Related Terms: Cardio-facio-cutaneous syndrome, CFC syndrome, Facio-cardio-cutaneous syndrome, lymphedema, BRAF, MAP2K1, MAP2K2, BRAF-Related Cardiofaciocutaneous Syndrome, KRAS-Related Cardiofaciocutaneous Syndrome, MAP2K1-Related Cardiofaciocutaneous Syndrome, MAP2K2-Related Cardiofaciocutaneous Syndrome, Noonan syndrome, Costello syndrome, ocular hypertelorism, atrial septal defect, pulmonic stenosis, hypertrophic cardiomyopathy, myopathy;RASopathy;Ras/MAPK;signal transduction pathway;skeletal myogenesis;type 2 predominance
This is another very rare condition that presents with lymphedema. First described in 1986 and was based on the observation of eight unrelated individuals with very similar facial appearances that were characterized by unusually sparse, brittle, curly hair; large head (macrocephaly); a prominent forehead and abnormal narrowing of the sides of the forehead (bitemporal constriction); mental retardation; failure to thrive; heart defects that are present at birth (congenital); short stature and skin abnormalities. CFC syndrome is a dominant genetic disorder caused by a sporadic gene abnormality (mutation) in one of three genes that have been termed BRAF, MEK1 and MEK2. . Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC. (Rare Diseases.Org)
It typically affects the heart, facial features and the skin, and It is estimated that the condition affects between 200 and 300 people worldwide. The condition also affects males and females equally.
Small head, Chorioretinopathy, Lymphedema, Reduced muscle tone during pregnancy, Small eyes, Flat back of head, Sloping forehead, Prominent upper lip groove, Prominent ears, Myopia, Downslanting eye slits, Optic atrophy Flat nose bridge, Broad nose tip, Large nose tip, Anteverted nostrils, Prominent lips, Swollen hands, Swollen feet
According to Dr. Katherine A. Rauen, MD, PhD who is the author of the NIH article on Cardiofaciocutaneous Syndrome, treatment is mutlifacted, with many focusing on the comorbidities of the condition. According to her, it is also important to prevent secondary complications:
Treatment of manifestations: care by a multidisciplinary team; management of cardiac structural defects, hypertrophic cardiomyopathy, and arrhythmias as in the general population; increased ambient humidity or hydrating lotions for xerosis and pruritus; increased caloric intake and a nasogastric tube or gastrostomy for severe feeding problems; surgical intervention for severe gastroesophageal reflux; routine management of growth hormone deficiency, ocular abnormalities; management of seizures may require polytherapy; occupational therapy, physical therapy, and speech therapy as needed.
Prevention of secondary complications: antibiotic prophylaxis for subacute bacterial endocarditis primarily for those with valve dysplasias; evaluation for hypertrophic cardiomyopathy or a predisposition to cardiac rhythm disturbances prior to anesthesia.
Surveillance: periodic echocardiogram (hypertrophic cardiomyopathy), electrocardiogram (rhythm disturbances), neurologic and eye examination, scoliosis check, and assessment of growth. (National Institute of Health link below)
According to the CFC Internation support site Management of the child with CFC syndrome should include the following evaluations:
Neurologic evaluation MRI of the brain to detect any structural changes of the brain Electroencephalogram (EEG) if seizures are suspected Growth and psychomotor developmental monitoring Endocrine evaluation for short stature Regular ophthalmology (eye) examinations Regular audiologic (hearing) examinations Regular cardiac (heart) evaluations Nutrition and feeding evaluation
Enrollment in early intervention therapies to promote growth, motor, and intellectual development – such as occupational therapy (OT), physical therapy (PT), or speech therapy.
Health care team (individual treated based on symptoms)
While there is presently no cure for the conditions itself, with proper management of the symptoms and early identification and intervention there is a great deal that can be done to maintain or improve the health of children with CFC. Treatment is also based on each individual and their specific characteristics.
Cardiofaciocutaneous syndrome is a disorder that affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). People with this condition also have delayed development and intellectual disability, usually ranging from moderate to severe.
Heart defects occur in most people with cardiofaciocutaneous syndrome. The heart problems most commonly associated with this condition include malformations of one of the heart valves (pulmonic stenosis), a hole between the two upper chambers of the heart (atrial septal defect), and a form of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy).
Cardiofaciocutaneous syndrome is also characterized by distinctive facial features. These include a high forehead that narrows at the temples, a short nose, widely spaced eyes (ocular hypertelorism), outside corners of the eyes that point downward (down-slanting palpebral fissures), droopy eyelids (ptosis), a small chin, and low-set ears. Overall, the face is broad and long, and the facial features are sometimes described as “coarse.”
Skin abnormalities occur in almost everyone with cardiofaciocutaneous syndrome. Many affected people have dry, rough skin; dark-colored moles (nevi); wrinkled palms and soles; and a skin condition called keratosis pilaris, which causes small bumps to form on the arms, legs, and face. People with cardiofaciocutaneous syndrome also tend to have thin, dry, curly hair and sparse or absent eyelashes and eyebrows.
