Information on the following diseases can be found in the Related Disorders section of this report:

• Noonan Syndrome
• Costello Syndrome
• Associated Congenital Disorders (General)

Most patients are initially referred because of feeding difficulties (poor suck) and failure to thrive. Later, psychomotor developmental delay and other clinical manifestations may be observed. In general, CFC patients have an easygoing behavior, and are cheerful and cooperative.

Facial Appearance
Affected individuals may have an unusually large head (macrocephaly), along with a high forehead and abnormal narrowing of the sides of the forehead (bitemporal constriction), causing the head to appear "box-like" in shape. The ears are abnormally angulated towards the back of the head (posteriorly angulated). The nose is short, bulbous and with anteverted nostrils. 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
According to the medical literature, all patients have some kind of ectodermal abnormality, either of skin, hair or nails. Children with CFC Syndrome usually have sparse, slow growing, curly scalp hair that is abnormally dry and brittle. They also have absent or sparse eyebrows and eyelashes. In some cases, the nails are fast growing. Skin involvement ranges from dry skin to the skin disease known as hyperkeratosis. The frequency with which skin abnormalities are found is: hyperkeratosis (37%); keratosis pilaris (33%); ichthyosis (31%); eczema (26%); hemangiomas (24%); hyperelastic skin (22%); hyperkeratosis of palms and soles (13%); café-au-lait spots (9%); generalized hyperpigmentation (5%); and cutis marmorata (2%).

Heart
Congenital heart defect is present in 77.8% of reported patients, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis), and/or an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects).

Mental Retardation
According to the medical literature, some 90% of children with CFC Syndrome have mild to severe mental retardation, most having moderate retardation. Motor delays are reported in 81.5% and speech delay in 46.3%.

Additional Abnormalities
Additional abnormalities that are present in some but not all cases include short stature; webbed neck; abnormal shape of the thorax (pectus carinatum); joint hyperextension; hypotonia (reduced muscle tone), especially during the first years of life; seizures; enlargement of the liver (hepatomegaly) and spleen (splenomegaly); and undescended testes (cryptorchidism) of boys.
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CFC syndrome is a dominant genetic disorder caused by an abnormality (mutation) in one of three genes that have been termed BRAF, MEK1 and MEK2. These genes are part of a pathway called Ras/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 the result of a sporadic gene abnormality (mutation) in the affected individual. The risk of passing the abnormal gene from an affected person to their child is 50% for each pregnancy.

Males and females are affected equally, and patients are reported from all continents. The number of patients reported in the medical literature is now close to 100. However, there are many more known cases.
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Symptoms of the following disorders may be similar to those of Cardiofaciocutaneous syndrome. Comparisons may be useful for a differential diagnosis:

Noonan syndrome, a rare genetic disorder, is characterized by a distinctive facial appearance similar to that seen in children with Cardiofaciocutaneous syndrome, webbing of the neck, short stature, characteristic abnormalities of the chest, congenital heart defects, and/or other abnormalities. In individuals with the disorder, malformations of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, "hooded" eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated). Individuals with Noonan syndrome may also have wispy scalp hair during infancy that becomes unusually wooly or curly during later childhood. In addition, in most cases, affected individuals have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the bone forming the center of the chest (sternum) and/or abnormal depression of the lower (inferior) portion of the sternum (pectus carinatum and/or pectus excavatum, respectively). In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum (cryptorchidism). In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis). Additional abnormalities associated with Noonan syndrome may include low levels of circulating platelets in the blood (thrombocytopenia) and/or other blood clotting abnormalities (coagulation factor deficiencies), potentially causing abnormal bruising and bleeding. Noonan syndrome has autosomal dominant inheritance. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). A gene responsible for Noonan syndrome has been located on the long arm of chromosome 12 (12q24). (For more information on this disorder, choose "Noonan" as your search term in the Rare Disease Database.)

As discussed above, there is disagreement in the medical literature concerning whether Noonan and Cardiofaciocutaneous syndromes are separate, distinct disorders or whether they represent varying manifestations of the same disease entity. Researchers suggest that variable expression of the same disease gene may cause Noonan syndrome in some individuals and Cardiofaciocutaneous syndrome in others, as seen in certain multigenerational families (kindreds). (For more information, please see the "Causes" section of this report above.)

