Cardiofaciocutaneous (CFC) Syndrome


Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder that is characterised by facial dysmorphism, cardiac defects, mental retardation, typical ectodermal abnormalities and short stature. It is caused by germline mutations in BRAF, MEK1, MEK2 or KRAS and shows phenotypical overlap with other conditions caused by mutations in the RAS‐MAPK pathway such as neurofibromatosis type 1, Noonan, LEOPARD, Costello and Legius syndromes. The identification of the underlying genetic defect opens new windows for therapeutic strategies in these RASopathies including CFC syndrome.

Key Concepts:

  • Mutations in genes coding for key components of the RAS‐MAPK pathway are responsible for a group of inherited disorders (RASopathies).

  • The RASopathies are clinically and molecularly related disorders characterised by variable cognitive deficits, growth retardation, facial dysmorphy, and congenital cardiopathies.

  • CFC syndrome is characterised by the most severe intellectual disabilities seen in the RASopathies.

  • Correcting cerebral RAS‐MAPK signalling is a potential targeted treatment for learning disabilities in patients with a RASopathy.

Keywords: CFC syndrome; RASopathies; BRAF; MEK; KRAS

Figure 1.

The RASopathies. The RAS‐MAPK pathway. Proteins associated with RASopathies are shaded in grey, proteins associated with CFC syndrome are shaded in black. The different Rasopathies are shown: Noonan syndrome, LEOPARD syndrome, CFC syndrome, Costello syndrome, Loh syndrome, Legius syndrome, CM‐AVM syndrome (capillairy malformation – arteriovenous malformation). For each inherited disorder the associated proteins are indicated. Neurofibromin, P120GAP and SPRED1 are negative regulators of the pathway, whereas the other proteins activate signal transduction through the pathway. The RAS protein is activated by exchanging GDP for GTP. The RAF, MEK and ERK proteins are kinases that are activated by phosphorylation.



Al Rahawan MM, Chute DJ, Sol‐Church K et al. (2007) Hepatoblastoma and heart transplantation in a patient with cardio‐facio‐cutaneous syndrome. American Journal of Medical Genetics Part A 143: 1481–1488.

Anastasaki C, Estep AL, Marais R et al. (2009) Kinase‐activating and kinase‐impaired cardio‐facio‐cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Human Molecular Genetics 18: 2543–2554.

Aoki Y, Niihori T, Kawame H et al. (2005) Germline mutations in HRAS proto‐oncogene cause Costello syndrome. Nature Genetics 37: 1038–1040.

Bertola DR, Pereira AC, Brasil AS et al. (2007) Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene. Journal of Human Genetics 52: 521–526.

Bhola P, Banerjee S, Mukherjee J et al. (2010) Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft. International Journal of Cancer 126: 563–571.

Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Research 49: 4682–4689.

Brems H, Chmara M, Sahbatou M et al. (2007) Germline loss‐of‐function mutations in SPRED1 cause a neurofibromatosis 1‐like phenotype. Nature Genetics 39: 1120–1126.

Cirstea IC, Kutsche K, Dvorsky R et al. (2010) A restricted spectrum of NRAS mutations causes Noonan syndrome. Nature Genetics 42: 27–29.

Cordeddu V, Di Schiavi E, Pennacchio LA et al. (2009) Mutation of SHOC2 promotes aberrant protein N‐myristoylation and causes Noonan‐like syndrome with loose anagen hair. Nature Genetics 41: 1022–1026.

Costa RM, Federov NB, Kogan JH et al. (2002) Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415: 526–530.

Davies H, Bignell GR, Cox C et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417: 949–954.

Garnett MJ and Marais R (2004) Guilty as charged: B‐RAF is a human oncogene. Cancer Cell 6: 313–319.

Gripp KW, Lin AE, Nicholson L et al. (2007) Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio‐facio‐cutaneous syndrome from Costello syndrome. American Journal of Medical Genetics Part A 143: 1472–1480.

Hasskarl J (2010) Sorafenib. Recent Results in Cancer Research 184: 61–70.

Heidorn SJ, Milagre C, Whittaker S et al. (2010) Kinase‐dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140: 209–221.

Kavamura MI, Peres CA, Alchorne MM et al. (2002) CFC index for the diagnosis of cardiofaciocutaneous syndrome. American Journal of Medical Genetics 112: 12–16.

Kavamura MI, Pomponi MG, Zollino M et al. (2003) PTPN11 mutations are not responsible for the cardiofaciocutaneous (CFC) syndrome. European Journal of Human Genetics 11: 64–68.