Infants with cardiofaciocutaneous syndrome typically have weak muscle tone (hypotonia), feeding difficulties, and a failure to grow and gain weight at the normal rate (failure to thrive). Additional features of this disorder in children and adults can include an unusually large head (macrocephaly), short stature, problems with vision, and seizures.
The signs and symptoms of cardiofaciocutaneous syndrome overlap significantly with those of two other genetic conditions, Costello syndrome and Noonan syndrome. The three conditions are distinguished by their genetic cause and specific patterns of signs and symptoms; however, it can be difficult to tell these conditions apart in infancy. Unlike Costello syndrome, which significantly increases a person's cancer risk, cancer does not appear to be a major feature of cardiofaciocutaneous syndrome.
How common is cardiofaciocutaneous syndrome?
Cardiofaciocutaneous syndrome is a very rare condition whose incidence is unknown. Researchers estimate that 200 to 300 people worldwide have this condition.
What genes are related to cardiofaciocutaneous syndrome?
Cardiofaciocutaneous syndrome can be caused by mutations in several genes. Mutations in the BRAF gene are most common, accounting for 75 percent to 80 percent of all cases. Another 10 percent to 15 percent of cases result from mutations in one of two similar genes, MAP2K1 and MAP2K2.
The BRAF, MAP2K1, and MAP2K2 genes provide instructions for making proteins that work together to transmit chemical signals from outside the cell to the cell's nucleus. This chemical signaling pathway is essential for normal development before birth. It helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement, and the self-destruction of cells (apoptosis).
Mutations in any of these genes can result in the characteristic features of cardiofaciocutaneous syndrome. The protein made from the mutated gene is overactive, which disrupts tightly regulated chemical signaling during development. The altered signaling interferes with the development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.
Some people with the signs and symptoms of cardiofaciocutaneous syndrome do not have an identified mutation in the BRAF, MAP2K1, or MAP2K2 gene. In these cases, affected individuals may actually have Costello syndrome or Noonan syndrome, which are caused by mutations in related genes. The proteins produced from these genes interact with one another as part of the same chemical signaling pathway. These interactions help explain why mutations in different genes can cause conditions with overlapping signs and symptoms.
Read more about the BRAF, MAP2K1, and MAP2K2 genes.
How do people inherit cardiofaciocutaneous syndrome?
Cardiofaciocutaneous syndrome is considered to be an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. All reported cases have resulted from new gene mutations and have occurred in people with no history of the disorder in their family.
Where can I find information about diagnosis, management, or treatment of cardiofaciocutaneous syndrome?
These resources address the diagnosis or management of cardiofaciocutaneous syndrome and may include treatment providers.
Gene Review: Cardiofaciocutaneous Syndrome Gene Tests: BRAF-Related Cardiofaciocutaneous Syndrome Gene Tests: MAP2K1-Related Cardiofaciocutaneous Syndrome Gene Tests: MAP2K2-Related Cardiofaciocutaneous Syndrome
To locate a healthcare provider, see http://ghr.nlm.nih.gov/handbook/consult/findingprofessionalHow can I find a genetics professional in my area? in the Handbook.
Where can I find additional information about cardiofaciocutaneous syndrome?
You may find the following resources about cardiofaciocutaneous syndrome helpful. These materials are written for the general public.
MedlinePlus - Health information (3 links) Additional NIH Resources - National Institutes of Health National Heart, Lung, and Blood Institute: Congenital Heart Defects Educational resources - Information pages Orphanet Patient support - For patients and families (5 links)
You may also be interested in these resources, which are designed for healthcare professionals and researchers.
What other names do people use for cardiofaciocutaneous syndrome?
For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.
What if I still have specific questions about cardiofaciocutaneous syndrome?
Ask the Genetic and Rare Diseases Information Center. Where can I find general information about genetic conditions?
The Handbook provides basic information about genetics in clear language. What does it mean if a disorder seems to run in my family? What are the different ways in which a genetic condition can be inherited? If a genetic disorder runs in my family, what are the chances that my children will have the condition? Why are some genetic conditions more common in particular ethnic groups?
These links provide additional genetics resources that may be useful.
Genetics and health Resources for Patients and Families Resources for Health Professionals
CFC International Cardio-Facio-Cutaneous International 183 Brown Road Vestal, NY 13850 USA Phone #: 607-772-9666
American Heart Association 8200 Brookriver Drive Suite N-100 Dallas, TX 75247 Phone #: 214-784-7212 800 #: 800-242-8721
Children's Craniofacial Association 13140 Coit Road Suite 517 Dallas, TX 75240 USA Phone #: 214-570-9099 800 #: 800-535-3643
Foundation for Ichthyosis & Related Skin Types 2616 N Broad Street Colmar, PA 18915 Phone #: 215-997-9400 800 #: 800-545-3286
Genetic and Rare Diseases (GARD) Information Center PO Box 8126 Gaithersburg, MD 20898-8126 Phone #: 301-251-4925 800 #: 888-205-2311
Hemangioma Support System c/o Cynthia Schumerth 1484 Sand Acres Drive DePere, WI 54115 Phone #: 920-336-9399 (after 8pm CST)
March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 Phone #: 914-997-4488 800 #: 888-663-4637
http://www.niams.nih.gov/}NIH/NationaI Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse One AMS Circle Bethesda, MD 20892-3675 USA Phone #: 301-495-4484 800 #: 877-226-4267
NIH/National Heart, Lung and Blood Institute P.O. Box 30105 Bethesda, MD 20892-0105 Phone #: 301-592-8573
The Arc 1660 L Street, NW, Suite 301 Washington, DC 20036 Phone #: 202-534-3700 800 #: 800-433-5255
The cardiofaciocutaneous syndrome Journal of Medical Genetics
Cardio-facio-cutaneous syndrome: does genotype predict phenotype? May 2011
Allanson JE, Annerén G, Aoki Y, Armour CM, Bondeson ML, Cave H, Gripp KW, Kerr B, Nystrom AM, Sol-Church K, Verloes A, Zenker M.
