U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Cardiofaciocutaneous Syndrome

Synonym: CFC Syndrome

, MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: February 9, 2023.

Estimated reading time: 36 minutes


Clinical characteristics.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, and woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Affected individuals typically have some form of neurologic and/or cognitive delay (ranging from mild to severe). Most individuals have severe feeding issues, which can contribute to poor growth, and many require nasogastric or gastrostomy tube feeding. Many affected individuals have eye findings, including strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Seizures may be present and can be refractory to therapy.


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.


Treatment of manifestations: Consensus medical management guidelines have been published. Care by a multidisciplinary team; increased caloric intake and a nasogastric or gastrostomy tube for severe feeding issues; surgical intervention for severe gastroesophageal reflux or malrotation; management of cardiac structural defects, hypertrophic cardiomyopathy, and arrhythmias as in the general population; increased ambient humidity or hydrating lotions for xerosis and pruritus; management of seizures may require polytherapy; routine management of growth hormone deficiency; standard treatment for peripheral neuropathy, Chiari I malformation, developmental delay / intellectual disability, constipation, musculoskeletal anomalies, hypotonia, chronic/recurrent otitis media, hearing loss, cryptorchidism, hydronephrosis, bleeding disorders / thrombocytopenia, and sleep disorders.

Surveillance: At each visit: measure blood pressure; measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for GERD, constipation, generalized dysmotility; assess for new manifestations such as seizures or changes in tone; monitor developmental progress, behavior, and educational needs; monitor for signs and symptoms of thyroid and/or growth hormone deficiency. Assess for scoliosis at each visit until skeletal maturity. Monitor for signs/symptoms of precocious or delayed puberty at each visit in childhood and adolescence. Refer to endocrinologist between the ages of two to three years (or earlier if there are concerns about growth) to monitor growth velocity. Monitor for ocular issues every six to 12 months as directed by ophthalmologist. Hearing evaluation every two to three years, or as clinically indicated. Echocardiogram every two to three years up to age 20 years in those who have an initial cardiac evaluation that is normal. Echocardiogram every three to five years in individuals older than age 20 years who have no previous heart disease found. Annual dermatologic evaluation. DXA scan in early adulthood. Reassess platelet count for evidence of thrombocytopenia in those who have evidence of easy bruising or bleeding.

Agents/circumstances to avoid: Avoid overexposure to heat, strenuous activity, and dehydration. In individuals with evidence of peripheral neuropathy, avoid drugs with a neurotoxic effect.

Pregnancy management: A pregnant female suspected of having CFC syndrome warrants high-risk obstetric care from a trained maternal-fetal medicine physician due to possible polyhydramnios, maternal cardiac issues, and/or maternal hypertension.

Genetic counseling.

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. 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. Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFC are possible.


Cardiofaciocutaneous (CFC) syndrome is one the RASopathies: a group of syndromes having overlapping clinical features resulting from a common pathogenetic mechanism [Tidyman & Rauen 2009a]. No consensus clinical diagnostic criteria have been established. The diagnosis of CFC syndrome is suspected by clinical findings and confirmed by molecular genetic testing.

Suggestive Findings

Cardiofaciocutaneous (CFC) syndrome should be suspected in individuals with the following clinical features:

  • Dysmorphic facial features (see Figure 1) as outlined in Clinical Characteristics. The face is triangular in shape and overall may be more coarse than in Noonan syndrome (a clinically similar condition often confused with CFC syndrome), but usually not as coarse as is typically seen in Costello syndrome.
  • Cardiac anomalies and rhythm disturbance, including pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, and heart valve anomalies
  • Severe feeding issues (gastroesophageal reflux disease, aspiration, vomiting, and oral aversion) and poor growth with relative macrocephaly
  • Ectodermal findings, such as xerosis; sparse, curly, and woolly or brittle hair; and dystrophic nails
  • Lymphedema and/or chylothorax
  • Eye anomalies, including strabismus, nystagmus, and/or optic nerve hypoplasia
  • Hypotonia
  • Developmental delay and cognitive impairment (mild to severe)
  • Seizure disorder
  • Cryptorchidism in males
Figure 1.

Figure 1.

Children with CFC syndrome A. Three young children with BRAF pathogenic variants. Ages are 2.5, 2, and 2 years.

Establishing the Diagnosis

The diagnosis of CFC syndrome is established in a proband with suggestive findings by the identification of a heterozygous pathogenic (or likely pathogenic) variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes does not establish or rule out the diagnosis of the disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CFC syndrome or another RASopathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

A RASopathy multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Cardiofaciocutaneous (CFC) Syndrome

Gene 1, 2Proportion of CFC Syndrome Attributed to Pathogenic Variants in Gene 3Proportion of Probands with a Pathogenic Variant 4 Detectable by Method
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
BRAF ~75%~100% 7Single deletion reported 8
KRAS <2%~100% 7Unknown 9
MAP2K1 ~25%~100% 7Unknown 9
MAP2K2 ~100% 7Several deletions have been reported, 10 but may not cause CFC syndrome. 11
Unknown 12NA

NA = not applicable


Genes are listed in alphabetic order.


See Molecular Genetics for information on variants detected in these genes.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]


A single report of a BRAF deletion associated with a CFC-like phenotype [Yu & Graf 2011] that was not supported by functional data


No data on detection rate of gene-targeted deletion/duplication analysis are available.


Nowaczyk et al [2014] reported several individuals with a MAP2K2 deletion associated with a CFC-like phenotype. This was supported by functional data of MAPK pathway dysregulation.


Lissewski et al [2015] disputed that gene deletions or duplications cause RASopathies.


Popov et al [2019] reported several individuals with features of CFC syndrome who had a heterozygous variant in YWHAZ.

