What is Cardiofaciocutaneous syndrome?

Cardiofaciocutaneous syndrome (CFC syndrome) belongs to the group of RASopathy disorders caused by genetic changes in the RAS/MAPK signaling pathway. This signaling pathway transmits information inside the cell. Genetic mutations in four different genes are known to cause CFC syndrome: BRAF (CFC1), KRAS (CFC2), MAP2K1 (CFC3), and MAP2K2 (CFC4). It is clinically characterized by various heart defects, a characteristic shape of the face, anomalies of the skin, changes in the muscles and skin, neurological anomalies, and developmental delays.

How is Cardiofaciocutaneous syndrome diagnosed?

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 with presentation of the following:

Heart:

  • Pulmonary stenosis (narrowing of the outflow tract from the right ventricle to the pulmonary artery)

  • Atrial septum defect (a hole in the cardiac septum between the two atria of the heart)

  • Ventricular septum defect (a hole in the cardiac septum between the two ventricles of the heart)

  • Hypertrophic cardiomyopathy (thickening of the heart muscle, usually of the left ventricle)

  • Heart valve defect

  • Dysrhythmia

Head and Face:

  • Large head

  • High and broad forehead with indentations in both temple regions

  • Underdeveloped brow ridges

  • Sparse eyebrows or none at all

  • Wide set eyes and drooping lid fissures

  • Eye anomalies: squinting, eye twitching, near or farsightedness, drooping lid, astigmatism

  • Short nose with a sunken nasal root and upturned nostrils

  • Prominent and broad philtrum (groove between the nose and upper lip), pointed arched palate

  • Low-lying ears rotated towards the back

Skin, Hair, Nails:

  • Skin: dry skin, excessive keratinization of the skin on the palms and the soles of the feet and on the arms, legs, and face, thickened hair follicles, eczema, hemangiomas, café au lait spots, red patches, pigment spots

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

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

Other Anomalies:

  • Muscles/skeleton: short neck, webbed neck, deformed rib cage, spinal deformations, flat feet

  • Neurology: primarily mild to severe developmental delays and muscle weakness

  • Gastrointestinal tract: failure to thrive, gastroesophageal reflux (return flow of the stomach contents into the esophagus), vomiting, and constipation

  • Dwarfism

Genetic Diagnostics

The diagnosis of “CFC syndrome” is confirmed by detection of a mutation – or genetic alteration – in the BRAF, KRAS, MAP2K1, or MAP2K2 gene.

What is the risk of cancer?

Malignant diseases can occur as part of CFC syndrome, although this is rarely the case. Currently, there are no precise statistics on cancer incidence. Leukemia, lymphomas, hepatoblastomas (liver tumors) and rhabdomyosarcomas (soft tissue tumors) have been described so far.

In addition, the following clinical manifestations are prominent in various age groups:

Pregnancy and Newborn Period

During pregnancy, there is a greater than average amount of amniotic fluid in most cases. The characteristic shape of the face (see “Diagnosis”) is already evident in newborns; moreover, malformations of the heart generally become apparent right from birth. There may also be feeding difficulties during the newborn period.

Infancy

During infancy, there may continue to be major problems with the ingestion of food that make it necessary to use a tube for feeding. In addition, there may be gastroesophageal reflux (return flow of the stomach contents into the esophagus) 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 psychomotor developmental delay with muscle weakness and delayed language development or a learning disability. The intensity of these anomalies may range from a mild to very severe manifestation; a few patients nevertheless 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 delays, ranging from mild to very severe, predominantly affecting motor function and speech

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

  • ENT: frequent middle ear infections and a narrowing of the external auditory canal

  • Eyes: squinting, eye twitching, underdeveloped optic nerve, corneal curvature, near or farsightedness

  • Heart: Manifestations in the heart such as a thickening of the heart muscle, structural anomalies, and rare dysrhythmia occur in 75-80% of CFC patients.

  • Kidneys / urogenital tract: in up to 33% of CFC patients as “abdominal testes” (where the testicles are inside the abdominal cavity) in male patients and also kidney cysts and stones, hydronephrosis (swelling of a kidney) and an expanded ureter due to urine retention

  • Blood: Von-Willebrand syndrome (coagulation disorder) is described.

  • Skin: Dry skin and thickened hair roots improve with advancing age, making it increasingly possible for hair to grow. Both excessive keratinization of the palms and the soles of the feet as well as lymphedemas increase with age. Pigment spots become more numerous over time. In addition, there is a tendency for severe skin infections to occur.

  • Muscles/skeleton: In the majority of CFC patients, there are muscular symptoms in the form of muscle weakness with reduced muscle mass and hyperelastic joints. Potential skeletal changes include rib cage deformities and spinal deformations or may become apparent through a restricted gait.

  • Appearance: The characteristic shape of the face (see “Diagnosis”) becomes less pronounced with increasing age.

There is an even male to female distribution of CFC syndrome.

What causes Cardiofaciocutaneous syndrome?

CFC syndrome is caused by mutations – or genetic changes – in the BRAF, KRAS, MAP2K1, or MAP2K2 gene. These genes encode proteins of the RAS/MAPK signaling pathway, which transmits information inside our cells.

Now if one of these genes is altered, the corresponding protein will not be produced properly and will no longer be able to correctly perform its normal function. This then results in a faulty transfer of information within the cell, which can lead to congenital anomalies and developmental delays.

There are probably several hundred people around the world who suffer from CFC syndrome. The general frequency of the disease is however unknown. It can be passed on from parents to their children, and is inherited as an autosomal-dominant disease. Spontaneous or new mutations, called de novo mutations, often occur as well.

Is there a treatment?

In light of the large number of potential manifestations, treatment should always be symptom-oriented and involve different specialist disciplines working together.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Regular clinical examinations should be conducted in order to determine anomalies with regard to the gastrointestinal tract, growth, cognitive development, and changes in the muscles and skeleton.

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

Awareness of the potential for an increased risk of leukemia, lymphomas, and liver / soft tissue tumors should be raised in patients. Specific cancer surveillance is not recommended.

Self-Care and Support

What should I pay special attention to?

Patients with CFC syndrome report an intolerance to heat, which is why exposure to excessive heat should be avoided.

You should see a doctor as soon as cramping seizures, anomalies of the skin, visual or hearing impairment, or changes or pain in muscles or bones occur. Unspecific symptoms such as abdominal, flank, or bone pain, fatigue, or a feeling of weakness should also be noted and reported to a doctor. You should likewise go to a doctor if new anomalies or complaints develop.

Support Groups and Additional Information