Cardiofaciocutaneous Syndrome - Disorder Mechanisms

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Inheritance

1

Autosomal Dominant

Autosomal dominant inheritance with complete penetrance. Nearly all cases arise de novo due to the severity of the phenotype limiting reproductive fitness. In a cohort of 43 cases, genotype distribution was BRAF (81%), MEK1 (14%), and MEK2 (5%).

Show evidence (1 reference)

PMID:36308388 PARTIAL Human Clinical

"We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes."

Large cohort study establishing genotype distribution in CFC syndrome, confirming BRAF as the predominant causative gene.

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Pathophysiology

1

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 link Keratinocyte link

MAPK Cascade link ERK1/2 Cascade link Cell Proliferation link

Show evidence (1 reference)

PMID:16439621 PARTIAL 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.

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Phenotypes

11

Cardiovascular 2

Congenital Heart Defects FREQUENT Abnormal heart morphology (HP:0001627)

Pulmonary Valve Stenosis FREQUENT Pulmonic stenosis (HP:0001642)

Head and Neck 1

Distinctive Facies VERY_FREQUENT Abnormal facial shape (HP:0001999)

Integument 2

Sparse Hair VERY_FREQUENT Sparse hair (HP:0008070)

Keratosis Pilaris FREQUENT Keratosis pilaris (HP:0032152)

Musculoskeletal 1

Kyphoscoliosis FREQUENT Kyphoscoliosis (HP:0002751)

Nervous System 2

Intellectual Disability VERY_FREQUENT Intellectual disability (HP:0001249)

Show evidence (1 reference)

PMID:38136934 PARTIAL 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.

Seizures FREQUENT Seizure (HP:0001250)

Prenatal and Birth 1

Polyhydramnios OCCASIONAL Polyhydramnios (HP:0001561)

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 Failure to thrive (HP:0001508)

Short Stature VERY_FREQUENT Short stature (HP:0004322)

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Genetic Associations

3

BRAF Mutations (Causative)

Show evidence (1 reference)

PMID:16439621 SUPPORT 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, with mutations distinct from common somatic cancer mutations, suggesting novel activation mechanisms.

MAP2K1/MAP2K2 Mutations (Causative)

Show evidence (1 reference)

PMID:16439621 SUPPORT 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/MEK2 mutations cause CFC syndrome in patients without BRAF mutations.

KRAS Mutations (Causative)

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Treatments

3

Cardiac Management

Action: Cardiac surgery Ontology label: surgical procedure MAXO:0000004

Management of congenital heart defects, including surgical correction of pulmonary stenosis when indicated.

Nutritional Support

Action: Nutritional support Ontology label: dietary intervention MAXO:0000088

Nutritional interventions for failure to thrive, including tube feeding when necessary.

MEK Inhibitor Therapy

Action: Pharmacotherapy Ontology label: pharmacotherapy MAXO:0000058

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 PARTIAL 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.

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Literature Summaries

2

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).

