Cardiofaciocutaneous (CFC) syndrome is one of the RASopathies and is a rare genetic disorder is typically characterized by unusually sparse, brittle, curly hair; relatively large head (relative 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) or acquired later; short stature and skin abnormalities. CFC syndrome is a dominant disorder often caused by de novo (new) mutations in one of four genes called BRAF, MAP2K1 (MEK1), 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.
Cardiofaciocutaneous Syndrome (CFC) is a rare genetic disorder that affects various parts of the body. This article aims to provide simple, easy-to-understand explanations of CFC, including its types, causes, symptoms, diagnostic tests, treatment options, and medications.
Types of Cardiofaciocutaneous Syndrome:
CFC is generally classified into four main types, each with specific genetic mutations. These types include:
- CFC Type 1: Caused by mutations in the BRAF gene.
- CFC Type 2: Associated with mutations in the MAP2K1 gene.
- CFC Type 3: Linked to mutations in the KRAS gene.
- CFC Type 4: Resulting from mutations in the BRAF gene, but with different symptoms.
Causes of Cardiofaciocutaneous Syndrome:
CFC is primarily caused by genetic mutations that affect the body’s signaling pathways. These mutations can occur spontaneously or be inherited from parents. The exact cause is not always clear, but it results in the abnormal development of various body systems.
CFC syndrome is a dominant genetic disorder caused by an abnormality (mutation) in one of four genes: BRAF (~75%), MAP2K1 (MEK1), MAP2K2 (MEK2) (~25%) and KRAS (<2%). These genes are part of a pathway called Ras/Mitogen-activated protein kinase (MAPK) that is important in cell growth and cell division. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene in CFC syndrome is usually the result of a sporadic gene abnormality (mutation) not inherited from either parent. Therefore, risk to the siblings of an affected individual is small. The theoretical risk of passing the abnormal gene from an affected person to their child is 50% for each pregnancy. However, there have been a few families documented in the literature of a mutated gene being passed through generations.
Symptoms of Cardiofaciocutaneous Syndrome:
CFC presents with a wide range of symptoms, which may include:
- Facial abnormalities, such as a high forehead or wide-set eyes.
- Skin issues, like dryness and hyperpigmentation.
- Heart problems, such as congenital heart defects.
- Delayed development, including motor and cognitive delays.
- Growth problems, leading to short stature.
- Gastrointestinal issues, like feeding difficulties.
- Hair abnormalities, such as sparse or curly hair.
- Intellectual disabilities, which can vary in severity.
- Vision and hearing problems.
- Joint problems, like muscle tightness.
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).
Heart
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.
Ocular
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.
Feeding/gastrointestinal
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.
Diagnostic Tests for Cardiofaciocutaneous Syndrome:
Diagnosing CFC often involves a combination of clinical evaluation and genetic testing. Some diagnostic tests include:
- Physical Examination: A doctor assesses the physical characteristics and developmental milestones.
- Genetic Testing: DNA testing to identify specific mutations associated with CFC.
- Imaging Studies: X-rays, ultrasounds, and echocardiograms to evaluate organ abnormalities.
- Electrocardiogram (ECG): Measures the heart’s electrical activity.
- Echocardiography: A specialized ultrasound to assess heart function.
- Ophthalmologic Examination: To detect vision problems.
- Hearing Tests: Evaluates hearing abilities.
- Developmental Assessments: Evaluating motor and cognitive skills.
Clinical examination may include a physician’s evaluation of heart and lung sounds through use of a stethoscope. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be detected through an abnormal heart murmur heard during such stethoscopic evaluation.
Specialized cardiac tests may include x-ray studies, electrocardiography (EKG), echocardiography, and/or cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart (cardiomegaly) or malformation of certain heart structures. An EKG, which records the electrical activities of the heart muscle, may reveal abnormal electrical patterns. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities.
Physicians may also closely evaluate the respiratory (ventilatory) capabilities of affected individuals with pulmonary stenosis and/or other heart abnormalities since associated cardiac defects may result in inadequate blood supply to the lungs and breathlessness.
Additional specialized tests may also be conducted to help identify and/or confirm the presence of other abnormalities that may occur in some cases of CFC syndrome. For example, according to the medical literature, computerized tomography (CT) scanning may help confirm the presence of hydrocephalus or, in some cases, degeneration of the outer layer of the brain (cortical atrophy) in some individuals with the disorder. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ’s tissue structure. In addition, electroencephalography (EEG), which records the brain’s electrical impulses, may reveal brain wave patterns that are characteristic of certain types of seizure activity. Examination with an instrument that visualizes the interior of the eye (ophthalmoscopy), other specialized imaging techniques, and/or other tests may also be used to diagnose and/or confirm certain eye abnormalities that may be associated with CFC syndrome.
Molecular genetic testing is available for mutations in the four genes known to cause CFC syndrome. Testing can be done by using a multi-gene panel that screens all of the genes currently known to cause a RASopathy since there is a considerable overlap among them or whole exome sequencing can be considered.
Treatments for Cardiofaciocutaneous Syndrome:
Treatment for CFC is often multidisciplinary, addressing the specific symptoms and needs of each individual. Common treatments include:
- Cardiac Care: Surgical or medical management for congenital heart defects.
- Physical Therapy: To improve mobility and muscle strength.
- Occupational Therapy: Enhances daily living skills.
- Speech Therapy: Helps with communication and feeding issues.
- Medications: May be prescribed for seizures, skin problems, or other symptoms.
- Growth Hormone Therapy: For short stature.
- Educational Support: Specialized education plans for intellectual disabilities.
- Early Intervention: Early childhood services to support development.
- Gastrointestinal Management: Dietary modifications or medications.
- Routine Monitoring: Regular check-ups to assess progress and manage symptoms.
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.
Medications Used in Cardiofaciocutaneous Syndrome:
Several medications may be used to manage specific symptoms of CFC, including:
- Antiseizure Medications: Such as phenytoin or carbamazepine for epilepsy.
- Topical Steroids: To treat skin issues like eczema.
- Growth Hormone: To stimulate growth in children with short stature.
- Antipsychotic Medications: For behavioral or psychiatric symptoms.
- Pain Relievers: To manage joint and muscle pain.
- Gastrointestinal Medications: Such as antacids or laxatives for digestive problems.
In Conclusion:
Cardiofaciocutaneous Syndrome is a complex genetic disorder with various types, caused by mutations in specific genes. It manifests with a range of symptoms affecting multiple organ systems. Diagnosis involves clinical evaluation and genetic testing, while treatment focuses on managing symptoms and improving quality of life. Medications may be prescribed to address specific issues. Early intervention and a multidisciplinary approach are key to providing the best possible care for individuals with CFC. If you suspect someone has CFC, it’s essential to consult with a healthcare professional for a proper diagnosis and tailored treatment plan.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. Thank you for giving your valuable time to read the article.