Clinical Characteristics

Clinical Description

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder in which individuals may have dysmorphic craniofacial features, cardiac issues, skin and hair abnormalities, hypotonia, eye abnormalities, gastrointestinal dysfunction, seizures, and varying degrees of neurocognitive delay [Pierpont et al 2014] (see Table 2). While many features have been seen in association with this condition, individuals with CFC syndrome display phenotypic variability and therefore not all have every finding.

Polyhydramnios is present in the vast majority of fetal cases diagnosed in utero. Maternal hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia may occur, and subjective decrease in fetal movement may be observed prenatally. Second- and third-trimester ultrasound abnormalities may include polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Operative delivery is not uncommon.

Neonatal outcomes of CFC individuals may include irregular heartbeat, intubation, need for feeding tube, edema, chylothorax, and hyperbilirubinemia, which may be confounded by the increased rate of prematurity [Jelin et al 2023].

Table 2.

Cardiofaciocutaneous Syndrome: Frequency of Select Features

Nearly allCommonLess frequent
Prenatal polyhydramnios
Characteristic facial features
Cardiac issues
Feeding difficulties
Poor growth
Skin issues
Neurocognitive delaysRanging from mild to profound
Eye anomalies
Musculoskeletal abnormalities
Hypotonia & motor developmental delay
Behavioral issues
Neonatal chylothorax &/or lymphedema
Otolaryngologic issuesMost commonly recurrent otitis media
Urogenital anomaliesMost commonly cryptorchidism in males
Hematologic issue
Immunologic issues

Dysmorphic features (see Figure 1) are often helpful in making the diagnosis. By late adolescence to early adulthood, the craniofacial appearance becomes less like that seen in Noonan syndrome. Dysmorphic features in CFC syndrome can include:

  • Relative macrocephaly
  • Triangular facies
  • Bitemporal narrowing
  • High anterior hairline
  • Hypoplasia of the supraorbital ridges
  • Widely spaced eyes
  • Telecanthus
  • Downslanted palpebral fissures
  • Epicanthal folds
  • Ptosis
  • Short nose with depressed bridge and anteverted nares
  • Ear lobe creases
  • Low-set ears that may be posteriorly rotated
  • Deep philtrum
  • Cupid's bow configuration of the upper lip
  • High-arched palate
  • Relative micrognathia

Cardiac issues occur in approximately 75%-80% of individuals. Cardiac abnormalities, when present, typically present at birth, although hypertrophic cardiomyopathy and rhythm disturbances may manifest later in life. Cardiac findings can include the following:

  • Pulmonic stenosis
  • Atrial septal defects and/or ventricular septal defects
  • Hypertrophic cardiomyopathy
  • Heart valve anomalies (mitral valve dysplasia, tricuspid valve dysplasia, and bicuspid aortic valve)
  • Rhythm disturbances

Gastrointestinal/feeding issues. Most affected individuals have severe feeding issues, which can contribute to poor growth. Many children require nasogastric or gastrostomy tube feeding, while some undergo a Nissen fundoplication procedure for severe gastroesophageal reflux. Oral feedings are typically achieved in early childhood. Constipation is typically reported and continues to be an issue throughout childhood and adolescence. Later in childhood, feeding difficulties and hypotonia often improve. Other issues may include the following:

  • Aspiration or swallowing problems, which may improve with age
  • Recurrent vomiting, which may be association with gastroesophageal reflux disease or malrotation
  • Oral aversion
  • Dysmotility
  • Intestinal malrotation
  • Umbilical and inguinal hernia

Poor growth affects most individuals with CFC syndrome. Growth parameters may be normal at birth, with appropriate birth weight and length; however, weight and length may drop to below the fifth centile during early infancy, while head circumference typically remains within the normal range, resulting in relative macrocephaly.

Ectodermal findings. All individuals with CFC syndrome will develop dermatologic issues. With age, the dryness of the skin and the follicular hyperkeratosis tend to improve, allowing hair to grow on the face and scalp [Roberts et al 2006]; however, palmoplantar hyperkeratosis and lymphedema may become more severe. Nevi, when present, increase in number over time [Siegel et al 2011]. Individuals with CFC syndrome have been known to develop severe skin infections.

  • Skin findings can include the following:
    • Xerosis
    • Hyperkeratosis of arms, legs, and face
    • Keratosis pilaris
    • Ichthyosis
    • Ulerythema ophryogenes
    • Eczema
    • Hemangiomas
    • Café au lait macules
    • Erythema, both on the face or generalized
    • Pigmented moles that may be progressive in number
    • Palmoplantar hyperkeratosis over pressure zones
  • Hair may be sparse to absent, but affected individuals may have normal eyelashes and eyebrows. Hair can be curly; fine or thick; and/or woolly or brittle.
  • Nails may be dystrophic; flat and broad nails; and/or fast growing.

Developmental delay (DD) and intellectual disability (ID). The vast majority of children, if not all, have some form of neurologic abnormality, neurocognitive delay, or learning issues. Overall, developmental delay typically ranges from mild to profound, although some individuals have IQs in the normal range. Developmental delay may be less obvious in mildly or moderately affected individuals, but speech and motor delays and difficulty walking become apparent in those who are more severely affected.

  • The vast majority of affected individuals have hypotonia due to a skeletal muscle myopathy, causing motor delays. The average age of walking in those who become ambulatory is around three years; however, many never achieve this goal.
  • A significant number of affected individuals remain nonverbal. In those who develop verbal language skills, the first word is said on average by age two years.
  • Some young adults participate in assisted living programs and may have supervised employment.

