A mental retardation syndrome having characteristic craniofacial dysmorphology, ectodermal anomalies and cardiac defects was reported by Blumberg and colleagues at the March of Dimes Birth Defects Conference in 1979. All three patients had characteristic facial features, ichthyosis with abnormal hair, ocular and cardiac abnormalities, postnatal growth failure and mental retardation. These three patients, along with five others, were subsequently reported by Reynolds and colleagues in 1986. The unique combination of characteristics that they noted in these patients included: (1) a distinct facial appearance with relatively disproportionately large head, high forehead, bitemporal constriction, downslanting palpebral fissures, depressed nasal bridge, and ear anomalies; (2) ectodermal abnormalities of the hair and skin; (3) psychomotor and growth failure; and (4) cardiac defects including pulmonic stenosis and atrial septal defects.  Reynolds went on to designate this collection of findings as the Cardio-Facio-Cutaneous syndrome or CFC syndrome. 

CFC syndrome is a rare genetic condition, with over 100 individuals reported in the literature. It is estimated that there are perhaps 200-300 individuals worldwide.  CFC syndrome affects both sexes and all ethnic groups.  Children with CFC syndrome may have certain features at birth or later in childhood that suggest the diagnosis of CFC syndrome, such as a high forehead, flattened nasal bridge, little to no hair, curly hair, areas of thickened or scaly skin and small stature. Most children with CFC syndrome also have a heart defect.  Children with CFC syndrome may also have neurological, visual, and/or feeding problems. While there is a wide spectrum of severity in CFC syndrome, most individuals will have some degree of learning difficulty and developmental delay.  Areas of development that may be delayed include gross motor skills and language development.  There are several characteristic facial features, however, that are evident in CFC syndrome that may overlap with other conditions, particularly Noonan Syndrome (NS) and Costello Syndrome (CS).  Therefore, accurate diagnosis is essential for proper medical management, genetic counseling, and anticipatory guidance. 

There are a wide range of features of CFC syndrome including:

• Craniofacial features
• Large forehead, relative macrocephaly (large head), bitemporal narrowing, down-slanting palpebral fissures (eyes) with epicanthic folds, ptosis (droopy eyelid), depressed nasal bridge, posteriorly rotated ears, high arched palate.  
• Heart Defects
• Pulmonic stenosis, atrial septal defects, ventricular septal defects, hypertrophic cardiomyopathy, heart valve anomalies and rhythm disturbances. These defects may be identified at birth or diagnosed later by the presence of a heart murmur.  Some individuals may have normal hearts.
• Ectodermal manifestations
• SKIN: Dry, hyperkeratotic (thickened), ichthyotic (scaly), keratosis pilaris (small, goose flesh), eczema (extreme dryness of skin and itchiness), hemangiomas, café-au-lait spots (flat, dark spots), erythema (redness to the skin), moles (very dark freckles). HAIR: sparse, curly, fine or thick, wooly or brittle hair; eyelashes and eyebrows may be absent or normal. NAILS: nail dystrophy and/or flat broad nails.
• Ocular findings
• Most common eye findings are hypertelorism (wide spaced eyes), strabismus, nystagmus, astigmatism, myopia, hyperopia, optic nerve hypoplasia, cortical blindness and cataracts. Individuals may also have epicanthal folds and ptosis. Any combination of these features might result in decreased vision and acuity.  Rare individuals may not have ocular abnormalities.
• Feeding/ Gastrointestinal (GI) problems
• Severe feeding problems may be associated with gastroesophageal reflux, vomiting, oral aversion; intestinal malrotation, hernia and constipation.  Most individuals have failure to thrive.
• Growth delays
• The feeding problems play a significant role in their growth retardation.  Growth failure may manifest as normal birth weight and length, but during early infancy weight and length may drop to below the 5th percentile while head size remains on the growth curve (relative macrocephaly). Some individuals may have growth hormone deficiency. 
• Neurologic findings
• Hypotonia (low muscle tone), seizure disorders, abnormal EEG (slow and dysrrhythmic), hydrocephalus, cortical atrophy, ventriculomegaly, frontal lobe hypoplasia, agenesis of the corpus callosum, Chiari malformation, pachygyria, microcephaly, cognitive impairment (ranging from mild to severe).

Recently, four different genes have been found to be associated with CFC syndrome (BRAF, MEK1, MEK2 and KRAS), however, most individuals with CFC syndrome have a new sporadic mutation in the BRAF gene.  Molecular genetic (DNA) testing for mutations in all of these genes is clinically available.

Currently, there is no cure to treat all of the symptoms of CFC syndrome.  However, with proper management and early intervention, much can be done to improve the health of children with CFC syndrome.  At present, treatment ultimately depends on the unique characteristics of each individual.  These can include heart surgery to repair a structural defect, medications and lotions for the skin problems, or eye surgeries or corrective lenses to improve vision. 

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)

All cases of CFC syndrome have been sporadic, meaning that only one person in the family has CFC syndrome. CFC affects males and females equally. As of yet, there have been no documented cases of CFC in sib-ships and no documented cases of mosaicism. Mutations to date have been de novo (new) with a consequent very low risk of recurrence. It is currently unclear whether or not a paternal age effect exists. Although there are no guidelines in place, prenatal diagnosis could be considered and offered to parents in subsequent pregnancies for reassurance and to evaluate the low likelihood of gonadal mosaicism.

 

Written by: Pilar L. Magoulas,  MS, CGC, Baylor College of Medicine
Reviewed and modified by Katherine A. Rauen, PhD, MD, University of California San Francisco and CFC International.

August 2006