Cardiofaciocutaneous Syndrome – Definition, Symptoms, and Treatment.

Definition

Cardiofaciocutaneous Syndrome is a rare genetic condition that typically affects the heart (cardio-), facial features (facio-) and skin (cutaneous). It is seen with equal frequency in males and females and across all ethnic groups. Children with CFC syndrome may have certain features that suggest the diagnosis, such as relatively large head size, down-slanting eyes, sparse eyebrows, curly hair, areas of thickened or scaly skin, and short stature.   Most will also have a heart defect. While there is a wide spectrum of severity in CFC syndrome, most individuals will have some degree of learning difficulty and developmental delay.

Cardiofaciocutaneous syndrome

There are several characteristic facial features 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.

History

CFC was first reported in1986 by Reynolds and by Baraitser and Patton. Eight individuals were described with distinct facial features, ectodermal abnormalities, cardiac malformations, and intellectual disability. At that time, many believed that the facial features of CFC overlapped with those of NS, and a controversy emerged regarding the delineation of CFC as a new, distinct syndrome versus a severe form of NS.

In 2001, PTPN was found to be one of the causal genes of NS, and it was possible to demonstrate that well-characterized individuals with CFC did not have a mutation in PTPN. Furthermore, individuals with CFC did not carry mutations in the HRAS gene, which causes CS, another phenotypically similar condition. Identification of these 2 genes for NS and CS suggested that CFC, NS, and CS were separate, distinct conditions, with overlapping phenotypes.

The final proof came in 2006 when 2 groups demonstrated that CFC is a heterogeneous disorder caused by mutations in different genes: BRAF, MEK1, MEK2, and KRAS. These discoveries led to the recognition that CFC was a distinct syndrome separate from NS and CS and also explained that the similarity between them lay in a common underlying molecular pathway, the Ras/ mitogen-activated protein kinase (MAPK) pathway.

Epidemiology

Around 300 cases have been published in the literature to date. Prevalence has been estimated at 1/810,000 people in Japan.

Features of the condition

Facial features: Large forehead, relative macrocephaly (large head), narrowing at the sides of the forehead, down-slanting eyes, ptosis (droopy eyelid), depressed nasal bridge, rotated ears.

Heart: Pulmonic stenosis (narrowing of the artery going from the heart to the lungs), atrial septal defects (holes in the upper chambers of the heart), ventricular septal defects (holes in the lower chambers of the heart), hypertrophic cardiomyopathy (enlarged heart muscle)

Skin and hair: Dry, thickened (hyperkeratotic), or scaly (ichythyotic), eczema (extreme dryness of skin and itchiness); sparse, curly, wooly or brittle hair; eyelashes and eyebrows may be absent or sparse.

Eye findings: wide-spaced eyes (hypertelorism), strabismus (eyes turning in/out), nystagmus (jittery eyes), near-sightedness, small optic (eye) nerves. These may result in decreased vision and acuity.

Feeding/ Gastrointestinal (GI) problems: Difficulty feeding, failure to thrive, reflux, vomiting, oral aversion; intestine malrotation, hernia, and constipation.

Growth: May have normal birth weight and length, but they may drop to below the 5^th percentile in infancy. Head remains on the growth curve (relative macrocephaly). Some may have growth hormone deficiency.

Neurologic findings: Hypotonia (low muscle tone), seizures, abnormal EEG, hydrocephalus (fluid on the brain), other brain changes; cognitive impairment (ranging from mild to severe).

The thin and sparse hair (b), curly hair (a and c), the absence of eyebrows (a, b and c), hyperkeratosis and wrinkled palm with wide squared tips (d)

Causes

• Cardiofaciocutaneous syndrome can be caused by mutations in several genes. Mutations in the BRAF gene are most common, accounting for 75 to 80 percent of all cases. Another 10 to 15 percent of cases result from mutations in one of two similar genes, MAP2K1 and MAP2K2. Fewer than 5 percent of cases are caused by mutations in the KRAS gene.
• The BRAF, MAP2K1, MAP2K2, and KRAS 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, known as the RAS/MAPK 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 alters tightly regulated chemical signaling during development. The altered signaling interferes with the development of many organs and tissues, leading to the signs and symptoms of cardiofaciocutaneous syndrome.
• Some people with the signs and symptoms of cardiofaciocutaneous syndrome do not have an identified mutation in the BRAF, MAP2K1, MAP2K2, or KRAS gene. In these cases, affected individuals may actually have Costello syndrome or Noonan syndrome, which are also caused by mutations in genes involved in RAS/MAPK signaling.
• The proteins produced from these genes are all part of the same chemical signaling pathway, which helps explain why mutations in different genes can cause conditions with such similar signs and symptoms. The group of related conditions that includes cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome is often called the RASopathies.

Symptoms of Cardiofaciocutaneous Syndrome

There is a wide range of features of CFC syndrome, including:

• True macrocephaly (large head) or relatively large head
• High forehead, hypertelorism (wide-spaced eyes), short nose, low set ears, and full lips. These characteristics can resemble Noonan syndrome to a great extent
• Brittle and sparse hair together with skin problems, such as scaly or thickened skin
• Heart defects relating to valves and openings between the left and right chambers (typically pulmonary artery stenosis), and hypertrophic cardiomyopathy (abnormal development of the muscle of the heart; see entry Cardiomyopathies in Children)
• Short stature gradually developing in infancy or childhood
• Motor and speech delay (though some follow a normal development)
• Learning disability
• Feeding problems in the first few years.

Facial features

Diagnosis and test

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Treatment of Cardiofaciocutaneous Syndrome

There is no “cure” for CFC syndrome, but there are several treatments and therapies available. Each treatment plan is tailored to the patient, based on their medical issues.

• For those with heart features, treatment is similar to people who have the same heart defect but do not have CFC syndrome. Individuals with CFC syndrome who do not have heart issues are evaluated every couple of years since heart issues can develop later in life.
• For those with delayed development, early treatments may include physical, occupational, and/or speech therapy.
• Infants with severe feeding issues may need surgery.

Management

Children should see their doctor regularly so they can:

• Check their growth and development. Children with delayed growth may need growth hormone therapy.
• Check for neurological symptoms, seizures and eye problems.
• For those with skin issues, hydrating lotions and other skin treatments may help.

Prevention of Cardiofaciocutaneous Syndrome

Cardiac: Certain congenital heart defects (notably valve dysplasias) require antibiotic prophylaxis for subacute bacterial endocarditis (SBE).

Anesthesia: Individuals with CFC syndrome may have an unrecognized hypertrophic cardiomyopathy or a predisposition to cardiac rhythm disturbances.