Other neurologic/neurodevelopmental features

  • Hypotonia. Global hypotonia is typically evident in the newborn period. Delayed motor skills, muscle weakness, and decreased muscle bulk is commonly present. As children grow older, muscle weakness appears to gradually improve, although individuals still may have gross motor delays.
  • Seizures. More than 50% of individuals with CFC syndrome develop a seizure disorder. Seizure types may include complex partial seizures, generalized tonic-clonic seizures, absence seizures, and/or infantile spasms. Most seizures begin in infancy or early childhood [Yoon et al 2007, Pierpont et al 2022]; however, a seizure disorder may develop later in childhood as well. Seizures may require polytherapy and can be refractory to therapy (see Treatment of Manifestations).
  • Head MRI findings may include Chiari I malformation, ventriculomegaly, hydrocephalus, prominent Virchow-Robin spaces, abnormal myelination, and structural anomalies.
  • Neuropathy may occur and is typically underreported. Musculoskeletal pain is not uncommon and may be acute or chronic [Leoni et al 2019].
  • Neurobehavioral issues are common and may include irritability, short attention span, stubbornness, and obsessive and/or aggressive behaviors. Anxiety is commonly reported. Autism may also be seen in individuals with CFC syndrome.

Eye abnormalities are present in most individuals and may result in decreased vision and acuity. Findings may include the following:

  • Strabismus
  • Nystagmus
  • Optic nerve hypoplasia
  • Astigmatism
  • Myopia
  • Hyperopia

Musculoskeletal. The vast majority of affected individuals have musculoskeletal findings including a paucity of muscle mass, skeletal myopathy, and lax joints [Tidyman et al 2011]. Orthopedic issues can include pectus deformity, pes planus, hip dysplasia, scoliosis, kyphosis, gait disturbances, and/or joint contractures of the elbow, knee, and/or hip. Contractures may be progressive and require surgical intervention. Many affected individuals require ambulatory assistance. Bone mineral density may also be reduced [Stevenson et al 2011].

Neonatal lymphatic issues. Chylothorax and lymphedema have been reported at birth, although the natural history of these findings has not been reported. Peripheral edema in older individuals may occur.

Otolaryngologic issues. Many affected children experience recurrent otitis media and are found to have narrow external auditory canals. Many require pressure equalization tubes.

Hyperacusis and hearing loss have been reported.

Renal/urogenital anomalies occur in up to 33% of individuals, with cryptorchidism in males being the most common. Renal cysts and stones as well as hydronephrosis and hydroureter can also occur. Bladder, uterine, and cervical abnormalities, though rare, have been reported.

Less common features

  • Endocrinology. Although the vast majority of affected children have not been formally tested, some have true growth hormone deficiency. Affected individuals are also at risk for the development of growth hormone resistance. Both delayed puberty and precocious puberty may occur in males and females. Hypothyroidism has also been reported.
  • Respiratory/sleep. Laryngotracheal abnormalities such as laryngotracheomalacia and laryngeal clefts have been reported. Sleep issues are common and may include poor sleeping patterns, night sweating, sleep apnea, and/or night terrors.
  • Bleeding diathesis has rarely been reported, including a case of von Willebrand disorder as well as a rare case of transient thrombocytopenia in a newborn.
  • Malignancy. Acute lymphoblastic leukemia has been reported in a few individuals [Niihori et al 2006, Makita et al 2007, Rauen et al 2010]. Hepatoblastoma was reported in an immunocompromised individual [Al-Rahawan et al 2007]. Other reported malignancies include non-Hodgkin lymphoma in one individual [Ohtake et al 2011] and large B cell lymphoma in one individual [Rauen et al 2010].

Phenotype Correlations by Gene


  • Pulmonic stenosis is more common in individuals with CFC syndrome due to a pathogenic variant in BRAF. Approximately 50% of individuals with BRAF-related CFC syndrome have pulmonic stenosis [Allanson et al 2011].
  • The frequency of seizures is higher among individuals with BRAF-related CFC syndrome compared to those with MAP2K2-related CFC syndrome [Pierpont et al 2022].

MAP2K1. The frequency of seizures is higher among individuals with MAP2K1-related CFC syndrome comparted to those with MAP2K2-related CFC syndrome [Pierpont et al 2022].

MAP2K2. Individuals with MAP2K2-related CFC syndrome have a lower risk of severe neurodevelopmental delay and epilepsy than individuals with MAP2K1-related CFC syndrome [Pierpont et al 2022].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified for specific pathogenic variants in BRAF, KRAS, MAP2K1, or MAP2K2.


Blumberg et al [1979] at the March of Dimes Birth Defects Conference reported three individuals with intellectual disability who also had characteristic craniofacial dysmorphology, ectodermal anomalies, and cardiac defects. These three persons, along with five others, were subsequently reported by Reynolds et al [1986], who designated this new disorder cardiofaciocutaneous syndrome. Also, Baraitser & Patton [1986] reported on a Noonan syndrome-like short stature syndrome with ectodermal anomalies that was presumed to be the same entity.


Hundreds of individuals with CFC syndrome have been reported in the literature. Overall prevalence is not known; prevalence in Japan is estimated at one in 810,000 [Abe et al 2012].

Differential Diagnosis

Costello syndrome. By definition, individuals identified as having a heterozygous HRAS pathogenic variant have the diagnosis of Costello syndrome. Costello syndrome is characterized by the following:

  • Slow growth in infancy as a result of severe postnatal feeding difficulties
  • Short stature
  • Developmental delay or intellectual disability
  • Coarse facial features (full lips, large mouth, full nasal tip)
  • Hair that may be curly, sparse, and fine with synophrys, trichomegaly, and abnormalities of the scalp hair shafts
  • Loose, soft skin with deep palmar and plantar creases
  • Papillomata of the face and perianal region
  • Diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers
  • Tight Achilles (calcaneal) tendons
  • Cardiac involvement including cardiac hypertrophy (usually typical hypertrophic cardiomyopathy [HCM]), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm / multifocal atrial tachycardia or ectopic atrial tachycardia)
  • Relative or absolute macrocephaly (typically). Postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia.

