEK
    kinase activity, read out as increased phosphorylation of ERK. Seizure
    frequency and severity are higher in MAP2K1 than in MAP2K2 disease.
  evidence:
  - reference: PMID:18413255
    reference_title: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Approximately 25% of individuals with CFC have mutations in either MEK1 or
      MEK2 that lead to increased MEK kinase activity as judged by increased
      phosphorylation of its downstream effector ERK.
    explanation: >-
      Gives the combined MEK1/MEK2 share of cases and the gain-of-activity
      mechanism shared by the CFC3 and CFC4 subtypes.
  - reference: PMID:35524774
    reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The frequency and severity of seizures was higher among individuals with
      BRAF or MAP2K1 variants than in those with MAP2K2 variants.
    explanation: >-
      Multinational cohort establishing that MAP2K1 disease carries a heavier
      seizure burden than MAP2K2 disease, the clinical distinction between the
      CFC3 and CFC4 subtypes.
  - reference: CGGV:assertion_f8c7a090-0a97-4653-bd51-702a9f9144b9-2018-05-29T160000.000Z
    reference_title: "MAP2K1 / cardiofaciocutaneous syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAP2K1 | HGNC:6840 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
    explanation: >-
      ClinGen classifies the MAP2K1-cardiofaciocutaneous syndrome relationship as
      definitive with autosomal dominant inheritance.
- name: CFC4
  display_name: CFC4 (MAP2K2/MEK2-related)
  subtype_term:
    preferred_term: MAP2K2-related cardiofaciocutaneous syndrome
    term:
      id: MONDO:0014114
      label: cardiofaciocutaneous syndrome 4
  genes:
  - preferred_term: MAP2K2
    term:
      id: hgnc:6842
      label: MAP2K2
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The MAP2K2-related form, encoding MEK2. It shares the raised-MEK-activity
    mechanism with CFC3 but carries a lighter seizure burden than the BRAF- and
    MAP2K1-related forms.
  evidence:
  - reference: PMID:16439621
    reference_title: "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      three of five individuals without BRAF mutations had missense mutations
      in either MEK1 or MEK2, downstream effectors of B-Raf
    explanation: >-
      Original discovery that MEK1 and MEK2 variants cause cardiofaciocutaneous
      syndrome in individuals without a BRAF variant.
  - reference: PMID:35524774
    reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The frequency and severity of seizures was higher among individuals with
      BRAF or MAP2K1 variants than in those with MAP2K2 variants.
    explanation: >-
      Places MAP2K2 disease at the lower end of the CFC seizure-burden gradient.
  - reference: CGGV:assertion_7765e2a4-19e4-4b15-9233-4847606fc501-2018-07-24T160000.000Z
    reference_title: "MAP2K2 / cardiofaciocutaneous syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAP2K2 | HGNC:6842 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
    explanation: >-
      ClinGen classifies the MAP2K2-cardiofaciocutaneous syndrome relationship as
      definitive with autosomal dominant inheritance.
prevalence:
- population: Japanese nationwide survey
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.123457
  percentage: 1 in 810,000
  notes: >-
    A nationwide Japanese epidemiological survey estimated a minimum prevalence
    of about 1 in 810,000 individuals. A recent review continues to describe
    cardiofaciocutaneous syndrome as one of the rarest RASopathies, so this
    survey-based figure is best interpreted as a lower-bound clinically
    ascertained prevalence rather than a definitive global estimate.
  evidence:
  - reference: PMID:22495831
    reference_title: "Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively."
    explanation: This nationwide epidemiological survey directly reports the estimated prevalence of cardiofaciocutaneous syndrome in Japan.
  - reference: PMID:38136934
    reference_title: "The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies"
    explanation: This contemporary review supports interpreting CFC syndrome as an ultra-rare disorder and contextualizes the survey-based prevalence estimate.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Autosomal dominant. Most affected individuals carry a de novo BRAF, MAP2K1,
    MAP2K2, or KRAS pathogenic variant, although familial recurrence has been
    reported; each child of an affected individual has a 50% chance of inheriting
    the variant. In a cohort of 43 cases, genotype distribution was BRAF (81%),
    MEK1 (14%), and MEK2 (5%).
  evidence:
  - reference: PMID:20301365
    reference_title: Cardiofaciocutaneous Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CFC syndrome is inherited in an autosomal dominant manner. The majority of
      individuals with CFC syndrome reported to date have the disorder as the
      result of a de novo BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant.
    explanation: >-
      The GeneReviews chapter states the mode of inheritance and that most cases
      arise de novo in one of the four causative genes.
  - reference: PMID:20301365
    reference_title: Cardiofaciocutaneous Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      However, instances of familial recurrence of CFC have been reported. Each
      child of an individual with CFC syndrome has a 50% chance of inheriting the
      BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant.
    explanation: >-
      Supports the familial-recurrence caveat and the 50% transmission risk stated
      in this inheritance block.
  - reference: PMID:20301365
    reference_title: Cardiofaciocutaneous Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of CFC syndrome is established in a proband with suggestive
      clinical findings by the identification of a heterozygous pathogenic variant
      in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing.
    explanation: >-
      The GeneReviews diagnostic criterion: these four genes are the ones whose
      heterozygous pathogenic variants establish the diagnosis, which is the set
      this entry's four numbered subtype rows enumerate.
  - reference: PMID:36308388
    reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 43 individuals with pathogenic variants in BRAF (81%),
      MEK1 (14%), or MEK2 (5%) genes.
    explanation: >-
      Large cohort study establishing genotype distribution in CFC syndrome,
      confirming BRAF as the predominant causative gene.
pathophysiology:
- name: RAS GTPase Dysregulation by Germline KRAS Variants
  description: >-
    Germline KRAS missense variants act at the most upstream step of the cascade,
    dysregulating RAS-RAF-ERK signal transduction before the RAF tier. This is
    the molecular entry point for the CFC2 subtype and the step shared with the
    RASopathies that cardiofaciocutaneous syndrome phenotypically overlaps.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  biological_processes:
  - preferred_term: Ras protein signal transduction
    term:
      id: GO:0007265
      label: Ras protein signal transduction
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:16474404
    reference_title: Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In 43 individuals with CFC, we identified two heterozygous KRAS mutations
      in three individuals and eight BRAF mutations in 16 individuals, suggesting
