Cardiofaciocutaneous Syndrome

Cardiofaciocutaneous Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Cardiofaciocutaneous Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • CFC syndrome
  • RASopathy
  • cardio-facial-cutaneous syndrome

Disorder Subdivisions

  • None

General Discussion

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.

Symptoms

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. In general, CFC individuals 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 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

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, fine or thick, curly scalp hair that is abnormally dry and brittle. They also have absent or sparse eyebrows and eyelashes. In some cases, 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 keratosis pilaris, ulerythema ophryogenes, and infantile hemangiomas.



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). There may also be hypertrophic cardiomyopathy (thickening of the heart muscle) and rhythm disturbances. These defects can occur at birth or can be diagnosed later in life.



Intellectual Disability

There is some form of cognitive or neurologic delay in all patients with some 90% of children with CFC Syndrome have mild to severe intellectual disability and most having moderate intellectual disability. Motor delays are reported in 81.5% and speech delay in 46.3%.



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. 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.



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), neoplasia (typically lymphyoblastic leukemia), especially during the first years of life; urogenital anomalies; seizures; and undescended testes (cryptorchidism) of boys.

Causes

CFC syndrome is a dominant genetic disorder caused by an abnormality (mutation) in one of four genes that have been termed BRAF (~75%), MAP2K1 (MEK1) and 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.

Affected Populations

Currently, there is no study providing an accurate estimate of the population prevalence of CFC syndrome. 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 200 and the total number worldwide is estimated to be several hundred. This may be an underestimate, however, because mildly affected adults may go undiagnosed.

Standard Therapies

Diagnosis

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 may be done in a step-wise manner to look for the most common gene mutations first, or testing may be done using a multi-gene re-sequencing panel.



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.



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.

Investigational Therapies

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.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/

References

TEXTBOOKS

Rauen KA. Ras/MAPK Pathway and the Cardio-Facio-Cutaneous Syndrome. Inborn Errors of Development. 2nd Edition. CJ Epstein, RP Erickson, A Wynshaw-Boris (eds.). Oxford University Press, New York. 2008.



Tidyman WE and Rauen KA. Molecular Causes of Cardio-facio-cutaneous Syndrome. In: Monographs in Human Genetics. Volume 17: Noonan Syndrome and Related Disorders. A matter of deregulated Ras signaling. Schmid M. ed. KARGER Publishers. Freiburg, Germany. 2008.



JOURNAL ARTICLES

Goodwin AF, S Oberoi, M Landan, C Charles, J Groth, A Martinez, C Fairley, LA Weiss, WE Tidyman, OD Klein, KA Rauen. Craniofacial and Dental Development in Cardio-facio-cutaneous Syndrome: The Importance of Ras Signaling Homeostasis. Clinical Genetics. 2012 Sep 4. [Epub ahead of print]



Stevenson, DA, S Allen, WE Tidyman, JC Carey, DH Viskochil, A Stevens, H Hanson, X Sheng, BA Thompson, M Okumura, K Reinker, B Johnson, KA Rauen. Peripheral Muscle Weakness in RASopathies: Handgrip Strength in Costello, Cardio-facio-cutaneous, Noonan and Neurofibromatosis Type 1 Syndromes. Muscle and Nerve. 2012;46(3):394-9.



Tidyman WE, HS Lee, KA Rauen. Skeletal muscle pathology in Costello and cardio-facio-cutaneous syndromes: Developmental consequences of germline Ras/MAPK activation on myogenesis. American Journal of Medical Genetics. 2011;157(2):104-14.



Rauen KA, WE Tidyman, AL Estep, S Sampath, HM Peltier, SJ Bale, Y Lacassie. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: Transmission through four generations. Am Journal of Medical Genetics. 2010;152A(4):807-14.



Siegel DH, J McKenzie, I Freiden KA Rauen. 2011. Dysregulation of Ras/MAPK Signaling in Epidermal Development: Dermatologic Findings in 61 Mutation Positive Individuals with Cardio-facio-cutaneous Syndrome. British Journal of Dermatology. 2010;164(3):521-9.



Tidyman WE and Rauen KA. The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation. Current Opinion in Genetics and Development, 2009;19(3):230-6.



Tidyman WE and Rauen KA. Clinical and Molecular Overview of Noonan Syndrome, Costello Syndrome and Cardio-facio-cutaneous Syndrome: Dysregulation of the Ras/MAPK Pathway. Expert Review in Molecular Medicine. 2008;10:e37



Yoon G, J Rosenberg, S Blaser, KA Rauen. Neurological Complications of the Cardio-facio-cutaneous Syndrome (CFC). Developmental Medicine and Child Neurology. 2007; 49: 894-899.



Rodriguez-Viciana P, O Tetsu, AL Estep, WE Tidyman, BA Conger, M Santa Cruz, F McCormick, KA Rauen. Germline mutations in genes within the MAPK cascade cause cardio-facio-cutaneous syndrome. Science. 2006; 311(5765):1287-90.



Roberts A, Allanson J, Jadico S K, et al. The cardiofaciocutaneous syndrome. J Med Genet. 2006;43, 833-842.



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.



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



INTERNET

Rauen KA. (Updated September 6, 2012). Cardiofaciocutaneous Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed January 17, 2013.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Cardiofaciocutaneous Syndrome. Entry No: 115150. Last Edited July 27, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed January 17, 2013.

Resources

Children's Craniofacial Association

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March of Dimes Birth Defects Foundation

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Foundation for Ichthyosis & Related Skin Types

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American Heart Association

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NIH/National Heart, Lung and Blood Institute

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Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

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Hemangioma Support System

c/o Cynthia Schumerth

1484 Sand Acres Drive

DePere, WI 54115

Tel: (920)336-9399



Vascular Birthmarks Foundation

P.O. Box 106

Latham, NY 12110

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Tel: (877)823-4646

Email: hvbf@aol.com

Internet: http://www.birthmark.org



Cardio-Facio-Cutaneous International

183 Brown Road

Vestal, NY 13850

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Tel: (607)772-9666

Fax: (607)748-0409

Email: info@cfcsyndrome.org

Internet: http://www.cfcsyndrome.org



Genetic and Rare Diseases (GARD) Information Center

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Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

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