About facio-cardio-cutaneous syndrome

What is facio-cardio-cutaneous syndrome?

Cardiofaciocutaneous (CFC) syndrome is one of the RASopathies and is a rare genetic disorder is typically characterized by unusually sparse, brittle, curly hair; large head (macrocephaly); a prominent forehead and abnormal narrowing of the sides of the forehead (bi-temporal narrowing); intellectual disability; failure to thrive; heart defects that are present at birth (congenital); short stature and skin abnormalities. CFC syndrome is a dominant de novo genetic disorder caused by a sporadic gene abnormality (mutation) in one of four genes that have been termed BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2), and KRAS. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC syndrome.

CFC syndrome was first described in 1986, based on the observation of eight unrelated patients who had intellectual disability and similar abnormalities in facial appearance, skin, hair, nails and heart.

What are the symptoms for facio-cardio-cutaneous syndrome?

Most individuals are initially referred because of feeding difficulties (poor suck) and Failure to thrive. Later, cognitive developmental delay and other clinical manifestations may be observed.

Facial Appearance

Affected individuals may have a relatively large head (macrocephaly) when compared to their height, a high forehead and abnormal narrowing of the sides of the forehead (bitemporal narrowing), causing the head to appear “box-like” in shape. The ears are abnormally angulated towards the back of the head and low set (posteriorly angulated) with the ear lobes occasionally having creasing. The nose is short, bulbous and with anteverted nostrils and a depressed bridge. There is also an underdevelopment (hypoplasia) of the ridges of the bone above the eyes (supraorbital ridges); widely spaced eyes (ocular hypertelorism); downslant of eyelid openings and drooping of one or both upperlids (ptosis).

Skin, hair and nails

Most patients have some kind of ectodermal abnormality, either of skin, hair or nails. Children with CFC Syndrome usually have sparse, slow growing, fine or thick, curly scalp hair that is abnormally dry and brittle. They also have absent or sparse eyebrows and eyelashes. In some children, the nails are dystrophic, with broad flat nails, and/or fast growing. Skin involvement ranges from dry skin to the skin disease known as hyperkeratosis. Pigmented nevi are very distinct to CFC syndrome and help define the syndrome. Other typical skin manifestations include small hard bumps (keratosis pilaris), facial skin lesions around the eyebrows (ulerythema ophryogenes), and benign vascular tumors (infantile hemangiomas).


Congenital heart defects are present in over 75% of patients, with the most common heart defects being pulmonic stenosis and atrial or ventricular septal defects. There may also be hypertrophic cardiomyopathy (thickening of the heart muscle) and rhythm disturbances. These defects may be diagnosed at birth or later in life.

Intellectual Disability

There is some form of cognitive or neurologic delay in nearly all patients with CFC syndrome. Most individuals fall in the range of moderate intellectual disability. Global developmental delay including gross motor and language delay is very common. Autism and other sensory behavioral issues have been reported in some individuals with CFC syndrome.


Symptoms affecting the eyes can effect both their appearance: ocular hypertelorism (increased distance between eyes), strabismus (uneven alignment of the eyes) and their function; involuntary eye movements, astigmatism, nearsightedness and/or farsightedness. Optic nerve hypoplasia, cortical blindness, and cataracts have been described. Although most individuals with CFC syndrome have ocular symptoms, some have a normal ophthalmologic examination.


Severe feeding problems manifest as gastroesophageal reflux (GER), aspiration, Vomiting, and affected individuals will avoid eating (avoidance of eating can lead to growth delays). Often individuals with gastrointestinal symptoms will require a feeding tube that may persist into early childhood. Other GI problems include dysmotility, intestinal malrotation (abnormal development of the intestine), hernia, and/or constipation. Some individuals have inflammation of the spleen and/or liver. Most children have malnutrition secondary to avoidance of eating. Fatty liver and anal stenosis (tightening of the anal sphincter) have also been reported.