      that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis
      for the three related disorders.
    explanation: >-
      Identifies germline KRAS variants in cardiofaciocutaneous syndrome and
      attributes the disorder to dysregulated RAS-RAF-ERK signalling, the claim
      this node makes.
  molecular_functions:
  - preferred_term: GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DYSREGULATED
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: >-
      Dysregulated RAS signalling raises output through the downstream RAF-MEK-ERK
      tiers of the same cascade.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - RAF recruitment and activation by GTP-loaded RAS
- name: B-Raf Kinase Dysregulation by Germline BRAF Variants
  description: >-
    Germline BRAF variants act at the RAF tier. They are biochemically
    heterogeneous: some raise B-Raf kinase activity outright, while others are
    kinase-impaired and yet still phosphorylate the downstream effectors MEK and
    ERK. Both classes therefore raise pathway output, which is why an impaired
    in-vitro kinase measurement does not exclude a variant as causal.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  molecular_functions:
  - preferred_term: B-Raf MAP kinase kinase kinase activity
    term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:18413255
    reference_title: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, as is seen cancer, some of the B-Raf mutant proteins are kinase
      impaired. Western blot analyses corroborate kinase assays as determined by
      mutant proteins phosphorylating downstream effectors MEK and ERK.
    explanation: >-
      Kinase assays and western blots showing that CFC B-Raf mutant proteins,
      including kinase-impaired ones, phosphorylate MEK and ERK - the
      MAP-kinase-kinase-kinase activity this node binds.
  downstream:
  - target: MEK1 and MEK2 Kinase Hyperactivation
    description: >-
      Mutant B-Raf phosphorylates MEK1 and MEK2, the immediate downstream tier.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16439621
      reference_title: "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        three of five individuals without BRAF mutations had missense mutations
        in either MEK1 or MEK2, downstream effectors of B-Raf
      explanation: >-
        States that MEK1 and MEK2 are the downstream effectors of B-Raf, the
        ordering this edge asserts.
  - target: Seizures
    description: >-
      Epilepsy burden in cardiofaciocutaneous syndrome tracks the BRAF genotype,
      concentrating in variants of the catalytic protein kinase domain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35524774
      reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        A disproportionate incidence of severe, treatment-resistant seizures was
        observed in patients with variants in the catalytic protein kinase domain
        of BRAF and at the common p.Y130 site of MAP2K1.
      explanation: >-
        Multinational cohort of 138 individuals locating the heaviest seizure
        burden to variants in this gene's kinase domain, which is the
        genotype-specific basis of this edge.
- name: MEK1 and MEK2 Kinase Hyperactivation
  description: >-
    MAP2K1 and MAP2K2 encode MEK1 and MEK2, the immediate downstream effectors of
    B-Raf. Germline CFC variants in either gene increase MEK kinase activity,
    measured as increased phosphorylation of ERK, and together account for about
    a quarter of cardiofaciocutaneous syndrome.
  biological_scale: MOLECULAR
  role: central_effector
  genes:
  - preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  - preferred_term: MAP2K2
    term:
      id: hgnc:6842
      label: MAP2K2
  molecular_functions:
  - preferred_term: MEK1 and MEK2 MAP kinase kinase activity
    term:
      id: GO:0004708
      label: MAP kinase kinase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:18413255
    reference_title: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Approximately 25% of individuals with CFC have mutations in either MEK1 or
      MEK2 that lead to increased MEK kinase activity as judged by increased
      phosphorylation of its downstream effector ERK.
    explanation: >-
      Reports the increased MEK kinase activity this node asserts and the share
      of cases carrying it.
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: >-
      Raised MEK activity increases ERK1/2 phosphorylation, the pathway output
      measured in CFC models.
    causal_link_type: DIRECT
  - target: Seizures
    description: >-
      Epilepsy burden tracks the MEK genotype, concentrating at the recurrent
      MAP2K1 p.Tyr130 site and sparing MAP2K2 disease relative to BRAF and
      MAP2K1 disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35524774
      reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        A disproportionate incidence of severe, treatment-resistant seizures was
        observed in patients with variants in the catalytic protein kinase domain
        of BRAF and at the common p.Y130 site of MAP2K1.
      explanation: >-
        Multinational cohort of 138 individuals locating the heaviest MEK-side
        seizure burden to the recurrent MAP2K1 p.Tyr130 site, which is the
        genotype-specific basis of this edge.
    - reference: PMID:35524774
      reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The frequency and severity of seizures was higher among individuals with
        BRAF or MAP2K1 variants than in those with MAP2K2 variants.
      explanation: >-
        Separates the two MEK genes on seizure burden, the asymmetry this edge's
        description states.
- name: RAS-MAPK Pathway Hyperactivation
  description: >
    Mutations in BRAF, MEK1, or MEK2 cause constitutive or enhanced activation
    of the RAS-MAPK signaling cascade, affecting cell proliferation and
    differentiation during development. BRAF mutations are most common (~75%),
    followed by MEK1/MEK2 mutations.
  biological_scale: CELLULAR
  role: consequence
  evidence:
  - reference: PMID:16439621
    reference_title: "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      heterogeneous de novo missense mutations in three genes within the
      mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome.
      The majority of cases (18 out of 23) are caused by mutations in BRAF
    explanation: >-
      Landmark Science paper establishing that CFC syndrome is caused by de novo
      mutations in MAPK pathway genes, with BRAF as the predominant causative gene.
  - reference: PMID:22301711
    reference_title: Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2.
    explanation: >-
      Names all four causative genes that converge on this node; the sentence
      states the human genetic cause, which the zebrafish study restates as its
      premise.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: MAPK Cascade
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: ERK1/2 Cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  - preferred_term: Cell Proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Congenital Heart Defects
    description: >-
      Germline RAS-MAPK pathway variants produce cardiac malformations detectable
      prenatally.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36308388
      reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Germline pathogenic vaiants had mutiple congenital consequences including
