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cardiofaciocutaneous syndrome

MIM.115150 7q34

Sunday 26 February 2006

Cardiofaciocutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation.

The cardiofaciocutaneous (CFC) syndrome can be caused by gain of function mutations in 1 of 4 different genes:
- CFC2 : KRAS (MIM.190070)
- CFC1 : BRAF (MIM.164757)
- CFC3 (MIM.615279) : MAP2K1 / MEK1 (MIM.176872)
- CFC4 (MIM.615279) : MAP2K1 / MEK2 (MIM.601263)

The protein products of these genes interact in a common RAS/ERK pathway that regulates cell differentiation, proliferation, and apoptosis. It can be considered as a "RASopathy".

It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively.


- hydrocephalus
- olygohydramnios
- normal stature
- pyloric stenosis
- cutaneous syndactyly of toes
- bilateral transverse palmar creases
- postnatal short stature
- failure to thrive
- relative macrocephaly
- dolichocephaly
- prominent forehead
- bitemporal narrowing
- shallow orbital ridges
- prominent philtrum
- coarse facial features
-  micrognathia
- posteriorly rotated ears
- earlobe creases
- hearing loss
- ptosis
- nystagmus
- strabismus
- down-slanting palpebral fissures
- hypertelorism
- exophthalmos
- epicanthal folds
- myopia
- loss of visual acuity
- absence of eyebrows and eyelashes
- nose
- short upturned nose
- bulbous nasal tip
- depressed nasal bridge
- submucous cleft palate
- high-arched palate
- atrial septal defects
- pulmonic stenosis
- hypertrophic cardiomyopathy
-  splenomegaly
- poor feeding in neonatal period
- delayed bone age
- osteopenia
- hyperextensible fingers
- multiple palmar creases
- multiple plantar creases
- severe atopic dermatitis
- ichthyosis
- hyperkeratosis (especially extensor surfaces)
- cavernous hemangioma
- multiple palmar creases
- sparse hair
- curly hair
- slow-growing hair
- absence of eyebrows and eyelashes
- nild to moderate mental retardation
- seizures
- hypotonia
- hypertonia
- hydrocephalus
- cortical atrophy
- frontal lobe hypoplasia
- hypoplasia or absence of the corpus callosum
- brain stem atrophy
- hyperkeratosis of eccrine duct orifices and follicles (Image)


- germline heterozygous mutations

  • KRAS
  • BRAF mutations

Differential diagnosis

-  Noonan syndrome (PTPN11 germline mutations)
- Costello syndrome (HRAS germline mutations)
- CFC-like phenotype and the same deletion of chromosome region 12q21.2q22 (12749059)

See also

- dysregulation of the RAS-RAF-ERK pathway


- Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007 Apr;7(4):295-308. PMID: 17384584

- Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006 Feb 12; PMID: 16474404

- Kavamura MI, Zollino M, Lecce R, Murdolo M, Brunoni D, Alchorne MM, Opitz JM, Neri G. Absence of 12q21.2q22 deletions and subtelomeric rearrangements in cardiofaciocutaneous (CFC) syndrome patients. Am J Med Genet A. 2003 Jun 1;119(2):177-9. PMID: 12749059