Endocrine Abnormalities

Affected individuals can have growth hormone deficiency and early onset puberty.

Growth Delays

Growth may be normal with appropriate birth weight and length; however, weight and length may drop to below the fifth percentile during early infancy while head circumference remains within the normal range, which gives the appearance of macrocephaly.

Additional Abnormalities

Additional abnormalities that are present in some but not all patients include short stature; webbed neck; abnormal shape of the thorax (pectus carinatum); joint hyperextension; hypotonia (reduced muscle tone), neoplasia (typically lymphyoblastic leukemia), especially during the first years of life; urogenital anomalies; Seizures; and undescended testes (cryptorchidism) of boys.

What are the causes for facio-cardio-cutaneous syndrome?

Cardiofaciocutaneous syndrome can be caused by variants (also known as mutations) in several genes. Variants in the BRAF gene are most common, accounting for 75 to 80 percent of all cases. Another 10 to 15 percent of cases result from variants in one of two similar genes, MAP2K1 and MAP2K2. Fewer than 5 percent of cases are caused by variants in the KRAS gene.

The BRAF, MAP2K1, MAP2K2, and KRAS genes provide instructions for making proteins that work together to transmit chemical signals from outside the cell to the cell's nucleus. This chemical signaling pathway, known as the RAS/MAPK pathway, is essential for normal development before birth. It helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement, and the self-destruction of cells (apoptosis).

Variants in any of these genes can result in the characteristic features of cardiofaciocutaneous syndrome. The protein made from the altered gene is overactive, which alters tightly regulated chemical signaling during development. The altered signaling interferes with the development of many organs and tissues, leading to the signs and symptoms of cardiofaciocutaneous syndrome.

Some people with the signs and symptoms of cardiofaciocutaneous syndrome do not have an identified variant in the BRAF, MAP2K1, MAP2K2, or KRAS gene. In these cases, affected individuals may actually have Costello syndrome or Noonan syndrome, which are also caused by variants in genes involved in RAS/MAPK signaling. The proteins produced from these genes are all part of the same chemical signaling pathway, which helps explain why variants in different genes can cause conditions with such similar signs and symptoms. The group of related conditions that includes cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome is often called the RASopathies.

What are the treatments for facio-cardio-cutaneous syndrome?

Treatment The treatment of CFC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; physicians who diagnose and treat skin disorders (dermatologists), heart abnormalities (cardiologists), eye disorders (ophthalmologists), and/or neurological abnormalities (neurologists); and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.

Specific therapies for CFC syndrome are symptomatic and supportive. In some individuals with congenital heart defects such as pulmonary stenosis and/or atrial septal defects, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, the surgical procedures performed will depend upon the location, severity, and/or combination of anatomical abnormalities and their associated symptoms.

In individuals with CFC syndrome, respiratory infections should be treated promptly and vigorously. Because of the potentially increased risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, individuals with atrial septal defects may be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.

In affected individuals with hydrocephalus, shunts may be implanted to drain excess cerebrospinal fluid away from the brain, relieving pressure. In addition, in some cases, treatment with anticonvulsant drugs may help prevent, reduce, or control seizures.

In individuals affected by certain ocular abnormalities, corrective glasses, contact lenses, and/or surgery may be used to help improve vision.

Oftentimes, children who are failing to thrive will require a nasogastic or gastrostomy tube (feeding tubes). An increased caloric intake may also be beneficial in conjunction with increase fiber if the affected individual suffers from constipation.

In addition, to help alleviate skin abnormalities, physicians may recommend certain lubricating lotions or ointments, such as petroleum jelly. Applying such lubricants may be particularly effective after bathing while the skin is moist. In affected individuals with hemangiomas, treatment may not be required in some cases. In other cases, physicians may recommend removal of hemangiomas, depending upon severity, location, the occurrence of associated bleeding, and/or other associated symptoms or difficulties (e.g., obstruction of vision due to location on an eyelid). Various removal techniques may be used (e.g., laser surgery, cryosurgery, plastic surgery).