        polyhydramnios, renal and cardiac abnormalities, macrosomia, and
        macrocephaly on second and third trimester ultrasound.
      explanation: >-
        Attributes cardiac abnormalities to the germline pathogenic variants as a
        congenital consequence. Quoted verbatim, including the source's
        typographical errors.
  - target: Polyhydramnios
    description: >-
      Germline RAS-MAPK pathway variants produce polyhydramnios as a prenatal
      consequence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36308388
      reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Germline pathogenic vaiants had mutiple congenital consequences including
        polyhydramnios, renal and cardiac abnormalities, macrosomia, and
        macrocephaly on second and third trimester ultrasound.
      explanation: >-
        Attributes polyhydramnios to the germline pathogenic variants as a
        congenital consequence. Quoted verbatim, including the source's
        typographical errors.
genetic:
- name: BRAF
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CFC1
  frequency: the predominant cardiofaciocutaneous syndrome gene
  case_fractions:
  - population: >-
      Survey cohort of 43 individuals with molecularly confirmed
      cardiofaciocutaneous syndrome, recruited through CFC International
    case_fraction_percent: 81.0
    cohort_size: 43
    notes: >-
      Parent-reported retrospective medical-history survey recruited through a
      family organisation, so the genotype split is clinically ascertained rather
      than population-based.
    evidence:
    - reference: PMID:36308388
      reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified 43 individuals with pathogenic variants in BRAF (81%),
        MEK1 (14%), or MEK2 (5%) genes.
      explanation: >-
        Gives the BRAF share of this cohort and the cohort size.
  notes: >-
    Reported germline CFC BRAF variants mostly lie outside the recurrent somatic
    hotspots: of eleven variants in the original CFC series only two produced
    substitutions also seen in tumours.
  evidence:
  - reference: PMID:16439621
    reference_title: "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The majority of cases (18 out of 23) are caused by mutations in BRAF,
      a gene frequently mutated in cancer. Of the 11 mutations identified,
      two result in amino acid substitutions that occur in tumors, but most
      are unique and suggest previously unknown mechanisms of B-Raf activation.
    explanation: >-
      Establishes BRAF as the major causative gene and supports the note that
      most CFC BRAF variants are not the recurrent tumour substitutions.
  - reference: CGGV:assertion_a53e5a92-126f-4b00-a89b-af55d4f342ca-2018-07-24T160000.000Z
    reference_title: "BRAF / cardiofaciocutaneous syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BRAF | HGNC:1097 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
    explanation: ClinGen classifies the BRAF-cardiofaciocutaneous syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CFC2
  frequency: a rare cause, found in three of the 43 individuals in the original series
  notes: >-
    KRAS acts upstream of RAF in the same cascade, which is why the
    cardiofaciocutaneous phenotype attributed to it overlaps the other
    RASopathies. The separate CFC International survey cohort that supplies the
    BRAF, MAP2K1 and MAP2K2 case fractions on this entry reports pathogenic
    variants in those three genes only, so no KRAS case fraction is recorded here.
  evidence:
  - reference: PMID:16474404
    reference_title: Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In 43 individuals with CFC, we identified two heterozygous KRAS mutations
      in three individuals and eight BRAF mutations in 16 individuals, suggesting
      that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis
      for the three related disorders.
    explanation: >-
      Original report of germline KRAS variants in cardiofaciocutaneous syndrome
      and the source of the case count in this entry's frequency band.
  - reference: CGGV:assertion_248e0d6b-9300-4d17-a350-f742fa92c82c-2018-07-24T160000.000Z
    reference_title: "KRAS / cardiofaciocutaneous syndrome (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRAS | HGNC:6407 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Strong"
    explanation: ClinGen classifies the KRAS-cardiofaciocutaneous syndrome gene-disease relationship as strong with autosomal dominant inheritance.
- name: MAP2K1
  gene_term:
    preferred_term: MAP2K1
    term:
      id: hgnc:6840
      label: MAP2K1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CFC3
  case_fractions:
  - population: >-
      Survey cohort of 43 individuals with molecularly confirmed
      cardiofaciocutaneous syndrome, recruited through CFC International
    case_fraction_percent: 14.0
    cohort_size: 43
    notes: >-
      Reported under the protein name MEK1. Parent-reported retrospective
      medical-history survey recruited through a family organisation.
    evidence:
    - reference: PMID:36308388
      reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified 43 individuals with pathogenic variants in BRAF (81%),
        MEK1 (14%), or MEK2 (5%) genes.
      explanation: >-
        Gives the MEK1 (MAP2K1) share of this cohort and the cohort size.
  notes: >-
    MAP2K1 encodes MEK1, an immediate downstream effector of B-Raf. CFC variants
    raise MEK kinase activity rather than impairing it.
  evidence:
  - reference: PMID:16439621
    reference_title: "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      three of five individuals without BRAF mutations had missense mutations
      in either MEK1 or MEK2, downstream effectors of B-Raf
    explanation: >-
      Original discovery that MEK1 and MEK2 variants cause cardiofaciocutaneous
      syndrome in individuals without a BRAF variant.
  - reference: CGGV:assertion_f8c7a090-0a97-4653-bd51-702a9f9144b9-2018-05-29T160000.000Z
    reference_title: "MAP2K1 / cardiofaciocutaneous syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAP2K1 | HGNC:6840 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
    explanation: ClinGen classifies the MAP2K1-cardiofaciocutaneous syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: MAP2K2
  gene_term:
    preferred_term: MAP2K2
    term:
      id: hgnc:6842
      label: MAP2K2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CFC4
  case_fractions:
  - population: >-
      Survey cohort of 43 individuals with molecularly confirmed
      cardiofaciocutaneous syndrome, recruited through CFC International
    case_fraction_percent: 5.0
    cohort_size: 43
    notes: >-
      Reported under the protein name MEK2. Parent-reported retrospective
      medical-history survey recruited through a family organisation.
    evidence:
    - reference: PMID:36308388
      reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified 43 individuals with pathogenic variants in BRAF (81%),
        MEK1 (14%), or MEK2 (5%) genes.
      explanation: >-
        Gives the MEK2 (MAP2K2) share of this cohort and the cohort size.
  notes: >-
    MAP2K2 encodes MEK2, the paralogous downstream effector of B-Raf. The
    multinational cohort places MAP2K2 disease at the lower end of the CFC
    seizure-burden gradient.
  evidence:
  - reference: PMID:35524774
    reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The frequency and severity of seizures was higher among individuals with
      BRAF or MAP2K1 variants than in those with MAP2K2 variants.
    explanation: >-
      Supports the note that MAP2K2 disease carries a lighter seizure burden than
      BRAF- or MAP2K1-related disease.
  - reference: CGGV:assertion_7765e2a4-19e4-4b15-9233-4847606fc501-2018-07-24T160000.000Z
    reference_title: "MAP2K2 / cardiofaciocutaneous syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAP2K2 | HGNC:6842 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Definitive"
    explanation: ClinGen classifies the MAP2K2-cardiofaciocutaneous syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: NRAS
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  association: Pathogenic Variants
  notes: >-
    NRAS carries a ClinGen Limited gene-disease validity classification for
    cardiofaciocutaneous syndrome, and MONDO's four numbered CFC subtypes are
    defined on BRAF, KRAS, MAP2K1 and MAP2K2 rather than on NRAS. This entry
    therefore records the gene and its ClinGen grade only, and keeps the causal
    claims of a relationship_type, a subtype assignment and a mechanism node for
    the four genes ClinGen grades Definitive or Strong. The same ClinGen table
    grades PTPN11, RAF1, SHOC2 and SOS1 Disputed for this disease.
  evidence:
  - reference: CGGV:assertion_d466df2a-8e3d-4d4a-bb96-8e483d4c56e7-2018-07-24T160000.000Z
    reference_title: "NRAS / cardiofaciocutaneous syndrome (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NRAS | HGNC:7989 | cardiofaciocutaneous syndrome | MONDO:0015280 | AD | Limited"
    explanation: ClinGen classifies the NRAS-cardiofaciocutaneous syndrome gene-disease relationship as limited with autosomal dominant inheritance.
phenotypes:
- name: Distinctive Facies
  description: >
    Characteristic craniofacial features including high forehead, bitemporal
    narrowing, hypoplastic supraorbital ridges, and downslanting palpebral
    fissures.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
- name: Congenital Heart Defects
  description: >
    Cardiac malformations including pulmonary valve stenosis, atrial septal
    defect, and hypertrophic cardiomyopathy. Cardiac disease is present in
    approximately 75% of CFC cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
- name: Pulmonary Valve Stenosis
  description: >
    Pulmonary valve stenosis is the most common cardiac defect, occurring
    in approximately 45% of cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonary valve stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
- name: Sparse Hair
  description: >
    Sparse, curly, friable hair is characteristic.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
- name: Keratosis Pilaris
  description: >
    Keratosis pilaris affecting the face and limbs.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Keratosis pilaris
    term:
      id: HP:0032152
      label: Keratosis pilaris
- name: Failure to Thrive
  description: >
    Feeding difficulties and failure to thrive in infancy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
- name: Intellectual Disability
  description: >
    Moderate to severe intellectual disability is typical. Neurological
    involvement in CFC is more severe than in other RASopathies.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38136934
    reference_title: "The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological involvement in CFC is more severe than in other RASopathies.
    explanation: >-
      Review confirming that CFC syndrome has the most severe cognitive
      impairment among the RASopathy spectrum disorders.
  - reference: PMID:35524774
    reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall frequency of intellectual disability and seizures was 82%
      and 55%, respectively.
    explanation: >-
      Multinational CFC cohort (n=138) quantifying intellectual disability at
      82%, supporting the very-frequent classification.
- name: Short Stature
  description: >
    Postnatal growth deficiency leading to short stature.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
- name: Kyphoscoliosis
  description: >
    Spinal curvature abnormalities are common skeletal features.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
- name: Seizures
  description: >
    Epilepsy is common in CFC syndrome, occurring in roughly half of affected
    individuals. Seizure frequency and severity are genotype-associated, being
    higher in individuals with BRAF or MAP2K1 variants than in those with
    MAP2K2 variants.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35524774
    reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall frequency of intellectual disability and seizures was 82%
      and 55%, respectively.
    explanation: >-
      Multinational CFC cohort (n=138) quantifying the overall seizure frequency
      at 55%.
  - reference: PMID:35524774
    reference_title: "Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency and severity of seizures was higher among individuals with
      BRAF or MAP2K1 variants than in those with MAP2K2 variants.
    explanation: >-
      Establishes the genotype-associated gradient of seizure burden in CFC
      syndrome.
- name: Polyhydramnios
  description: >
    Prenatal manifestation of RAS/MAPK dysregulation, commonly observed
    on second and third trimester ultrasound.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:36308388
    reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second and third trimester ultrasound abnormalities included polyhydramnios,
      macrocephaly, macrosomia, and renal and cardiac abnormalities.
    explanation: >-
      Study of 43 CFC cases documenting prenatal phenotype including
      polyhydramnios as a manifestation of germline RAS/MAPK dysregulation.
treatments:
- name: Cardiac Management
  description: >
    Management of congenital heart defects, including surgical correction
    of pulmonary stenosis when indicated.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Nutritional Support
  description: >
    Nutritional interventions for failure to thrive, including tube feeding
    when necessary.
  treatment_term:
    preferred_term: Nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: MEK Inhibitor Therapy
  description: >
    MEK inhibitors are under investigation for treatment of RASopathies,
    with potential to ameliorate some features. Zebrafish model studies
    suggest MEK inhibitors could treat progressive phenotypes.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  evidence:
  - reference: PMID:38136934
    reference_title: "The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Encouraging zebrafish model system studies suggested that, in the future,
      MEK inhibitors could be a suitable treatment of progressive phenotypes
      of CFC in children.
    explanation: >-
      Review summarizing preclinical evidence supporting MEK inhibitor
      therapy for CFC syndrome based on zebrafish model studies.
datasets:
references:
- reference: PMID:20301365
  title: "Cardiofaciocutaneous Syndrome."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301365
Cardiofaciocutaneous Syndrome.
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Cardiofaciocutaneous Syndrome
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 12

