Cardiofaciocutaneous syndrome (CFC syndrome) belongs to the group of RASopathies and can be caused by genetic mutations in four different genes: BRAF (CFC1, OMIM #115150), KRAS (CFC2, OMIM #615278), MAP2K1 (CFC3, OMIM #615279), and MAP2K2 (CFC4, OMIM #615280). Clinical symptoms include various heart defects, characteristic facies, cutaneous abnormalities, musculoskeletal and neurological abnormalities, and developmental delay.

Key Data

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Synonym CFC syndrome
Genes BRAF (approx. 75%), KRAS (approx. 2%), MAP2K1 (approx. 25%), MAP2K2 (approx. 25%)
Gene products Serine/threonine protein kinase B-raf (BRAF)
GTPase KRas (KRAS)
Dual specificity mitogen-activated protein kinase 1 (MAP2K1)
Dual specificity mitogen-activated protein kinase 2 (MAP2K2)
Function Part of the RAS/MAPK signaling pathway
Heredity Autosomal dominant, but often de novo mutations
Prevalence The general prevalence is unknown. There are probably a few hundred-people suffering from CFC syndrome around the world. The prevalence in Japan is around 1:810.000.
Genotype-phenotype correlation 50% of CFC patients with a BRAF mutation have pulmonary stenosis (in contrast to only 37% of CFC patients with MAP2K1/MAP2K2 mutations).

Patients with BRAF mutation p.Gln257Arg (the most frequent CFC syndrome mutation) exhibit a very marked phenotypic pattern.

Patients with MAP2K1 and MAP2K2 mutations tend towards Keratosis pilaris and more progressive nevi than do patients with a BRAF mutation.

Penetrance Complete
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To date, there are no diagnostic criteria for CFC syndrome, which is why a suspected diagnosis is generally made on the basis of abnormal clinical findings and confirmed by genetic diagnostics.

Suspected Diagnosis

CFC syndrome is suspected when the following findings apply:


  • Pulmonary stenosis

  • Atrial septal defect

  • Ventricular septal defect

  • Hypertrophic cardiomyopathy

  • Heart valve defect (mitral or tricuspid valve dysplasia, bicuspid aortic valve)

  • Dysrhythmia


  • Macrocephaly

  • High and broad forehead and bitemporal impressions

  • Hypoplasia of the superciliary arch (brow ridge)

  • Sparse eyebrows or none at all

  • Hypertelorism and drooping palpebral fissures

  • Ocular abnormalities: strabismus, nystagmus, myopia, hyperopia, ptosis, astigmatism

  • Short nose with a sunken nasal root and anteverted nostrils

  • Prominent and broad philtrum, gothic palate

  • Low-lying ears rotated towards the back


  • Skin: xerosis, hyperkeratosis that is palmoplantar and on the arms, legs, and face, ichthyosis, keratosis pilaris, eczema, hemangiomas, Café-au-lait spots, erythema, pigment spots

  • Hair: sparse, frizzy, thin or thick, woolly, or brittle hair; sparse eyebrows and eyelashes or none at all

  • Nails: dystrophic, flat, and wide nails; rapid nail growth

Other Abnormalities:

  • Musculoskeletal: short neck, pterygium colli, deformed rib cage, kyphosis, scoliosis, pes planus

  • Neurology: primarily mild to severe psychomotor retardation and muscular hypotonia

  • Gastroenterology: failure to thrive, gastroesophageal reflux, vomiting, oral aversion, and constipation

  • Dwarfism

Genetic Diagnostics

The diagnosis of “CFC syndrome” is confirmed by the detection of a heterozygous germline mutation in the BRAF, KRAS, MAP2K1, or MAP2K2 gene. Initially panel studies (RASopathies / Noonan spectrum) should be performed. If these are not available, testing serial single-genes by sequence analysis may be conducted in the following order: BRAF, MAP2K1, MAP2K1, and finally KRAS. If no mutations are revealed, a targeted deletion/duplication analysis or a CGH array may be performed. It may also be worth considering exome or genome sequencing.

Differential Diagnoses

  • Costello syndrome

  • Noonan syndrome

Clinical Presentation

The occurrence of CFC syndrome in male and female patients is evenly distributed.

Prenatal and Neonatal Period

In most cases polyhydramnios occurs during the prenatal period. The characteristic facies (see “Diagnosis”) are already evident in infants; moreover, cardiac abnormalities generally become apparent right from birth. There may also be feeding difficulties during the neonatal period.


During infancy, there may continue to be major problems with the ingestion of food that make it necessary to use a nasogastric or gastrostomy tube for feeding. In addition, there may be gastroesophageal reflux and constipation as well. It is possible that all of this will result in failure to thrive.

All children with CFC syndrome develop a neurological abnormality in the form of a psychomotor developmental delay with muscular hypotonia and delayed language development or a learning disability. The intensity of these abnormalities may range from a mild to very severe manifestation; nevertheless, a few patients exhibit normal IQ.

Childhood and Adolescence

The following manifestations may occur at this age:

  • Difficulties ingesting food

  • Dwarfism: in nearly all children and adolescents with CFC syndrome

  • Different degrees of psychomotor developmental delay, ranging from mild to very severe, mainly affecting motor function and speech

  • Cramping seizures: Approximately 50% of CFC patients suffer from cramping seizures, which usually occur for the first time during infancy or early childhood, although they also may not develop until later in childhood.

  • ENT: recurring otitis and a constricted external auditory canal

  • Eyes: strabismus, nystagmus, hypoplasia of the optic nerve, astigmatism, myopia, or hyperopia

  • Heart: Cardiac manifestations such as hypertrophic cardiomyopathy, structural abnormalities, and rare dysrhythmia occur in 75-80% of CFC patients.

  • Kidneys / urogenital tract: in up to 33% of CFC patients as cryptorchidism for male patients, along with renal cysts and stones, hydronephrosis, and hydroureter

  • Blood: Von-Willebrand syndrome is described.

  • Skin: Xerosis and follicular hyperkeratosis improve with advancing age, making it increasingly possible for hair to grow. Palmoplantar hyperkeratosis and lymphedemas increase with age. Nevi become more numerous over time. In addition, there is a tendency for severe skin infections to occur.

  • Musculoskeletal: In the majority of CFC patients, there are muscular symptoms in the form of hypotonia with reduced muscle mass and hyperelastic joints. Potential skeletal changes include rib cage deformities, scoliosis, and kyphosis or may become apparent through a restricted gait.

  • Appearance: The characteristic facies (see “Diagnosis”) becomes less apparent with increasing age.

  • Neoplasia: This rarely occurs as part of CFC syndrome. There have been reports of acute lymphatic leukemia (ALL), hepatoblastoma, lymphomas, and rhabdomyosarcoma in the past.

Therapeutic Considerations

In light of the large number of potential manifestations, treatment should always be symptom-orientated and interdisciplinary, with the involvement of the corresponding specialist disciplines.

The manifestations that occur as part of CFC syndrome are generally treated according to the ones that occur sporadically.

Surveillance Recommendations

Surveillance Recommendations

Clinical examinations should be conducted on a regular basis to check for gastroenterological abnormalities, growth, cognitive development, and musculoskeletal changes.

In addition, regular cardiological, neurological, ENT, ophthalmological, and dermatological examinations should be undertaken.

Patients should be made aware of their potentially increased risk of neoplasia. Specific cancer surveillance is not recommended.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with cardiofaciocutaneous syndrome that we can recommend to you for more information.

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