Costello syndrome is a rare genetic disorder characterized by growth delay after birth (postnatal), leading to short stature; a distinctive facial appearance; excessive, loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral) and nostrils (nares); and/or mental retardation. Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly); a large, depressed nasal bridge; abnormally wide nostrils; low-set ears with large, thick lobes; and/or unusually thick lips. Other physical features may include the development of dry, hardened, thickened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis) and/or abnormally deep creases on the palms and soles. In addition, some affected individuals may also have congenital heart defects. Most cases of Costello syndrome occur sporadically, with no family history of the disorder. Such cases are thought to represent new dominant gene mutations. (For more information on this disorder, choose "Costello" as your search term in the Rare Disease Database.)

There may be additional congenital disorders that are characterized by craniofacial malformations, hair abnormalities, skin changes, congenital heart defects, mental retardation, and/or other symptoms and findings similar to those associated with Cardiofaciocutaneous syndrome. (For information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Diagnosis
In most cases, Cardiofaciocutaneous 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 Cardiofaciocutaneous 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 Cardiofaciocutaneous 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 Cardiofaciocutaneous syndrome.

Treatment
The treatment of Cardiofaciocutaneous 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 Cardiofaciocutaneous 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 Cardiofaciocutaneous 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.

In addition, in some cases, physicians may recommend certain lubricating lotions or ointments, such as petroleum jelly, to help alleviate skin abnormalities. 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 Cardiofaciocutaneous syndrome reach their potential. Special services that may be of assistance may include special remedial education, speech therapy, and/or other medical, social, and/or vocational services.

Genetic counseling may be of benefit 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 Cardiofaciocutaneous syndrome.

NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s).

Families of individuals with CFC syndrome ages 1-25 are invited to participate in a research study to investigate communication and literacy in children and adolescents with CFC. This research is being conducted by Rene Pierpont, M.S., as part of a doctoral dissertation at the University of Wisconsin. The study has been approved by the CFC International IRB as well as the University of Wisconsin IRB.

The contact details are:
Rene Pierpont
Department of Psychology
University of Wisconsin - Madison
email: eipierpont@wisc.edu
Phone:608-772-1980

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD:The Johns Hopkins University; Entry No: 115150; Last Update: 11/12/2002.

TEXTBOOKS
Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. City, state, W.B. Saunders Co; 1997:122-27.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 4th ed. Oxford, England. Oxford Unviersity Press; xxxx:

ARTICLES
Ades LC, Sillence DO, Rogers M. Cardiofaciocutaneous syndrome. Clin Dysmorph. 1992;1:145-50.

Borradori L, Blanchet-Bardon C. Skin manifestations of cardio-facio-cutaneous syndrome. J Am Acad Dermatol. 1993;28:815-29.

Dunya I, Hoon A, Traboulsi El. Retinal dystrophy in the cardiofaciocutaneous syndrome. J Pediatr Ophthalmol Strabismus. 1993:30:264-65.

Fryer AE, Holt PJ, Hughes HE. The Cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: Are they the same? Am J Med Genet.1991;38:548-51.

Grebe TA, Clericuzio C. Neurologic and gastrointestinal dysfunction in cardio-facio-cutaneous syndrome: identification of a severe phenotype. Am J Med Genet. 2000;95:135-43.

Leichtman LG. Are cardio-facio-cutaneous syndrome and noonan syndrome distinct? A case of CFC offspring of a mother with noonan syndrome. Clin Dysmorph. 1996;5:61-64.

Neri G, Opitz JM. Heterogeneity of cardio-facio-cutaneous syndrome. Am J Med Genet. 2000;95:144.

Pierard GE, et al. Cutaneous presentation of the cardio-facio-cutaneous syndrome. J Am Acad Dermatol. 1990;22:920-22.

Raymond G, Holmes LB. Cardio-facio-cutaneous (CFC) syndrome: Neurological features in two children. Dev Med Child Neurol. 1993;35:727-41.

Wieczorek D, et al. Cardio-facio-cutaneous (CFC) syndrome-a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome. Clin Genet. 1997;52:37-46.