Individuals with Costello syndrome are at an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.

Although BRAF pathogenic variants have been identified in individuals with a Costello syndrome-like phenotype who did not have an HRAS pathogenic variant [Rauen 2006], on closer clinical examination, the clinical diagnosis was consistent with cardiofaciocutaneous (CFC) syndrome. Costello syndrome and CFC syndrome have many overlapping phenotypic features, underscoring the difficulty in making a clinical diagnosis based on phenotypic features alone. The author feels strongly that individuals with BRAF pathogenic variants have the diagnosis of CFC syndrome, even if they have features that may be present in Costello syndrome or have phenotypic overlap with Noonan syndrome (see following).

Noonan syndrome is characterized by the following:

  • Characteristic facies that includes features similar to CFC, such as triangular facies, macrocephaly, broad forehead, downslanting palpebral fissures, short nose with depressed nasal bridge and anteverted nares, a high-arched palate, and low-set, posteriorly rotated ears.
  • Short stature. Although birth length is usually normal, final adult height approaches the lower limit of normal.
  • Congenital heart defect. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 25%-71% of individuals. Hypertrophic cardiomyopathy, found in 20%-29% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot.
  • Developmental delay of variable degree. Up to one third of affected individuals have mild intellectual disability.
  • Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities.

More than ten genes are known to be associated with Noonan syndrome. More commonly involved genes include PTPN11, SOS1, RIT1, and RAF1. Pathogenic variants in KRAS (associated with <5% of Noonan syndrome) are also known to be associated with CFC syndrome; see Genetically Related Disorders.

Craniofacial findings in CFC syndrome are reminiscent of those described in Noonan syndrome (macrocephaly, broad forehead, bitemporal narrowing, hypoplasia of the supraorbital ridges, downslanting palpebral fissures with ptosis, short nose with depressed nasal bridge and anteverted nares, low-set ears with prominent helices that may be posteriorly rotated, and high-arched palate), underscoring the importance of molecular genetic testing to establish the correct diagnosis.

Noonan syndrome is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant Noonan syndrome have a de novo pathogenic variant, an affected parent is recognized in 30%-75% of families. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.


Clinical practice guidelines for cardiofaciocutaneous (CFC) syndrome have been published [Pierpont et al 2014] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CFC syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Cardiofaciocutaneous (CFC) Syndrome

Constitutional Complete physical exam incl measurement of growth parametersTo assess for poor growth
Neurologic Neurologic eval 1
  • To incl brain MRI in persons w/rapid ↑ in head growth, regression of developmental skills, seizures, changes in neurologic findings, or concerns about optic nerve hypoplasia on ophthalmologic eval
  • Consider EEG if seizures are a concern.
  • Consider nerve conduction velocities & electromyogram in those w/suspected peripheral neuropathy.
  • Education about ↑ risk for development of infantile spasms, seizures, hydrocephalus, & Type 1 Chiari malformation
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Neuropsychiatric evalFor persons age >12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or findings suggestive of ASD
Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk & nutritional status
  • Consider swallowing study &/or studies for GERD.
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
  • Be mindful of possible malrotation.
  • Assessment for signs/symptoms of constipation
Eyes Ophthalmologic evalTo assess for ptosis, amblyopia, refractive error, strabismus, optic nerve abnormalities, cataracts, delayed visual maturation, cortical visual impairment, or more complex findings that may require subspecialty referral
Musculoskeletal Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Contractures, hip dysplasia, & kyphoscoliosis
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Hearing Audiologic evalAssess for hearing loss.
Cardiovascular Cardiac eval incl measurement of blood pressure, echocardiogram, & electrocardiogram
  • With special assessment for pulmonary stenosis, hypertrophic cardiomyopathy, &/or septal defects
  • If there are concerns about arrhythmia, then consider 24-hour Holter eval.
Genitourinary Abdominal ultrasoundTo evaluate for renal & (rarely) splenic anomalies
Consider pelvic ultrasound.For uterine anomalies in pubertal/postpubertal females, as clinically indicated
Skin Dermatologic eval 2
  • Skin issues typically evolve over time.
  • If there is significant lymphedema or large hemangiomas, consider referral to vascular anomalies specialist or clinic.
Endocrine Consider obtaining TSH, free T4, IGF-1, & IGFBP-3.Consider referral to endocrinologist.
Consider celiac disease screening in those w/growth failure.
Physical exam for evidence of precocious puberty in children & for initiation & progression through puberty in adolescents
Obtain DXA scan in younger & older adultsTo assess for ↓ bone mineralization
Hematologic/Lymphatic CBC w/platelet count, platelet function studies, & von Willebrand screening
  • In persons w/history of bruising or bleeding problems, consider referral to hematologist if there are abnormalities on these screening blood tests.
  • Eval for bleeding issues should be done prior to any invasive or surgical procedure.
Respiratory/Sleep Clinical assessment for signs & symptoms of tracheomalacia in infants & young childrenLaryngotracheal abnormalities such as laryngotracheomalacia & laryngeal clefts have been reported.
Consider sleep study.Sleep issues are common & may incl poor sleeping patterns, night sweating, sleep apnea, &/or night terrors.
Genetic counseling By genetics professionals 3To inform affected persons & their families re nature, MOI, & implications of CFC syndrome to facilitate medical & personal decision making
Family support
& resources
Assess need for:

Adapted in part from Pierpont et al [2014], Table 1

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone


Affected individuals are also at risk for the development of neuropathy and complaints of pain.


