NORD gratefully acknowledges Pilar L. Magoulas, MS, CGC, Certified Genetic Counselor, Assistant Professor, Dept of Molecular and Human Genetics, Baylor College of Medicine /Texas Children's Hospital; Sarah Fagan, NORD Editorial Intern from the University of Notre Dame; and Katherine A Rauen, MD, PhD, Chief, Division of Genomic Medicine, University of California Davis, for assistance in the preparation of this report.
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.
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.
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.
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.
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.
Affected individuals can have growth hormone deficiency and early onset puberty.
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 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.
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.
Currently, there is no study providing an accurate estimate of the population prevalence of CFC syndrome. However one study in Japan, reported the incidence to be approximately 1 in 810,000. It is thought that males and females are affected equally. There are patients are reported from all continents. The number of affected individuals reported in the medical literature is now close to 400 and the total number worldwide is estimated to be more than this. This may be an underestimate, however, because mildly affected adults may go undiagnosed.
In most cases, CFC syndrome is diagnosed during infancy based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests. Congenital heart defects that may occur in association with CFC syndrome (e.g., pulmonary stenosis and/or atrial septal defects) may be detected and/or confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart.
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.
Clinical Testing and Work-Up
Individuals known to have or suspected to have CFC syndrome may have the following evaluations. a complete physical examination including measurement growth parameters; cardiac evaluation including echocardiogram and electrocardiogram; neurologic evaluation; MRI of the brain to detect any structural changes; electroencephalogram if seizures are suspected; full abdominal ultrasound examination to evaluate for renal and urogenital anomalies; psychomotor developmental evaluation; endocrine evaluation if growth delay is suspected; ophthalmologic examination; audiologic examination; nutrition and feeding evaluation, consider swallow study; and dermatologic evaluation. Consensus guidelines for the management of individuals with CFC were published in 2012 and should be referenced in the care of any patient with this diagnosis.
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 derived from vitamin A (retinoids such as tretinoin, etretinate, or acitretin) may be effective in relieving some of the symptoms associated with ichthyosis. However, such vitamin A derivatives may interfere with bone growth in children in some cases. Therefore, according to the medical literature, such medications should be avoided in children unless other forms of treatment have failed. In addition, certain vitamin A derivatives are known to cause severe birth defects; therefore, such medications should not be taken during pregnancy. Such vitamin A derivatives have not yet been approved by the Food and Drug Administration (FDA) for the treatment of ichthyosis. Further research is needed to determine the long-term safety and effectiveness of vitamin A derivatives in the treatment of ichthyosis such as that occurring in some cases of CFC syndrome.
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