Early intervention may be beneficial in helping children with CFC syndrome reach their potential. Special services that may be of assistance may include special remedial education, speech therapy, occupational therapy, physical therapy, and/or other medical, social, and/or vocational services.

Genetic counseling is recommended for affected individuals and their families. Other treatment for the disorder is symptomatic and supportive.

What are the risk factors for facio-cardio-cutaneous syndrome?

Facio-cardio-cutaneous syndrome is a rare, genetic disorder that affects the skin, heart and blood vessels. It can cause facial abnormalities, heart defects and neurological problems. Facio-cardio-cutaneous syndrome is inherited in an autosomal dominant manner, which means that only one copy of the mutated gene from each parent is required for a child to inherit the disorder.

The symptoms of facio-cardio-cutaneous syndrome vary from person to person and can be mild or severe. Facial abnormalities can range from mild features like a small chin or thin upper lip to severe features such as an underdeveloped jawbone and cleft palate (opening in the roof of your mouth). Cardiac defects may include an abnormal opening between chambers of the heart (patent ductus arteriosus) or holes in one or more heart valves (ventricular septal defect). Neurological problems may include intellectual disability or seizures.

The exact cause of FCCS is unknown, but there are risk factors that increase the likelihood that a child will be born with the condition. These risk factors include:

  • A parent who has been diagnosed with FCCS or another mutation of the same gene as FCCS
  • An affected sibling who has been diagnosed with FCCS or another mutation of the same gene as FCCS
  • Family history of the disease
  • Defects in certain genes, including MYH7, NKX2-5, and TAZ
Thickening of the heart muscle (cardiomyopathy),A wide nose bridge with a high arched palate (choanal atresia),Fine hair on the face (trichomegaly), arms, and legs,Heart defects such as arrhythmias (abnormal heart rhythms) and an enlarged atrium or ventricle in your heart

White spots on the nails,A thickening of the skin around the neck or chest,A webbed neck (the neck appears to be joined together),An abnormally large tongue,Abnormalities in fingernails and teeth (they may be malformed or crooked)

Anticonvulsant drugs

Is there a cure/medications for facio-cardio-cutaneous syndrome?

Facio-cardio-cutaneous syndrome (FCCS) is a rare genetic condition that can cause significant disability in children. The condition is typically diagnosed in early childhood and affects the skin, heart, and skeletal muscles. Symptoms may include facial abnormalities, short stature, skeletal muscle weakness, heart defects, and learning disabilities.

There is no cure for FCCS. Treatment is focused on managing symptoms and preventing complications from occurring.

Treatment options include:

  • Physical therapy to improve strength and mobility
  • Speech therapy to help with language development
  • Occupational therapy to address sensory processing issues
  • Special education services for learning disabilities
  • Antihistamines (Benadryl, Claritin)
  • Decongestants (i.e., Sudafed)
  • Nasal sprays (i.e., Afrin)
  • Topical steroids (i.e., Flonase)
  • Lidocaine cream applied to the affected area(s) may provide relief from itching. You can also try applying an over-the-counter antihistamine cream or lotion (such as hydrocortisone).
  • Some people find relief from wearing protective clothing, such as gloves and long sleeves/pants made of tightly woven fabrics (cotton), which prevents irritants from reaching the skin directly.
Thickening of the heart muscle (cardiomyopathy),A wide nose bridge with a high arched palate (choanal atresia),Fine hair on the face (trichomegaly), arms, and legs,Heart defects such as arrhythmias (abnormal heart rhythms) and an enlarged atrium or ventricle in your heart

White spots on the nails,A thickening of the skin around the neck or chest,A webbed neck (the neck appears to be joined together),An abnormally large tongue,Abnormalities in fingernails and teeth (they may be malformed or crooked)

Anticonvulsant drugs

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