Skin issues may include keratosis pilaris, ulerythema ophryogenes, eczema, progressive multiple pigmented nevi, dystrophic nails, lymphedema, hemangiomas, hyperkeratosis, and generalized hyperpigmentation.


Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Consensus clinical management guidelines have been published [Pierpont et al 2014] (full text).

There is no cure for CFC syndrome.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5). Specialized NF/Ras pathway genetics clinics are available in the United States, United Kingdom, and European Union.

Table 5.

Treatment of Manifestations in Individuals with Cardiofaciocutaneous Syndrome

Poor weight gain / Severe feeding issues
  • ↑ caloric intake may be considered.
  • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
  • Children w/severe gastroesophageal reflux may require a Nissen fundoplication.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Seizures may be refractory to single-agent therapy & may require polytherapy.
  • In those w/infantile spasms, consult w/cardiologist prior to starting steroid medication because of baseline risk of developing cardiomyopathy.
  • Education of parents/caregivers 1
Chiari malformation Standard treatment per neurosurgeon
Peripheral neuropathy Standard supportive treatment per neurologist or rehabilitation medicine specialistAvoidance of drugs that are neurotoxic (See Agents/Circumstances to Avoid.)
Developmental delay / Intellectual disability See Developmental Delay / Intellectual Disability Management Issues.
Malrotation Standard treatment per surgeon
Constipation ↑ fiber in diet, stool softeners, prokinetics, osmotic agents, or laxatives as neededConsider referral to gastroenterologist if symptoms are severe.
GERD Standard treatment
Eyes Standard treatment per ohthalmologistRefractive errors, strabismus
Standard treatment per ophthalmic subspecialistMore complex findings (e.g., cataract, retinal dystrophy)
Low vision services
  • Children: through early intervention programs &/or school district
  • Adults: low vision clinic &/or community vision services / OT / mobility services
Musculoskeletal abnormality Standard treatment per orthopedist
  • Scoliosis, hip dysplasia, joint contractures, or pectus deformity managed as in general population.
  • Eval for bleeding issues should be done prior to any invasive or surgical procedure.
Chronic/recurrent otitis media Standard treatment per ENT specialist, which may incl placement of PE tubes
Hearing loss Hearing aids may be helpful per otolaryngologist.Community hearing services through early intervention or school district
Cardiovascular defects / Hypertrophic cardiomyopathy Standard treatment per cardiologist
Standard treatment per urologist
  • Xerosis & pruritus may be relieved by ↑ ambient humidity or using hydrating lotions.
  • Hyperkeratoses, lymphedema, & hemangiomas are treated as in general population.
  • Antibiotic treatment for skin infection, esp in presence of lymphedema
  • Nevi may be progressive.
  • For those w/significant lymphedema, mgmt through lymphedema or vascular anomalies clinic may be indicated.
Endocrine Those persons who are growth &/or thyroid hormone deficient should be managed by an endocrinologist.
  • Growth hormone therapy may be considered.
  • Persons w/diagnosis of hypertrophic cardiomyopathy must be monitored closely while on growth hormone therapy.
Standard treatment for pubertal abnormalities (precocious or delayed puberty)
Bleeding disorders /
Standard treatment per hematologist
Sleep disorders Standard treatment as in general population
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement and/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

Adapted in part from Pierpont et al [2014], Table 1

ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PE = pressure equalizer; PT = physical therapy


Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder or anxiety, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.


To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended. Lifelong periodic follow up is warranted.

Table 6.

Recommended Surveillance for Individuals with Cardiofaciocutaneous Syndrome

  • Measurement of growth parameters, incl weight, length/height, & head circumference
  • Refer to endocrinologist at age 2-3 yrs (or earlier if there are concerns about growth) to monitor growth velocity. 1
At each visit
Feeding Eval of nutritional status & safety of oral intake
Gastrointestinal Monitor for gastrointestinal reflux, constipation, & generalized dysmotility.
Neurologic Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, or need for brain MRI. 2At each visit, w/periodic neurologist evals as needed
Development Monitor developmental progress & educational needs.At each visit
Eyes Monitor for ocular issues (such as myopia, hyperopia, cataracts) by ophthalmologistEvery 6-12 mos as directed by ophthalmologist
Musculoskeletal Assess for scoliosis 3, 4At each visit until skeletal maturity
Hearing Hearing evalEvery 2-3 yrs, or more frequently if hearing loss has been identified
Cardiovascular 5 Blood pressure measurementAt each clinic visit
Persons up to age 20 yrsEchocardiogram every 2-3 yrs, if initial cardiac eval is normal
Persons older than age 20 yearsEchocardiogram every 3-5 yrs, if no previous heart disease found
Skin Dermatologic eval for skin issues, progression of nevi formation, & monitoring of lymphedemaAnnually or as directed by dermatologist
Endocrine Monitor for signs/symptoms of thyroid &/or growth hormone deficiency.At each visit
Monitor for signs of precocious or delayed puberty.At each visit in childhood & adolescence
DXA scanIn young adults, w/follow up as clinically indicated
Hematologic Reassess platelet count for evidence of thrombocytopeniaIn those who have evidence of easy bruising or bleeding

Adapted in part from Pierpont et al [2014], Table 1

DXA = dual-energy x-ray absorptiometry


Growth failure may be a sign of growth hormone deficiency or thyroid hormone deficiency.


Affected individuals are at risk of developing Chari I malformation.


Perform spine MRI prior to any spinal surgery to assess for Chiari malformation and/or spinal abnormalities [Pierpont et al 2014].


Evaluation for bleeding issues should be done prior to any invasive or surgical procedure [Pierpont et al 2014].


Periodic echocardiogram and electrocardiogram are necessary throughout life, as hypertrophic cardiomyopathy and rhythm disturbances may develop later in life.

