Cardiofaciocutaneous syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at December 2, 2016
StartDiseasesCardiofaciocutaneous syndrome

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder. It affects many areas of the body, including the heart, face, and skin. The disorder can be challenging to diagnose because it resembles other rare genetic conditions. Though there is no cure for the condition, an individual's symptoms can be managed.

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Definition & Facts

CFC syndrome was initially described in 1986 based on eight unrelated patients who exhibited intellectual disability and similar abnormalities of the face, nail, skin, hair, and heart. CFC syndrome is a very rare genetic disorder. Though its prevalence is not known, researchers estimate that the condition affects 200 to 300 people worldwide. 

Symptoms & Complaints

Infants with cardiofaciocutaneous syndrome often have feeding difficulties, poor muscle tone, and a failure to gain weight and grow at a normal pace (failure to thrive). Children with CFC may suffer from malnutrition as a result. 

Individuals with CFC syndrome have facial abnormalities. These may include an abnormally large head, a high forehead with unusual narrowing of the sides, a small chin, and low-set ears that are angled toward the back of the head.

The eyes may be widely spaced with a downward slant. One or both eyelids may be droopy as well. The nose may be short and bulbous with a depressed bridge. The ridges of the bone located above the eyes may also be underdeveloped. 

Most individuals who have CFC syndrome also have skin abnormalities. These abnormalities may include dry skin, rough skin, wrinkled soles and palms, and dark-colored moles.

Some individuals with cardiofaciocutaneous syndrome may have keratosis pilaris, a condition that causes small bumps on the arms, legs, face, and buttocks. The bumps are harmless, but they may make the skin feel like sandpaper. Individuals with CFC syndrome also tend to have thin, dry, curly hair and little or no eyebrows and eyelashes

Congenital heart defects are also common in individuals with CFC syndrome. The most common congenital heart defects seen in patients with the condition are pulmonary stenosis and atrial septal defect. Pulmonary stenosis occurs when blood flow from the lower right heart chamber (ventricle) to the lungs is obstructed. An atrial septal defect is a hole between the two upper chambers of the heart. Hypertrophic cardiomyopathy, a condition that enlarges the heart as well as weakens the heart is also present in some people with CFC syndrome.

Intellectual disability is present in all patients with the condition, with most having moderate intellectual disability. In addition, motor delays are also common in these individuals. Additionally, most people with CFC syndrome have eye problems, such as nearsightedness, farsightedness, involuntary eye movements, or astigmatism.

Gastrointestinal diseases are also common. Gastroesophageal reflux disease, abnormal development of the intestine, vomiting, constipation, and hernia are common gastrointestinal issues seen in CFC syndrome patients.

Seizures, webbed neck, and short stature occur in some but not all patients. Additionally, some males with cardiofaciocutaneous syndrome have undescended testes.

Causes

CFC syndrome is a genetic disorder. Genetic mutations in four genes have specifically been linked to the disorder. Mutations in the BRAF gene are the most common in CFC syndrome patients. The condition can also be caused by mutations in the genes MAP2K1, MAP2K2, and KRAS.

All of these genes provide directions on creating proteins that work together to send chemical signals from outside the cell to the cell's nucleus. This chemical pathway is known as the RAS/MAPK pathway, and it is important for normal prenatal development. The pathway also helps control the growth and division of cells, cell movement, the self-destruction of cells, and the process by which cells mature to carry out functions.

The protein created by the mutated gene becomes overactive and changes the chemical signaling during development. The altered signaling interferes with the development of many tissues and organs, leading to the symptoms of CFC syndrome. Cardiofaciocutaneous syndrome typically results from new genetic mutations. Most people with the condition have no family history of CFC syndrome. 

Diagnosis & Tests

Diagnosis of CFC syndrome can be challenging at times, as two other genetic disorders, Costello syndrome and Noonan syndrome, also have similar symptoms.

Costello syndrome and Noonan syndrome are also caused by mutations in genes involved with RAS/MAPK signaling. Costello syndrome is characterized by distinctive facial abnormalities, mental retardation, growth delays, short stature, benign (noncancerous) growths around the mouth and nostrils, and excessively loose skin on the soles, fingers, palms, and neck. Noonan syndrome is characterized by distinctive facial abnormalities, short stature, congenital heart defects, webbed neck, and chest abnormalities. 

CFC syndrome is typically diagnosed in infants. A physician will conduct a physical examination and ask the patient's parents about his or her medical history and symptoms.

A physician may order chest X-rays, an electrocardiogram, and an echocardiogram to look for heart abnormalities. Chest x-rays can show an abnormally large heart. An electrocardiogram (EKG) measures the heart's electrical activity and can show unusual electrical patterns. In an echocardiogram, sound waves aimed at the heart help physicians look at the structure and motion of the heart and determine if there are any defects. Additionally, molecular genetic testing is utilized to look for mutations in the genes known to cause cause CFC syndrome. 

Treatment & Therapy

There is no cure for cardiofaciocutaneous syndrome. However, a patient's symptoms can be managed. Patients with pulmonary stenosis may undergo a balloon valvuloplasty or open-heart surgery. In a balloon valvuloplasty, a catheter (a long, thin tube) is inserted into a vein in the leg and threaded to the heart. The physician places an uninflated balloon into the narrowed pulmonary valve. The physician inflates the balloon, once it is in place, widening the valve to increase blood flow.

If a balloon valvuloplasty isn't possible, patients with pulmonary stenosis may need to undergo open-heart surgery in order to repair the pulmonary artery or the heart valve or to have the heart valve replaced with an artificial one.

Patients who have an atrial septal defect may be prescribed medication or undergo surgery. Beta blockers can be utilized to regulate heartbeat, and anticoagulants may be used to reduce the risk of blood clots. A patient's atrial septal defect can be repaired with surgery, and this is typically recommended during a patient's childhood. 

Individuals with CFC syndrome who have seizures may be prescribed anticonvulsant medications to help prevent and reduce seizures. Vision problems may be corrected or improved with glasses, contact lenses, or surgery. Many infants and children who avoid eating require a feeding tube. Additionally, physicians may recommend lubricating lotions or ointments to help treat skin abnormalities. 

Special education programs may be useful for children with CFC syndrome. Children with this condition may also benefit from speech therapy, occupational therapy, and physical therapy.

Prevention & Prophylaxis

There is no way to prevent cardiofaciocutaneous syndrome.