Key Pathophysiology Nodes

  • RAS-MAPK Pathway Hyperactivation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1002/ajmg.a.63020
  • DOI:10.1101/2024.08.09.24311751
  • DOI:10.3389/fimmu.2025.1598896
  • DOI:10.3390/children11111342
  • DOI:10.3390/genes14122111
Falcon ▸
Pathophysiology description
Edison Scientific Literature 17 citations 2026-02-04T22:39:57.804118

Pathophysiology description Cardiofaciocutaneous syndrome is a multisystem RASopathy caused by germline gain‑of‑function variants that hyperactivate the RAS–RAF–MEK–ERK (MAPK) cascade, impairing developmental programs that govern proliferation, differentiation, migration, survival and metabolism across ectodermal, cardiac, and neural tissues (e.g., skin/hair, myocardium, brain). At the molecular level, missense variants in pathway components—most often BRAF, and less frequently MAP2K1 (MEK1), MAP2K2 (MEK2), and rarely KRAS; de novo 14‑3‑3 (YWHAZ) variants have also been reported—drive ERK1/2 hyperactivation and downstream transcriptional reprogramming, establishing a cell‐state bias that produces the characteristic craniofacial, cutaneous, cardiac, and neurodevelopmental phenotype (reviewed Nov 22, 2023; DOI:10.3390/genes14122111) (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2, scorrano2023thecardiofaciocutaneoussyndrome pages 2-3, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). Dysregulation manifests prenatally as lymphatic dysfunction (e.g., polyhydramnios, hydrops), fetal overgrowth parameters (macrocephaly/macrosomia), and structural anomalies (cardiac and renal), reflecting perturbed signaling in lymphatic endothelial, cardiac progenitor/myocyte, and neuroepithelial lineages (AJMG A, Oct 2023; DOI:10.1002/ajmg.a.63020) (jelin2023obstetricalandneonatal pages 2-2, jelin2023obstetricalandneonatal pages 1-1).

Although oncogenic BRAF/MAPK activation is common in cancer, historically CFC was thought to have minimal malignancy risk; however, an updated pooled analysis suggests an elevated early‑childhood cancer incidence, warranting nuanced surveillance across RASopathies (medRxiv preprint, Aug 2025; DOI:10.1101/2024.08.09.24311751) (bess2025aliteraturereview pages 9-13). Preclinical and early translational observations indicate MEK inhibition can normalize hyperactive ERK signaling in relevant models, and limited clinical experience across RASopathies (notably Noonan syndrome) supports off‑label MEK inhibitor use for life‑threatening lymphatic and cardiac complications; targeted trials are needed for CFC (Genes 2023; DOI:10.3390/genes14122111) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10).

Core Pathophysiology - Primary mechanisms: germline gain‑of‑function or pathway‑activating missense variants in RAS/MAPK components that elevate ERK1/2 activity and perturb developmental gene expression programs in multiple tissues (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 1-2). - Dysregulated pathways: canonical RAS–RAF–MEK–ERK signaling; positive regulation of ERK1/2 cascade predominates, overwhelming feedback control (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Affected cellular processes: proliferation, differentiation (neuronal, cardiomyocyte, keratinocyte), migration, survival; lymphangiogenesis and endothelial function are implicated by prenatal/neonatal lymphatic findings (AJMG A 2023) (jelin2023obstetricalandneonatal pages 2-2, jelin2023obstetricalandneonatal pages 1-1, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5).

Key Molecular Players - Genes/Proteins (HGNC): BRAF (dominant cause, ~75% of molecularly confirmed CFC), MAP2K1 (MEK1) and MAP2K2 (MEK2) (each up to ~25% collectively across cohorts), rare KRAS, with recent reports of YWHAZ de novo variants that enhance RAF‑stimulated ERK phosphorylation; all converge on ERK1/2 hyperactivation (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 2-3, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Quote: “Currently, BRAF, MAP2K1, MAP2K2 and, rarely, KRAS have been associated with CFC… variants are mainly missense with a gain‑of‑function mechanism… leading to ERK1‑2 hyperactivation.” (Genes 2023; published Nov 22, 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Quote: “YWHAZ… S230W variant that ‘enhanced Raf‑stimulated Erk phosphorylation’ consistent with gain‑of‑function.” (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Chemical Entities (CHEBI): MEK inhibitors—trametinib and selumetinib—are the principal targeted agents explored off‑label across RASopathies (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Cell Types (CL): cardiomyocytes (HCM), neural progenitors/neurons (ID, epilepsy), keratinocytes and dermal fibroblasts (skin/hair phenotypes), lymphatic endothelial cells (chylothorax/lymphatic dysplasia) (Genes 2023; AJMG A 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, jelin2023obstetricalandneonatal pages 2-2). - Anatomical Locations (UBERON): heart (pulmonary valve, ventricular myocardium), skin, brain, lymphatic vasculature (Genes 2023; AJMG A 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, jelin2023obstetricalandneonatal pages 2-2).

Biological Processes (for GO annotation) - MAPK cascade (GO:0000165); positive regulation of ERK1/2 cascade (GO:0070374); cell proliferation (GO:0008283); neuron differentiation (GO:0030182); cardiac muscle cell development (GO:0055013); keratinocyte differentiation (GO:0030216); lymphangiogenesis (GO:0001946). These processes map directly to observed neurodevelopmental, cardiac, skin, and lymphatic phenotypes (Genes 2023; AJMG A 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, jelin2023obstetricalandneonatal pages 2-2).

Cellular Components - Plasma membrane (RAS activation), cytosol (RAF–MEK–ERK relay), and nucleus (ERK‑dependent transcriptional programs) are critical compartments of dysregulated signaling in CFC (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5).

Disease Progression - Initiation: de novo germline activating variant in BRAF/MEK1/MEK2/KRAS (or YWHAZ) establishes constitutive or exaggerated ERK signaling. - Prenatal phase: lymphatic dysfunction and growth pattern anomalies detectable by ultrasound—polyhydramnios, (sometimes) nonimmune hydrops, macrocephaly/macrosomia, and structural cardiac/renal anomalies; increased operative delivery and neonatal complications are reported (AJMG A; published Oct 2023; DOI:10.1002/ajmg.a.63020) (jelin2023obstetricalandneonatal pages 2-2, jelin2023obstetricalandneonatal pages 1-1). - Neonatal/infancy: hypotonia and feeding difficulties; congenital heart disease (pulmonary valve stenosis, septal defects, and/or HCM) commonly present; progressive skin/hair features emerge (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 1-2). - Childhood: neurodevelopmental disability (moderate ID common), epilepsy with gene‑specific frequencies; brain MRI often shows ventriculomegaly and other anomalies; dermatologic features (ichthyosis, xerosis, nevi; hair abnormalities) are typical; variable growth abnormalities (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 1-2). - Adolescent/adult: persistent multisystem morbidity; evolving data suggest non‑zero malignancy risk that may be enriched in early childhood (medRxiv 2025) (bess2025aliteraturereview pages 9-13).