Agents/Circumstances to Avoid

Individuals with CFC syndrome report heat intolerance; therefore, overexposure to heat and strenuous activity should be avoided. Hydrate as needed.

In individuals with evidence of peripheral neuropathy, drugs with a neurotoxic effect should be avoided, per standard supportive treatment according to the individual's neurologist or rehabilitation medicine specialist.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

A pregnant female suspected of having CFC syndrome warrants high-risk obstetric care from a trained maternal-fetal medicine physician due to possible polyhydramnios, maternal cardiac issues, and/or maternal hypertension.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cardiofaciocutaneous (CFC) syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • 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.
  • Individuals diagnosed with CFC syndrome may have an affected parent; instances of familial recurrence of CFC are increasingly reported in the medical literature [Rauen et al 2010, Stark et al 2012, Rauen et al 2021]. Therefore, it is critical that the parents of the proband are examined for signs of CFC syndrome and the medical history of the parents obtained.
  • Molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The family history of some individuals diagnosed with CFC syndrome may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with CFC syndrome has a 50% chance of inheriting the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CFC syndrome-causing pathogenic variant identified in the proband, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and to the parents of an affected child.

Prenatal Testing and Preimplantation Genetic Testing

Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CFC are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Cardiofaciocutaneous Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Cardiofaciocutaneous Syndrome (View All in OMIM)


Molecular Pathogenesis

The four genes currently known to be associated with cardiofaciocutaneous (CFC) syndrome are in the Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The MAPK signaling cascade of dual-specificity kinases [Rauen et al 2011] (see Figure 1) is highly conserved among eukaryotic organisms and is critically involved in cell proliferation, differentiation, motility, apoptosis, and senescence. The Ras/Raf/MEK/ERK signal transduction pathway is activated by extracellular stimuli. Activated Ras recruits Raf, the first kinase of the cascade, to the cell membrane. Activated Raf phosphorylates MEK1 (encoded by MAP2K1) and/or MEK2 (encoded by MAP2K2), which then phosphorylates ERK1 and/or ERK2 (aka MAPK). Noonan syndrome has been associated with pathogenic variants in PTPN11 (protein product SHP2), SOS1, SOS2, RAF1 (protein product CRAF), NRAS, RIT1, LZTR1, RRAS2, KRAS, and other rarer genes. Pathogenic variants in HRAS are causative for Costello syndrome. CFC syndrome is associated with pathogenic variants in BRAF, MAP2K1, and MAP2K2. Because KRAS pathogenic variants were identified in individuals clinically diagnosed with CFC syndrome or with Noonan syndrome [Niihori et al 2006, Schubbert et al 2006], the role of its protein product, GTPase KRas (KRAS), in CFC syndrome warrants further study.

Mechanism of disease causation. The vast majority of pathogenic variants are missense or small in-frame deletions that cause a gain-of-function activation of the protein product BRAF, MEK1, MEK2, or KRAS that leads to activation of the Ras/MAPK pathway. This results in increased phosphorylation and, thus, activation of ERK1 and/or ERK2.

Table 8.

Cardiofaciocutaneous (CFC) Syndrome: Notable Pathogenic Variants by Gene

Gene 1Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
BRAF NM_004333​.6
c.770A>Gp.Gln257ArgMost common pathogenic variant in persons w/CFC syndrome [Niihori et al 2006, Rodriguez-Viciana et al 2006]
MAP2K1 NM_002755​.4
c.389A>Gp.Tyr130CysMost common pathogenic variant [Rodriguez-Viciana & Rauen 2008]
MAP2K2 NM_030662​.4
401A>Gp.Tyr134CysMost common pathogenic variant [Rodriguez-Viciana & Rauen 2008]

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Genes from Table 1 are in alphabetic order.

Cancer and Benign Tumors

BRAF. Somatic pathogenic variants in BRAF have been reported in approximately 8% of tumors, most frequently in melanoma, thyroid, colorectal, and ovarian cancers, and have also been found in benign nevi and premalignant colon polyps. BRAF pathogenic variants have also been seen in Langerhans cell histiocytosis and non-Langerhans cell histiocytoses [Badalian-Very et al 2010, Diamond et al 2016, Durham et al 2019].

KRAS. Single-nucleotide variants in KRAS account for approximately 85% of pathogenic variants in the Ras gene family. KRAS oncogenic variants are common in pancreatic cancer, colon cancer, small intestinal cancer, biliary cancer, and lung cancer. The vast majority of oncogenic pathogenic variants occur in hot spots in codons 12, 13, or 61. These are not the same pathogenic variants that are found in CFC syndrome [Schubbert et al 2006]. Somatic activating KRAS variants have been identified in arteriovenous malformations of the brain [Nikolaev et al 2018].

MAP2K1/MAP2K2. Somatic pathogenic variants in MAP2K1 and MAP2K2 have been reported in various tumors, including ovarian cancer and non-small cell lung carcinoma [Estep et al 2007, Marks et al 2008]. MAP2K1 and MAP2K2 pathogenic variants also occur in Langerhans cell histiocytosis and non-Langerhans cell histiocytoses [Diamond et al 2016, Durham et al 2019]. Somatic MAP2K1 pathogenic variants are associated with extracranial arteriovenous malformation [Couto et al 2017].

Chapter Notes

Author Notes

Dr Rauen serves on the Medical Advisory Board for CFC International, Inc, and is codirector and member of the Professional Advisory Board for the Costello Syndrome Family Network. She also is a member of the RASopathies Network Scientific Advisory Board and the Global Genes Advisory Board.


Special thanks to CFC International, the Costello Syndrome Family Network, and RASopathiesNet for their ongoing support of research in genomic medicine.

