Cardio-Facio-Cutaneous Syndrome

Gene: BRAF

Protein: Serine/threonine-protein kinase B-raf

Gene: KRAS

Protein: GTPase KRas

Gene: MEK1 (MAP2K1)

Protein: dual specificity mitogen-activated protein kinase kinase 1

Gene: MEK2 (MAP2K2)

Protein: dual specificity mitogen-activated protein kinase kinase 2

Clinical Characteristics

  • Polyhydramnios in prenatal period
  • Cardiac abnormalities:
    • Pulmonic stenosis and other valve dysplasias
    • Septal defects
    • Hypertrophic cardiomyopathy
    • Rhythm disturbances
  • Distinctive craniofacial appearance:
    • High forehead, bitemporal narrowing, hypoplastic supraorbital ridges
    • Wide-set and down-slanting eyes, epicanthal folds, ptosis
    • Short nose with depressed bridge and upturned nares
    • Low-set posteriorly rotated ears with earlobe creases
    • Deep philtrum, cupid's bow lip, high-arched palate, micrognathia
  • Cutaneous abnormalities:
    • Skin: dry skin, keratosis pilaris, palmoplantar hyperkeratosis, multiple palmar creases
    • Hair: sparse curly hair, absent eyelashes and eyebrows
    • Nails: dystrophic and/or fast growing
  • Neurologic involvement:
    • Cognitive delay ranging from mild to severe
    • Hypotonia and developmental delay
    • May include seizures, abnormal EEG or structural brain abnormalities
  • Growth delay:
    • Postnatal short stature
    • Failure to thrive with contributory gastrointestinal and feeding issues
    • Head circumference remains within normal range resulting in relative macrocephaly
  • Inheritance pattern: Autosomal dominant; all reported cases have been sporadic

What Can Be Learned From This Test

Testing can be performed in tiers, moving to the next tier only if the preceding test is negative. Testing can also be performed concurrently, or in any order requested. The following strategy is suggested for cardiofaciocutaneous (CFC) syndrome testing.

  • Tier 1 sequencing of exons 6 and 11 through 16 of BRAF
  • Tier 2 sequencing of exons 2, 3, 6 and 7 of MEK1 and MEK2
  • Tier 3 sequencing of the entire coding region of KRAS

Testing will detect point mutations, small deletions and small insertions in the regions of the genes that are analyzed. It will not detect a partial or whole gene deletion or duplication.

For CFC syndrome, mutations are detected in:

  • Exons 6 or 11 through 16 of BRAF in 75-80% of affected individuals
  • Exons 2 or 3 of MEK1 or MEK2 in 10-15% of affected individuals
  • KRAS in fewer than 5% of affected individuals

A negative test does not completely rule out a diagnosis of CFC syndrome, since it is unclear at this time if all the genes associated with CFC syndrome have been identified.

Clinical overlap is seen between CFC syndrome, Noonan syndrome and Costello syndrome. Tests for Noonan syndrome and Costello syndrome are also available in our lab and can be requested if clinically indicated.

Sample Requirements

Draw 2ml–4ml of blood in EDTA/purple-top tube (minimum of 1ml–2ml for infants).

Turnaround time: 10-14 business days for each gene; about 3-4 weeks for all 3 tiers

CPT Codes and Cost

Tier 1

Code: 81479

Cost: $600

Tier 2

Code: 81479

Cost: $525

Tier 3

Code: 81405

Cost: $425

Known Variant Testing

Code: 81479

Cost: $225

Additional Information