Department of Genetics at Children’s Hospital of Eastern Ontario. email@example.com
Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10–30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype–phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (approximately 75%), while 46 (approximately 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413–427].
While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype–phenotype correlation, being more common in individuals with a BRAF mutation.
RASopathies: Clinical Diagnosis in the First Year of Life. Sept 2011
Digilio MC, Lepri F, Baban A, Dentici ML, Versacci P, Capolino R, Ferese R, De Luca A, Tartaglia M, Marino B, Dallapiccola B.
Medical Genetics and Pediatric Cardiology, Bambino Gesù Pediatric Hospital, IRCCS.
Diagnosis within Noonan syndrome and related disorders (RASopathies) still presents a challenge during the first months of life, since most clinical features used to differentiate these conditions become manifest later in childhood. Here, we retrospectively reviewed the clinical records referred to the first year of life of 57 subjects with molecularly confirmed diagnosis of RASopathy, to define the early clinical features characterizing these disorders and improve our knowledge on natural history.
Mildly or markedly expressed facial features were invariably present. Congenital heart defects were the clinical issue leading to medical attention in patients with Noonan syndrome and LEOPARD syndrome. Feeding difficulties and developmental motor delay represented the most recurrent features occurring in subjects with cardiofaciocutaneous syndrome and Costello syndrome. Thin hair was prevalent among SHOC2 and BRAF mutation-positive infants. Café-au-lait spots were found in patients with LS and PTPN11 mutations, while keratosis pilaris was more common in individuals with SOS1, SHOC2 and BRAF mutations.
In conclusion, some characteristics can be used as hints for suspecting a RASopathy during the first months of life, and individual RASopathies may be suspected by analysis of specific clinical signs.
In the first year of life, these include congenital heart defects, severity of feeding difficulties and delay of developmental milestones, hair and skin anomalies, which may help to distinguish different entities, for their subsequent molecular confirmation and appropriate clinical management.
Rasopathies: developmental disorders that predispose to cancer and skin manifestations]. Jul2011
[Article in Spanish] Hernández-Martín A, Torrelo A.
Servicio de Dermatología, Hospital Infantil del Niño Jesús, Madrid, Spain. ahernandez firstname.lastname@example.org
Proteins belonging to the RAS/mitogen activated protein kinase (MAPK) pathway play key roles in cell proliferation, differentiation, survival, and death. For more than 30 years now we have known that 30% of human cancers carry somatic mutations in genes encoding proteins from this pathway. Whereas somatic mutations have a high malignant potential, germline mutations are linked to developmental abnormalities that are often poorly clinically differentiated, although each is dependent upon the specific gene affected. Thus, all patients share varying degrees of mental retardation or learning difficulties, heart disease, facial dysmorphism, skin anomalies, and, in some cases, predisposition to cancer. These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. Recognizing the skin manifestations of rasopathies can facilitate diagnosis of these syndromes.
Neuro-cardio-facial-cutaneous syndrome]. Jun-Jul 2011
[Article in French]
Source Service de dermatologie, hôpital Saint-Éloi, 34295 Montpellier cedex 5, France. email@example.com
The concept of neuro-cardio-facio-cutaneous (NCFC) syndrome has recently been formulated in order to bring together a number of hereditary diseases that include a number of shared phenotypic features to differing degrees: (i) craniofacial dysmorphia; (ii) delayed growth; (iii) mental retardation or learning difficulties; (iv) cardiac malformations (most commonly pulmonary valve stenosis and hypertrophic cardiomyopathy); (v) cutaneous anomalies, and in some cases, predisposition to certain forms of malignant solid tumors and blood diseases, associated at the physiopathological level with deregulation of the Ras-MAP kinase cellular signaling pathways 1. NCFC subsumes neurofibromatosis type1, Legius syndrome, LEOPARD syndrome, Noonan syndrome, Costello syndrome and cardiofaciocutaneous (CFC) syndrome. While the majority of these diseases are readily distinguishable in clinical terms, with or without diagnostic criteria, none of them have any pathognomonic signs. Many cases attest to the strong clinical homologies and forms of overlapping between these different diseases. In recent years, the discovery of germinal mutations of these different diseases has in fact reinforced the unifying clinical and biochemical concept of NCFC syndrome.
Orthopaedic conditions in Ras/MAPK related disorders. July-Aug 2011