References

(scorrano2023thecardiofaciocutaneoussyndrome pages 1-2): Giovanna Scorrano, Emanuele David, Elisa Calì, Roberto Chimenz, Saverio La Bella, Armando Di Ludovico, Gabriella Di Rosa, Eloisa Gitto, Kshitij Mankad, Rosaria Nardello, Giuseppe Donato Mangano, Chiara Leoni, and Giorgia Ceravolo. The cardiofaciocutaneous syndrome: from genetics to prognostic–therapeutic implications. Genes, 14:2111, Nov 2023. URL: https://doi.org/10.3390/genes14122111, doi:10.3390/genes14122111. This article has 18 citations and is from a poor quality or predatory journal.
(scorrano2023thecardiofaciocutaneoussyndrome pages 2-3): Giovanna Scorrano, Emanuele David, Elisa Calì, Roberto Chimenz, Saverio La Bella, Armando Di Ludovico, Gabriella Di Rosa, Eloisa Gitto, Kshitij Mankad, Rosaria Nardello, Giuseppe Donato Mangano, Chiara Leoni, and Giorgia Ceravolo. The cardiofaciocutaneous syndrome: from genetics to prognostic–therapeutic implications. Genes, 14:2111, Nov 2023. URL: https://doi.org/10.3390/genes14122111, doi:10.3390/genes14122111. This article has 18 citations and is from a poor quality or predatory journal.
(scorrano2023thecardiofaciocutaneoussyndrome pages 3-5): Giovanna Scorrano, Emanuele David, Elisa Calì, Roberto Chimenz, Saverio La Bella, Armando Di Ludovico, Gabriella Di Rosa, Eloisa Gitto, Kshitij Mankad, Rosaria Nardello, Giuseppe Donato Mangano, Chiara Leoni, and Giorgia Ceravolo. The cardiofaciocutaneous syndrome: from genetics to prognostic–therapeutic implications. Genes, 14:2111, Nov 2023. URL: https://doi.org/10.3390/genes14122111, doi:10.3390/genes14122111. This article has 18 citations and is from a poor quality or predatory journal.
(jelin2023obstetricalandneonatal pages 2-2): Angie C. Jelin, Amanda Mahle, Susan H. Tran, Teresa N. Sparks, and Katherine A. Rauen. Obstetrical and neonatal outcomes of cardio‐facio‐cutaneous syndrome: prenatal consequences of ras/mapk dysregulation. American Journal of Medical Genetics Part A, 191:323-331, Oct 2023. URL: https://doi.org/10.1002/ajmg.a.63020, doi:10.1002/ajmg.a.63020. This article has 5 citations.
(jelin2023obstetricalandneonatal pages 1-1): Angie C. Jelin, Amanda Mahle, Susan H. Tran, Teresa N. Sparks, and Katherine A. Rauen. Obstetrical and neonatal outcomes of cardio‐facio‐cutaneous syndrome: prenatal consequences of ras/mapk dysregulation. American Journal of Medical Genetics Part A, 191:323-331, Oct 2023. URL: https://doi.org/10.1002/ajmg.a.63020, doi:10.1002/ajmg.a.63020. This article has 5 citations.
(bess2025aliteraturereview pages 9-13): Jazmyn Bess, Toniya Brown, Sonia Bhala, Anaqa Faizer, Muzzammil Ahmadzada, Alicia A Livinski, Alex Pemov, Jung Kim, Philip S Rosenberg, Gina M Ney, and Douglas R Stewart. A literature review and pooled case analysis of cardiofaciocutaneous syndrome to estimate cancer risk. medRxiv : the preprint server for health sciences, Aug 2025. URL: https://doi.org/10.1101/2024.08.09.24311751, doi:10.1101/2024.08.09.24311751. This article has 2 citations.
(scorrano2023thecardiofaciocutaneoussyndrome pages 8-10): Giovanna Scorrano, Emanuele David, Elisa Calì, Roberto Chimenz, Saverio La Bella, Armando Di Ludovico, Gabriella Di Rosa, Eloisa Gitto, Kshitij Mankad, Rosaria Nardello, Giuseppe Donato Mangano, Chiara Leoni, and Giorgia Ceravolo. The cardiofaciocutaneous syndrome: from genetics to prognostic–therapeutic implications. Genes, 14:2111, Nov 2023. URL: https://doi.org/10.3390/genes14122111, doi:10.3390/genes14122111. This article has 18 citations and is from a poor quality or predatory journal.
(majo2025cardiofaciocutaneoussyndromeand pages 11-11): Benedetta Elena Di Majo, Chiara Leoni, Eleonora Cartisano, Chiara Fossati, Germana Viscogliosi, Valentina Trevisan, Lucia Pia Bruno, Francesca Conti, Mattia Moratti, Emilia Monaco, Donato Rigante, Beatrice Rivalta, Caterina Cancrini, Aleksandra Szczawińska-Popłonyk, Aleksander Jamsheer, Monika Obara-Moszyńska, Viktoria Zakharova, Anna Shcherbina, Julija Rodina, Beyhan Tüysüz, Saumya Shekhar Jamuar, Jiin Ying Lim, Jeannette Goh, Anna Cereda, Teresa Agovino, Ilaria Contaldo, Maria Luigia Gambardella, Adriana Cristina Balduzzi, Alessia Cherubino, Giovanni Antonio Marrocco, Silvia Bellesi, Valentina Carusi, Gabriele Rumi, Andrea Biondi, Giuseppe Zampino, and Francesco Saettini. Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort. Frontiers in Immunology, Jul 2025. URL: https://doi.org/10.3389/fimmu.2025.1598896, doi:10.3389/fimmu.2025.1598896. This article has 2 citations and is from a peer-reviewed journal.
(koslaUnknownyearmap2k2(mek2)in pages 1-4): M Kośla. Map2k2 (mek2) in cardiofaciocutaneous (cfc) syndrome-research roadmap. Unknown journal, Unknown year.
(koslaUnknownyearmap2k2(mek2)in pages 10-10): M Kośla. Map2k2 (mek2) in cardiofaciocutaneous (cfc) syndrome-research roadmap. Unknown journal, Unknown year.

{ }

Source YAML

click to show

name: Cardiofaciocutaneous Syndrome
creation_date: '2026-02-06T03:39:54Z'
updated_date: '2026-04-03T00:00:00Z'
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:
- RASopathies
prevalence:
- population: Japanese nationwide survey
  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
    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
    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
  description: >
    Autosomal dominant inheritance with complete penetrance. Nearly all cases
    arise de novo due to the severity of the phenotype limiting reproductive
    fitness. In a cohort of 43 cases, genotype distribution was BRAF (81%),
    MEK1 (14%), and MEK2 (5%).
  evidence:
  - reference: PMID:36308388
    reference_title: "Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation."
    supports: PARTIAL
    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-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.
  evidence:
  - reference: PMID:16439621
    reference_title: "Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome."
    supports: PARTIAL
    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.
  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
genetic:
- name: BRAF Mutations
  association: Causative
  notes: >
    BRAF mutations account for ~75% of CFC cases. Unlike somatic BRAF V600E
    mutations in cancer, germline CFC mutations are typically kinase-impaired
    but still activate the pathway through RAF dimerization (Q257R, E501G).
  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: >-
      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, with mutations distinct from
      common somatic cancer mutations, suggesting novel activation mechanisms.
- name: MAP2K1/MAP2K2 Mutations
  association: Causative
  notes: >
    MEK1 (MAP2K1) and MEK2 (MAP2K2) mutations account for ~25% of CFC cases.
    These mutations typically increase MEK kinase activity.
  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: >-
      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/MEK2 mutations cause CFC syndrome in
      patients without BRAF mutations.
- name: KRAS Mutations
  association: Causative
  notes: >
    Rare KRAS mutations can cause CFC syndrome, overlapping with Noonan syndrome.
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: PARTIAL
    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.
- 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 with gene-specific frequencies.
    Seizures occur in approximately 57% of BRAF cases, 61% of MAP2K1 cases,
    and 30% of MAP2K2 cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- 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.
  treatment_term:
    preferred_term: Cardiac surgery
    term:
      id: MAXO:0000004
      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: MAXO:0000088
      label: dietary intervention
- 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: Pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:38136934
    reference_title: "The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications."
    supports: PARTIAL
    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: