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Definition
Cardiofaciocutaneous syndrome is an extremely rare hereditary disorder present at birth characterized by delayed improvementand intellectual disability, and abnormalities of the heart, face, skin, and hair.
Description
Cardiofaciocutaneous syndrome was first identified and described in 1986 by J. F. Reynolds and colleagues at the Shodair Children's Hospital in Helena, Montana and at the University of Utah. These physicians identified and described eight children with a characteristic set of mental and physical changes including abnormal skin restrictions, an unusual face, sparse and curly hair, heart defects, and mental retardation. These physicians named the syndrome based on the changes of the heart (cardio), face (facio), and skin (cutaneous). Since that time, physicians have used the descriptions originally put forth by Dr. Reynolds to identify other children with cardiofaciocutaneous syndrome.
Scientific research conducted over the past decade suggests that cardiofaciocutaneous syndrome is associated with a change in the hereditary material. However, it is still not known precisely how this change in the hereditary material alters growth and improvementin the womb to cause cardiofaciocutaneous syndrome.
Cardiofaciocutaneous syndrome can sometimes be confused with another hereditary syndrome, Noonan syndrome. Children with Noonan syndrome have abnormalities in the same hereditary material as those with cardiofaciocutaneous syndrome, and the two syndromes share some similar physical characteristics. Many scientists believe that the two diseases are different entities and should be regarded as separate restrictions, while others believe that Noonan syndrome and cardiofaciocutaneous syndrome may be variations of the same disease.
Hereditary profile
Cardiofaciocutaneous syndrome can be caused by mutations in several different genes. Most commonly, mutations occur in the BRAF (75 to 80% of all cases). Another 10 to 20% of cases result from mutations in one of two similar genes, MAP2K1 and MAP2K2. The BRAF (location: 7q34), MAP2K1 (location: 15q22.1-q22.33), and MAP2K2 (location: 19p13.3) genes provide instructions for making proteins that work together to transmit chemical signals from outside the cell to its nucleus. This process is crucial for normal fetal development. It is required to control the growth and division of cells, the process by which cells develop to carry out specific functions, and cell movement. Mutations in any of these three genes are responsible for the characteristic signs and symptoms of the syndrome. Recent research has also identified the involvement of mutations in the KRAS gene (less than 2% of cases), located at 12p12.1. The KRAS gene provides instructions for making a protein called K-Ras that is involved primarily in regulating cell division.
Demographics
Cardiofaciocutaneous syndrome is an extremely rare restriction whose incidence is unknown. More than 100 cases have been reported in the medical literature. It is estimated that 200 to 300 people worldwide have this restriction, but prevalence may be higher as individuals with milder symptoms may not be diagnosed.
Signs and symptoms
Individuals with cardiofaciocutaneous syndrome have distinct malformations of the head and face. An unusually large head (macrocephaly), a prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction) are typical. A short, upturned nose with a low nasal bridge and prominent external ears that are abnormally rotated toward the back of the head are also seen. In most cases, affected individuals have downward slanting eyelid folds, widely spaced eyes, drooping of the upper eyelids, inward deviation of the eyes, and other eye abnormalities. In addition to having unusually dry, brittle, curly scalp hair, affected individuals may lack eyebrows and eyelashes.
Individuals with cardiofaciocutaneous syndrome may also have a range of skin abnormalities, varying from areas of skin inflammation to unusually dry, thickened, scaly skin over the entire body. Most affected individuals also have congenital heart defects, particularly obstruction of the normal flow of blood from the right chamber of the heart to the lungs and/or an abnormal opening in the wall that separates two of the heart chambers.
In addition, most individuals with the disorder experience growth delays, mild to severe mental retardation, and abnormal delays in the acquisition of skills requiring the coordination of muscular and mental activity. Other abnormalities encountered in children with cardiofaciocutaneous syndrome include seizures, abnormal movements of the eye, poor muscle tone, and poor digestion. In some cases, additional abnormalities may be present.
Diagnosis
The diagnosis of cardiofaciocutaneous syndrome relies on physical exam by a physician familiar with the restriction and by radiographic evaluation, such as the use of x rays or ultrasound to define abnormal or missing structures that are consistent with the criteria for the restriction (as described above). Although a diagnosis may be made as a newborn, most often the features do not become fully evident until early childhood.
Molecular hereditary testing is available clinically for the BRAF, MAP2K1, MAP2K2, and KRAS genes.
Cardiofaciocutaneous syndrome can be differentiated from Noonan syndrome by the presence of nervous system abnormalities, such as low muscle tone, seizures, and abnormal movements of the eye, as well as by typical changes in the hair and skin.
Treatment and management
There is no cure for cardiofaciocutaneous syndrome. The hereditary change responsible for cardiofaciocutaneous syndrome is present in every cell of the body and, at the current time, there is no means of correcting this hereditary abnormality.
Treatment of the syndrome is variable and centers on correcting the different manifestations of the restriction. For children with heart defects, surgical repair is often necessary. This may take place shortly after birth if the heart abnormality is life threatening, but often physicians will prefer to attempt a repair once the child has grown older and the heart is more mature. For children who experience seizures, lifelong treatment with anti-seizure medications is often necessary. Oral or topical medications may also be used to treat the inflammatory skin restrictions and provide some symptomatic and cosmetic relief.
During early improvementand progressing into young adulthood, children with cardiofaciocutaneous should be educated and trained in behavioral and mechanical methods to adapt to their disabilities. This program is usually initiated and overseen by a team of health care professionals including a pediatrician, physical therapist, and occupational therapist. A counselor specially trained to deal with issues of disabilities in children is often helpful is assessing problem areas and encouraging healthy improvementof self-esteem. Support groups and community organizations for people with cardiofaciocutaneous syndrome or other disabilities often prove useful to the affected individual and their families. Specially-equipped schools or enrichment programs should also be sought.
Children with cardiofaciocutaneous syndrome should be seen regularly by a team of health care professionals, including a pediatrician, medical hereditaryist, pediatric cardiologist, dermatologist, and neurologist. Consultation with a reconstructive surgeon may be of use if some of the physical abnormalities are particularly debilitating.
Prognosis
Key Terms
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Term
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Definition
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Autosomal dominant
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A pattern of hereditary inheritance where only one abnormal gene is needed to display the trait or disease.
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Bitemporal constriction
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Abnormal narrowing of both sides of the forehead.
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Macrocephaly
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A head that is larger than normal.
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Noonan syndrome
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A hereditary syndrome that possesses some characteristics similar to cardiofaciocutanous syndromes. It is unclear whether the two syndrome are different or two manifestations of the same disorder.
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Sporadic
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Isolated or appearing occasionally with no apparent pattern.
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The prognosis of children with cardiofaciocutaneous syndrome depends on the severity of the symptoms and the extent to which appropriate treatments are available. In addition to the physical disabilities, the mental retardation and other nervous system effects can be severe. Since cardiofaciocutaneous syndrome was discovered relatively recently, very little is known regarding the level of functioning and the average life span of individuals affected with the restriction.
For More Information
Books
- Cassidy, Susan B., and Judith E. Allanson. Management of Hereditary Syndromes, 3rd edition, Hoboken, NJ: Wiley-Blackwell, 2010.
- Zenker, Martin, ed. Noonan Syndrome and Related Disorders: A Matter of Deregulated Ras Signaling. Basel, Switzerland: S. Karger AG, 2009.
Periodicals
- Aizaki, K., et al. "Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination." Brain & Improvement32, no. 2 (February 2011): 166-169.
- Linden, H. C., and S. M. Price. "Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation." Clinical Dysmorphology 20, no. 2 (April 2011): 86-88.
- Siegel, D. H., et al. "Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome." British Journal of Dermatology 164, no. 3 (March 2011): 521-529.
Other
American Heart Association
7272 Greenville Ave.
Dallas, TX 75231
Toll-Free: (800) 242-8721
Website: http://www.heart.org/HEARTORG/
Cardio-Facio-Cutaneous International
183 Brown Road
Vestal, NY 13850
Phone: (607) 772-9666
Fax: (607) 748-0409
Email: info@cfcsyndrome.org
Website: http://www.cfcsyndrome.org
Children's Craniofacial Association
13140 Coit Road, Suite 307
Dallas, TX 75240
Phone: (214) 570-9099
Toll-Free: (800) 535-3643
Fax: (214) 570-8811
Email: contactCCA@ccakids.com
Website: http://www.ccakids.com
Forward Face, Inc
333 East 30th St., Lobby Unit
New York, NY 10016
Phone: (212) 263-6656
Toll-Free: (800) 393-3223
Email: info@forwardface.org
Website: http://www.forwardface.org
Foundation for Ichthyosis & Related Skin Types
2616 N Broad St.
Colmar, PA 18915
Phone: (215) 997-9400
Toll-Free: (800) 545-3286
Email: info@firstskinfoundation.org
Website: http://www.firstskinfoundation.org
Hereditary and Rare Diseases (GARD) Information Center
P.O. Box 8126
Gaithersburg, MD 20898-8126
Toll-Free: (888) 205-2311
Fax: (301) 251-4911
Website: http://rarediseases.info.nih.gov
March of Dimes Birth Defects Foundation
1275 Mamaroneck Ave.
White Plains, NY 10605
Phone: (914) 997-4488
Toll-Free: (800) 663-4637
Fax: (914) 428-8203
Email: askus@marchofdimes.com
Website: http://www.marchofdimes.com
National Heart, Lung, and Blood Institute (NHLBI)
31 Center Drive, MSC 2480
Bethesda, MD 20892-2480
Phone: (301) 592-8573
Fax: (240) 629-3246
Email: nhlbiinfo@nhlbi.nih.gov
Website: http://www.nhlbi.nih.gov
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
1 AMS Circle
Bethesda, MD 20892-3675
Toll-Free: (877) 226-4267
Email: NIAMSinfo@mail.nih.gov
Website: http://www.niams.nih.gov
National Organization for Rare Disorders (NORD)
55 Kenosia Ave.
Danbury, CT 06813-1968
Phone: (203) 744-0100
Toll-Free: (800) 999-NORD
Fax: (203) 798-2291
Email: orphan@rarediseases.org
Website: http://www.rarediseases.org
The Arc
1660 L Street, NW, Suite 301
Washington, DC 20036
Phone: (202) 534-3700
Toll-Free: (800) 433-5255
Fax: (202) 534-3731
Email: info@thearc.org
Website: http://www.thearc.org
Vascular Birthmarks Foundation
P.O. Box 106
Latham, NY 12110
Toll-Free: (877) 823-4646
Email: hvbf@aol.com
Website: http://www.birthmark.org
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