Revision History

  • 9 February 2023 (ma) Comprehensive update posted live
  • 3 March 2016 (ha) Comprehensive update posted live
  • 6 September 2012 (cd) Revision: multigene panels for Noonan / Costello / LEOPARD / cardiofaciocutaneous syndrome(s) (RAS/MAPK pathway) available clinically
  • 23 December 2010 (me) Comprehensive update posted live
  • 18 January 2007 (me) Review posted live
  • 14 September 2006 (kar) Original submission


Literature Cited

  • Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, Ohashi H, Mizuno S, Ogata T, Kure S, Niihori T, Matsubara Y, et al. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A. 2012;158A:1083-94. [PubMed: 22495831]
  • Allanson JE, Annerén G, Aoki Y, Armour CM, Bondeson ML, Cave H, Gripp KW, Kerr B, Nystrom AM, Sol-Church K, Verloes A, Zenker M. Cardio-facio-cutaneous syndrome: does genotype predict phenotype? Am J Med Genet C Semin Med Genet. 2011;157C:129-35. [PMC free article: PMC3086095] [PubMed: 21495173]
  • Al-Rahawan MM, Chute DJ, Sol-Church K, Gripp KW, Stabley DL, McDaniel NL, Wilson WG, Waldron PE. Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome. Am J Med Genet A. 2007;143A:1481-8. [PubMed: 17567882]
  • Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, Kuo FC, Ligon AH, Stevenson KE, Kehoe SM, Garraway LA, Hahn WC, Meyerson M, Fleming MD, Rollins BJ. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919-23. [PMC free article: PMC3173987] [PubMed: 20519626]
  • Baraitser M, Patton MA. A Noonan-like short stature syndrome with sparse hair. J Med Genet 1986;23:161-4 [PMC free article: PMC1049573] [PubMed: 3712393]
  • Blumberg B, Shapiro L, Punnett HH, Rimoin D, Kirtenmacher M. A new mental retardation syndrome with characterisitc facies, ichthyosis and abnormal hair. Paper. Chicago, IL: March of Dimes Birth Defects Conference. 1979.
  • Couto JA, Huang AY, Konczyk DJ, Goss JA, Fishman SJ, Mulliken JB, Warman ML, Greene AK. Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am J Hum Genet. 2017;100:546-54. [PMC free article: PMC5339083] [PubMed: 28190454]
  • Diamond EL, Durham BH, Haroche J, Yao Z, Ma J, Parikh SA, Wang Z, Choi J, Kim E, Cohen-Aubart F, Lee SC, Gao Y, Micol JB, Campbell P, Walsh MP, Sylvester B, Dolgalev I, Aminova O, Heguy A, Zappile P, Nakitandwe J, Ganzel C, Dalton JD, Ellison DW, Estrada-Veras J, Lacouture M, Gahl WA, Stephens PJ, Miller VA, Ross JS, Ali SM, Briggs SR, Fasan O, Block J, Héritier S, Donadieu J, Solit DB, Hyman DM, Baselga J, Janku F, Taylor BS, Park CY, Amoura Z, Dogan A, Emile JF, Rosen N, Gruber TA, Abdel-Wahab O. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov. 2016;6:154-65. [PMC free article: PMC4744547] [PubMed: 26566875]
  • Durham BH, Lopez Rodrigo E, Picarsic J, Abramson D, Rotemberg V, De Munck S, Pannecoucke E, Lu SX, Pastore A, Yoshimi A, Mandelker D, Ceyhan-Birsoy O, Ulaner GA, Walsh M, Yabe M, Petrova-Drus K, Arcila ME, Ladanyi M, Solit DB, Berger MF, Hyman DM, Lacouture ME, Erickson C, Saganty R, Ki M, Dunkel IJ, Santa-María López V, Mora J, Haroche J, Emile JF, Decaux O, Geissmann F, Savvides SN, Drilon A, Diamond EL, Abdel-Wahab O. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25:1839-42. [PMC free article: PMC6898787] [PubMed: 31768065]
  • Estep AL, Palmer C, McCormick F, Rauen KA. Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PLoS One. 2007;2:e1279. [PMC free article: PMC2093994] [PubMed: 18060073]
  • Geoghegan S, King G, Henchliffe J, Ramsden SC, Barry RJ, Green AJ, O'Connell SM. A sibling pair with cardiofaciocutaneous syndrome (CFC) secondary to BRAF mutation with unaffected parents-the first cases of gonadal mosaicism in CFC? Am J Med Genet A. 2018 Jul;176(7):1637-1640. [PubMed: 29704308]
  • Jelin AC, Mahle A, Tran SH, Sparks TN, Rauen KA. Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation. Am J Med Genet A. 2023;191:323-31. [PMC free article: PMC9839479] [PubMed: 36308388]
  • Leoni C, Triumbari EKA, Vollono C, Onesimo R, Podagrosi M, Giorgio V, Kuczynska E, Veltri S, Tartaglia M, Zampino G. Pain in individuals with RASopathies: prevalence and clinical characterization in a sample of 80 affected patients. Am J Med Genet A. 2019;179:940-7. [PubMed: 30854769]
  • Lissewski C, Kant SG, Stark Z, Schanze I, Zenker M. 2015. Copy number variants including RAS pathway genes—How much RASopathy is in the phenotype? Am J Med Genet 2015 Part A 167A:2685–2690. [PubMed: 25974318]
  • Makita Y, Narumi Y, Yoshida M, Niihori T, Kure S, Fujieda K, Matsubara Y, Aoki Y. Leukemia in cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. J Pediatr Hematol Oncol. 2007;29:287-90. [PubMed: 17483702]
  • Marks JL, Gong Y, Chitale D, Golas B, McLellan MD, Kasai Y, Ding L, Mardis ER, Wilson RK, Solit D, Levine R, Michel K, Thomas RK, Rusch VW, Ladanyi M, Pao W. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res. 2008;68:5524-8. [PMC free article: PMC2586155] [PubMed: 18632602]
  • Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38:294-6 [PubMed: 16474404]
  • Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B, Khyzha N, DiStefano PV, Suutarinen S, Kiehl TR, Mendes Pereira V, Herman AM, Krings T, Andrade-Barazarte H, Tung T, Valiante T, Zadeh G, Tymianski M, Rauramaa T, Ylä-Herttuala S, Wythe JD, Antonarakis SE, Frösen J, Fish JE, Radovanovic I. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med. 2018;378:250-61. [PMC free article: PMC8161530] [PubMed: 29298116]
  • Nowaczyk MJ, Thompson BA, Zeesman S, Moog U, Sanchez-Lara PA, Magoulas PL, Falk RE, Hoover-Fong JE, Batista DA, Amudhavalli SM, White SM, Graham GE, Rauen KA. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin Genet. 2014;85:138-46. [PMC free article: PMC4480871] [PubMed: 23379592]
  • Ohtake A, Aoki Y, Saito Y, Niihori T, Shibuya A, Kure S, Matsubara Y. Non-Hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome. J Pediatr Hematol Oncol. 2011;33:e342-6. [PubMed: 20523244]
  • Pierpont EI, Kenney-Jung DL, Shanley R, Zatkalik AL, Whitmarsh AE, Kroening SJ, Roberts AE, Zenker M. Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: a multinational cohort study. Genet Med. 2022;24:1556-66. [PubMed: 35524774]
  • Pierpont ME, Magoulas PL, Adi S, Kavamura MI, Neri G, Noonan J, Pierpont EI, Reinker K, Roberts AE, Shankar S, Sullivan J, Wolford M, Conger B, Santa Cruz M, Rauen KA. Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2014;134:e1149-62. [PMC free article: PMC4179092] [PubMed: 25180280]
  • Popov IK, Hiatt SM, Whalen S, Keren B, Ruivenkamp C, van Haeringen A, Chen M-J, Cooper GM, Korf BR and Chang C. A YWHAZ variant associated with cardiofaciocutaneous syndrome activates the RAF-ERK pathway. Front Physiol. 2019;10:388. [PMC free article: PMC6465419] [PubMed: 31024343]
  • Rauen KA. Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. Am J Med Genet A. 2006;140:1681-3 [PubMed: 16804887]
  • Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-69. [PMC free article: PMC4115674] [PubMed: 23875798]
  • Rauen KA, Banerjee A, Bishop WR, Lauchle JO, McCormick F, McMahon M, Melese T, Munster PN, Nadaf S, Packer RJ, Sebolt-Leopold J, Viskochil DH. Costello and cardio-facio-cutaneous syndromes: moving toward clinical trials in RASopathies. Am J Med Genet C Semin Med Genet. 2011;157C:136-46. [PMC free article: PMC4145816] [PubMed: 21495172]
  • Rauen KA, Maeda Y, Egense A, Tidyman WE. Familial cardio-facio-cutaneous syndrome: Vertical transmission of the BRAF p.G464R pathogenic variant and review of the literature. Am J Med Genet A. 2021;185:469-75. [PubMed: 33274568]
  • Rauen KA, Tidyman WE, Estep AL, Sampath S, Peltier HM, Bale SJ, Lacassie Y. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. Am J Med Genet A. 2010. 152A:807-14. [PMC free article: PMC4180666] [PubMed: 20358587]
  • Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz JM. New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome. Am J Med Genet. 1986;25:413-27 [PubMed: 3789005]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G. The cardiofaciocutaneous syndrome. J Med Genet. 2006;43:833-42 [PMC free article: PMC2563180] [PubMed: 16825433]
  • Rodriguez-Viciana P, Rauen KA. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89. [PubMed: 18413255]
  • Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 2006;311:1287-90 [PubMed: 16439621]
  • Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30:695-702. [PMC free article: PMC4028130] [PubMed: 19206169]
  • Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38:331-6 [PubMed: 16474405]
  • Siegel DH, McKenzie J, Freiden I, Rauen KA. Dermatological findings in 61 mutation-positive individuals with cardio-facio-cutaneous syndrome. Br J Dermatol. 2011;164:521-9. [PMC free article: PMC4063552] [PubMed: 21062266]
  • Stark Z, Gillessen-Kaesbach G, Ryan MM, Cirstea IC, Gremer L, Ahmadian MR, Savarirayan R, Zenker M. Two novel germline KRAS mutations: expanding the molecular and clinical phenotype. Clin Genet. 2012;81:590-4. [PubMed: 21797849]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Stevenson DA, Schwarz EL, Carey JC, Viskochil DH, Hanson H, Bauer S, Weng HY, Greene T, Reinker K, Swensen J, Chan RJ, Yang FC, Senbanjo L, Yang Z, Mao R, Pasquali M. Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet. 2011;80:566-73. [PMC free article: PMC3246507] [PubMed: 21204800]
  • Tidyman WE, Lee HS, Rauen KA. Skeletal muscle pathology in Costello and cardio-facio-cutaneous syndromes: developmental consequences of germline Ras/MAPK activation on myogenesis. Am J Med Genet C Semin Med Genet. 2011;157C:104-14. [PubMed: 21495178]
  • Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009a;19:230-6. [PMC free article: PMC2743116] [PubMed: 19467855]
  • Yoon G, Rosenberg J, Blaser S, Rauen KA. Neurological complications of cardio-facio-cutaneous syndrome. Dev Med Child Neurol. 2007;49:894-9. [PubMed: 18039235]
  • Yu S, Graf WD. BRAF gene deletion broadens the clinical spectrum neuro-cardio-facial-cutaneous syndromes. J Child Neurol. 2011;26:1593-6. [PubMed: 21862832]
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1186PMID: 20301365


Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...