Phenotypic Manifestations (HPO) - Cardiac: pulmonary valve stenosis (HP:0001642) and hypertrophic cardiomyopathy (HP:0001639) are frequent; atrial/ventricular septal defects occur (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Neurologic: intellectual disability (HP:0001249) with high prevalence; seizures (HP:0001250) show gene‑specific frequencies and severity; hypotonia (neonatal onset common); ventriculomegaly on imaging (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Dermatologic: ichthyosis/xerosis (HP:0008064), sparse/curly/friable hair (HP:0008070), numerous nevi; expert cohorts describe a characteristic but heterogeneous dermatologic pattern (Genes 2023; BJD 2019) (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Growth/prenatal: macrocephaly (HP:0000256), macrosomia (when present), polyhydramnios (HP:0001561); neonatal complications are more common than background (AJMG A 2023) (jelin2023obstetricalandneonatal pages 1-1, jelin2023obstetricalandneonatal pages 2-2).

Genotype–Phenotype Correlations (recent synthesis) - Gene‑level trends: BRAF is most frequent and associates with high rates of cardiac disease and epilepsy/ID; MAP2K1 associates with higher seizure frequency and greater motor impairment; MAP2K2 tends to have lower seizure risk and milder neurocognitive impact compared with MAP2K1; KRAS is rare with cardiac prominence; YWHAZ de novo variants enhance ERK signaling (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 2-3, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Quote: seizure frequencies “57%… with BRAF…, 61%… with MAP2K1… and 30%… with MAP2K2,” and MAP2K1 p.Y130C/H/N and BRAF kinase-domain variants correlate with severe epilepsy (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Prenatal genotype distribution: in a 43‑case survey cohort, pathogenic variants were BRAF 81%, MEK1 14%, MEK2 5% (AJMG A 2023) (jelin2023obstetricalandneonatal pages 1-1).

Immune involvement and cancer risk - Immune dysregulation: emerging multi‑center cohort data (n=56) describe recurrent but heterogeneous immunologic abnormalities in CFC—lymphopenia, hypogammaglobulinemia (IgG, IgA, IgM reductions), and increased infection susceptibility—with genotype links (BRAF with T‑cell lymphopenia; MAP2K1 with monocytosis and B‑cell abnormalities) (Frontiers in Immunology, Jul 2025; DOI:10.3389/fimmu.2025.1598896) (majo2025cardiofaciocutaneoussyndromeand pages 11-11). - Cancer risk: pooled literature review (n≈690) estimates cumulative cancer incidence by age 10 of 3% (95% CI 1.1–5.5), with elevated standardized incidence ratios (all sites SIR≈4.96; ALL SIR≈24.23); the authors caution about limitations and potential biases and call for refined surveillance studies (medRxiv, Aug 2025; DOI:10.1101/2024.08.09.24311751) (bess2025aliteraturereview pages 9-13).

Current applications and real‑world implementations - Prenatal diagnostics: prenatal phenotype definition (polyhydramnios, macrocephaly/macrosomia, structural anomalies) supports the increasing use of prenatal exome/NGS for suspected RASopathies; counseling includes elevated rates of operative delivery and neonatal complications (AJMG A 2023; DOI:10.1002/ajmg.a.63020) (jelin2023obstetricalandneonatal pages 2-2, jelin2023obstetricalandneonatal pages 1-1). - Targeted pathway therapy (off‑label MEK inhibition): preclinical models (zebrafish; human lymphatic endothelial cells) demonstrate rescue of RASopathy phenotypes with MEK inhibitors, and case experiences across RASopathies (notably Noonan syndrome) report improvement in life‑threatening lymphatic disease and hypertrophic cardiomyopathy; disease‑specific trials for CFC are lacking (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Representative clinical example in RASopathies: trametinib led to resolution of refractory chylothorax and ventricular hypertrophy in a newborn with Noonan syndrome at 18‑month follow‑up (Children, Oct 2024; DOI:10.3390/children11111342) (). While not CFC, it exemplifies pathway‑directed therapy in germline RAS/MAPK hyperactivation and informs potential CFC indications.

Expert opinions and analysis - Contemporary expert review emphasizes RAS/MAPK hyperactivation as the unifying mechanism in RASopathies, with MEK inhibitors as promising repurposed agents for severe, progressive complications; however, standardized protocols and trials specific to each disorder (including CFC) remain unmet needs (Genes 2023; published Nov 22, 2023; DOI:10.3390/genes14122111) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Quote: “There is no specific treatment for CFC syndrome. Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children.” (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2). - Surveillance: updated pediatric cancer predisposition perspectives for RASopathies support nuanced, syndrome‑specific surveillance, acknowledging improved outcomes with targeted agents in low‑grade and benign neoplasms and the need for multidisciplinary care; recommendations continue to evolve as risk estimates are refined (context summarized within Genes 2023 and bolstered by pooled risk analysis) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10, bess2025aliteraturereview pages 9-13).

Relevant statistics and data (recent) - Genotype distribution in a 43‑case cohort: BRAF 81%, MEK1 14%, MEK2 5%; median GA 37 weeks; median birthweight 3501 g; cesarean 48% (AJMG A, Oct 2023; DOI:10.1002/ajmg.a.63020; URL: https://doi.org/10.1002/ajmg.a.63020) (jelin2023obstetricalandneonatal pages 1-1). - Prenatal complications: hyperemesis 12%, gestational diabetes 9%, gestational hypertension 7%, preeclampsia 7%; ultrasound abnormalities (polyhydramnios, macrocephaly, macrosomia, renal/cardiac) commonly observed (AJMG A 2023; published Oct 2023) (jelin2023obstetricalandneonatal pages 1-1). - Cardiac and neurologic frequencies (synthesis): cardiac disease ~75% (PVS ~45%, HCM ~40%); seizure prevalence by gene: BRAF ~57%, MAP2K1 ~61%, MAP2K2 ~30%; ventriculomegaly on MRI ~44% (Genes 2023; open‑access review, Nov 2023; DOI:10.3390/genes14122111) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - Cancer risk: cumulative incidence by age 10 ≈3% (95% CI 1.1–5.5), with SIR ≈4.96 for all cancers and ≈24.23 for ALL (medRxiv, Aug 2025; DOI:10.1101/2024.08.09.24311751; URL: https://doi.org/10.1101/2024.08.09.24311751) (bess2025aliteraturereview pages 9-13).

Embedded ontology‑aligned summary | Category | Item (name) | Identifier (ontology ID/code) | Role/Relevance | Notes | |---|---|---:|---|---| | Genes/Proteins | BRAF | HGNC:BRAF | RAF-family serine/threonine kinase; primary causal gene | Major CFC gene (~75% cases); somatic oncogenic roles noted (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10, jelin2023obstetricalandneonatal pages 2-2) | | Genes/Proteins | MAP2K1 (MEK1) | HGNC:MAP2K1 | Dual-specificity kinase activating ERK1/2 | Causally implicated in CFC; variants alter ERK signaling and seizure risk (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Genes/Proteins | MAP2K2 (MEK2) | HGNC:MAP2K2 | Partner MEK kinase activating ERK1/2 | CFC-linked; distinct genotype–phenotype trends vs MAP2K1 (koslaUnknownyearmap2k2(mek2)in pages 1-4) | | Genes/Proteins | KRAS | HGNC:KRAS | Small GTPase upstream of RAF | Rare causal gene in CFC; associated with cardiac/coarse facies (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Genes/Proteins | NRAS | HGNC:NRAS | RAS-family GTPase | Reported in RASopathies/CFC spectrum (koslaUnknownyearmap2k2(mek2)in pages 1-4) | | Genes/Proteins | YWHAZ | HGNC:YWHAZ | 14-3-3 adaptor modulating RAF/ERK signaling | Recently reported de novo variants perturb RAS/MAPK (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Primary pathway | RAS/MAPK cascade | GO:0000165 (MAPK cascade) | Central dysregulated signaling cascade in CFC | Pathogenic variants cause ERK1/2 hyperactivation driving multisystem disease (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Dysregulated process | Positive regulation of ERK1/2 cascade | GO:0070374 | Upstream→ERK overactivation | Mechanistic core of CFC pathophysiology (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Dysregulated process | Cell proliferation | GO:0008283 | Altered growth control in multiple tissues | Explains organ overgrowth/oncogenic potential (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10, bess2025aliteraturereview pages 9-13) | | Dysregulated process | Neuron differentiation | GO:0030182 | Neurodevelopmental disruption | Underlies ID, seizures and brain MRI anomalies (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Dysregulated process | Cardiac muscle cell development | GO:0055013 | Cardiogenesis and cardiomyopathy mechanisms | Links to PVS, HCM and septal defects in CFC (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Dysregulated process | Keratinocyte differentiation | GO:0030216 | Skin/ectodermal phenotypes | Explains ichthyosis, abnormal hair/skin findings (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 1-2) | | Dysregulated process | Lymphangiogenesis | GO:0001946 | Lymphatic development/abnormalities | Relates to chylothorax/lymphatic phenotypes described (jelin2023obstetricalandneonatal pages 2-2, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Cellular component | Plasma membrane | GO:0005886 | Location of receptor/RAS activation | RAS activation at membrane initiates cascade (koslaUnknownyearmap2k2(mek2)in pages 1-4) | | Cellular component | Cytosol | GO:0005829 | Cytoplasmic signaling/transduction | MEK/ERK signaling transduces in cytosol before nuclear entry (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Cellular component | Nucleus | GO:0005634 | ERK-dependent transcriptional effects | Downstream transcriptional programs affecting development (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Cell type | Cardiomyocyte | CL:0000746 | Primary cardiac muscle cell affected in HCM | Hypertrophy and dysfunction described in CFC/RASopathies (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Cell type | Neural progenitor cell | CL:0000047 | Neurodevelopmental cell population | Implicated in ID, cortical malformations and seizures (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Cell type | Keratinocyte | CL:0000312 | Epidermal cell type | Skin phenotypes (hyperkeratosis, nevi) in CFC (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2) | | Cell type | Lymphatic endothelial cell | CL:0002138 | Lymphatic vessel lining cells | Involved in chylothorax/lymphatic dysplasia responses (jelin2023obstetricalandneonatal pages 2-2) | | Cell type | Fibroblast | CL:0000057 | Connective tissue cell; model cell type | Patient fibroblasts used in functional studies (koslaUnknownyearmap2k2(mek2)in pages 10-10) | | Anatomical location | Heart | UBERON:0000948 | Major organ with congenital and progressive disease | PVS, HCM, ASD/VSD frequent in CFC (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Anatomical location | Skin | UBERON:0002097 | Ectodermal organ with characteristic findings | Hair anomalies, pigmented nevi, ichthyosis reported (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2) | | Anatomical location | Brain | UBERON:0000955 | CNS site of neurodevelopmental impact | Ventriculomegaly, cortical anomalies, epilepsy (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Anatomical location | Lymphatic vessel | UBERON:0004535 | Lymphatic system involvement site | Neonatal chylothorax/lymphatic disease reports (jelin2023obstetricalandneonatal pages 2-2) | | Phenotype | Hypertrophic cardiomyopathy | HPO:HP:0001639 | Key cardiac morbidity in CFC | Reported in ~40% of cases; therapeutic target for MEK inhibitors (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Phenotype | Pulmonary valve stenosis | HPO:HP:0001642 | Common congenital cardiac lesion | Frequent in CFC cohorts (~45%) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Phenotype | Seizures | HPO:HP:0001250 | Neurological morbidity with gene-specific rates | High prevalence; gene-specific frequencies reported (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Phenotype | Intellectual disability | HPO:HP:0001249 | Core neurodevelopmental outcome | Varies by gene (BRAF/MAP2K1 > MAP2K2) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5) | | Phenotype | Ichthyosis | HPO:HP:0008064 | Dermatologic manifestation | Documented in mutation-positive cohorts (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2) | | Phenotype | Sparse hair | HPO:HP:0008070 | Ectodermal/signature finding | Part of craniofacial/skin phenotype (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2) | | Phenotype | Macrocephaly | HPO:HP:0000256 | Prenatal/postnatal growth feature | Reported prenatally and postnatally in cohorts (jelin2023obstetricalandneonatal pages 2-2) | | Phenotype | Polyhydramnios (prenatal) | HPO:HP:0001561 | Obstetrical ultrasound finding | Observed in CFC pregnancies (jelin2023obstetricalandneonatal pages 2-2) | | Chemical entities | Trametinib | CHEBI:85083 | MEK1/2 inhibitor; repurposed/off-label in RASopathies | Case reports/series show benefit for cardiac/lymphatic disease; trials needed (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) | | Chemical entities | Selumetinib | CHEBI:90227 | MEK1/2 inhibitor; approved for NF1 plexiform neurofibromas | Potentially repurposed in RASopathies; emerging case evidence (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10) |

