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.
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|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.
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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.
CFC syndrome is suspected when the following findings apply:
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.
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:
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.
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.
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.