Table: Compact ontology-aligned mapping of genes, pathways, processes, cells, anatomy, phenotypes and repurposed drugs relevant to Cardiofaciocutaneous syndrome, with concise role notes and literature context citations for use in knowledgebases and curation.

Gene/protein annotations with ontology terms - BRAF (HGNC:BRAF): kinase in RAF family; pathway: MAPK cascade (GO:0000165); processes: positive regulation of ERK1/2 cascade (GO:0070374), cell proliferation (GO:0008283); components: plasma membrane→cytosol→nucleus; evidence: review synthesis and cohort summaries (Genes 2023; Nov 22, 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 1-2). - MAP2K1 (HGNC:MAP2K1) and MAP2K2 (HGNC:MAP2K2): dual‑specificity kinases that activate ERK1/2; processes as above; gene‑specific seizure/ID and motor phenotypes (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5). - KRAS/NRAS (HGNC:KRAS/HGNC:NRAS): small GTPases upstream of RAF; rare causes of CFC but central to pathway dysregulation (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 2-3). - YWHAZ (HGNC:YWHAZ): 14‑3‑3 adaptor; de novo variants enhance RAF‑ERK signaling (Genes 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10).

Phenotype associations (HPO terms) - Hypertrophic cardiomyopathy (HP:0001639); Pulmonary valve stenosis (HP:0001642); Seizures (HP:0001250); Intellectual disability (HP:0001249); Ichthyosis (HP:0008064); Sparse hair (HP:0008070); Macrocephaly (HP:0000256); Polyhydramnios (HP:0001561) (Genes 2023; AJMG A 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 1-2, jelin2023obstetricalandneonatal pages 2-2, jelin2023obstetricalandneonatal pages 1-1).

Cell type involvement (CL terms) - Cardiomyocyte (CL:0000746); Neural progenitor cell (CL:0000047); Keratinocyte (CL:0000312); Lymphatic endothelial cell (CL:0002138); Fibroblast (CL:0000057) (Genes 2023; AJMG A 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, jelin2023obstetricalandneonatal pages 2-2).

Anatomical locations (UBERON terms) - Heart (UBERON:0000948); Skin (UBERON:0002097); Brain (UBERON:0000955); Lymphatic vessel (UBERON:0004535) (Genes 2023; AJMG A 2023) (scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, jelin2023obstetricalandneonatal pages 2-2).

Chemical entities (CHEBI terms) - Trametinib (CHEBI:85083); Selumetinib (CHEBI:90227)—MEK1/2 inhibitors considered for pathway overactivation in RASopathies including prospective use in CFC (Genes 2023; case evidence in RASopathies) (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10).

Evidence items and sources (selected, with dates/links) - Scorrano G et al. The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic–Therapeutic Implications. Genes. Published Nov 22, 2023. DOI:10.3390/genes14122111. URL: https://doi.org/10.3390/genes14122111 (review) (scorrano2023thecardiofaciocutaneoussyndrome pages 1-2, scorrano2023thecardiofaciocutaneoussyndrome pages 2-3, scorrano2023thecardiofaciocutaneoussyndrome pages 3-5, scorrano2023thecardiofaciocutaneoussyndrome pages 8-10). - Jelin AC et al. Obstetrical and neonatal outcomes of CFC: prenatal consequences of Ras/MAPK dysregulation. Am J Med Genet A. Published Oct 2023. DOI:10.1002/ajmg.a.63020. URL: https://doi.org/10.1002/ajmg.a.63020 (jelin2023obstetricalandneonatal pages 2-2, jelin2023obstetricalandneonatal pages 1-1). - Bess J et al. A Literature Review and Pooled Case Analysis of CFC to Estimate Cancer Risk. medRxiv. Posted Aug 2025. DOI:10.1101/2024.08.09.24311751. URL: https://doi.org/10.1101/2024.08.09.24311751 (bess2025aliteraturereview pages 9-13). - Di Majo BE et al. Cardiofaciocutaneous syndrome and immunodeficiency: international multicenter cohort. Frontiers in Immunology. Published Jul 2025. DOI:10.3389/fimmu.2025.1598896. URL: https://doi.org/10.3389/fimmu.2025.1598896 (majo2025cardiofaciocutaneoussyndromeand pages 11-11). - Pascarella A et al. Refractory Chylothorax and Ventricular Hypertrophy Treated with Trametinib in Noonan Syndrome: 18‑Month Follow‑Up. Children. Published Oct 2024. DOI:10.3390/children11111342. URL: https://doi.org/10.3390/children11111342 ().

Notes and gaps - While 2023–2024 literature consolidates CFC molecular mechanisms and prenatal phenotype, high‑quality prospective data on immune complications and cancer risk are still emerging and largely derive from 2025 analyses; CFC‑specific interventional data for MEK inhibitors remain limited to preclinical models and extrapolation from related RASopathies. This motivates genotype‑informed surveillance and participation in disease‑specific trials when available (scorrano2023thecardiofaciocutaneoussyndrome pages 8-10, bess2025aliteraturereview pages 9-13, majo2025cardiofaciocutaneoussyndromeand pages 11-11).

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