Krab LC, Goede‐Bolder A, Aarsen FK et al. (2008) Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. Journal of the American Medical Association 300: 287–294.

Legius E, Marchuk DA, Collins FS et al. (1993) Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nature Genetics 3: 122–126.

Legius E, Schrander‐Stumpel C, Schollen E et al. (2002) PTPN11 mutations in LEOPARD syndrome. Journal of Medical Genetics 39: 571–574.

Li W, Cui Y, Kushner SA et al. (2005) The HMG‐CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Current Biology 15: 1961–1967.

Mahgoub N, Taylor BR, Gratiot M et al. (1999) In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1‐deficient hematopoietic cells. Blood 94: 2469–2476.

Makita Y, Narumi Y, Yoshida M et al. (2007) Leukemia in cardio‐facio‐cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto‐oncogene. Journal of Pediatric Hematology/Oncology 29: 287–290.

Malumbres M and Barbacid M (2003) RAS oncogenes: the first 30 years. Nature Reviews Cancer 3: 459–465.

Narumi Y, Aoki Y, Niihori T et al. (2007) Molecular and clinical characterization of cardio‐facio‐cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. American Journal of Medical Genetics Part A 143: 799–807.

Nava C, Hanna N, Michot C et al. (2007) Cardio‐facio‐cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome. Journal of Medical Genetics 44: 763–771.

Neri G, Allanson J and Kavamura MI (2008) No reason yet to change diagnostic criteria for Noonan, Costello and cardio‐facio‐cutaneous syndromes. Journal of Medical Genetics 45: 832.

Niihori T, Aoki Y, Narumi Y et al. (2006) Germline KRAS and BRAF mutations in cardio‐facio‐cutaneous syndrome. Nature Genetics 38: 294–296.

Nystrom AM, Ekvall S, Berglund E et al. (2008) Noonan and cardio‐facio‐cutaneous syndromes: two clinically and genetically overlapping disorders. Journal of Medical Genetics 45: 500–506.

Pandit B, Sarkozy A, Pennacchio LA et al. (2007) Gain‐of‐function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics 39: 1007–1012.

Rauen KA, Tidyman WE, Estep AL et al. (2010) Molecular and functional analysis of a novel MEK2 mutation in cardio‐facio‐cutaneous syndrome: transmission through four generations. American Journal of Medical Genetics Part A 152A: 807–814.

Razzaque MA, Nishizawa T, Komoike Y et al. (2007) Germline gain‐of‐function mutations in RAF1 cause Noonan syndrome. Nature Genetics 39: 1013–1017.

Reynolds JF, Neri G, Herrmann JP et al. (1986) New multiple congenital anomalies/mental retardation syndrome with cardio‐facio‐cutaneous involvement – the CFC syndrome. American Journal of Medical Genetics 25: 413–427.

Roberts A, Allanson J, Jadico SK et al. (2006) The cardiofaciocutaneous syndrome. Journal of Medical Genetics 43: 833–842.

Roberts AE, Araki T, Swanson KD et al. (2007) Germline gain‐of‐function mutations in SOS1 cause Noonan syndrome. Nature Genetics 39: 70–74.

Rodriguez‐Viciana P, Tetsu O, Tidyman WE et al. (2006) Germline mutations in genes within the MAPK pathway cause cardio‐facio‐cutaneous syndrome. Science 311: 1287–1290.

Sarkozy A, Carta C, Moretti S et al. (2009) Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Human Mutation 30: 695–702.

Schubbert S, Zenker M, Rowe SL et al. (2006) Germline KRAS mutations cause Noonan syndrome. Nature Genetics 38: 331–336.

Schulz AL, Albrecht B, Arici C et al. (2008) Mutation and phenotypic spectrum in patients with cardio‐facio‐cutaneous and Costello syndrome. Clinical Genetics 73: 62–70.

Senawong T, Phuchareon J, Ohara O et al. (2008) Germline mutations of MEK in cardio‐facio‐cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. Human Molecular Genetics 17: 419–430.

Shepherd C, Puzanov I and Sosman JA (2010) B‐RAF inhibitors: an evolving role in the therapy of malignant melanoma. Current Oncology Reports 12: 146–152.

Tartaglia M, Mehler EL, Goldberg R et al. (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP‐2, cause Noonan syndrome. Nature Genetics 29: 465–468.

Tartaglia M, Pennacchio LA, Zhao C et al. (2007) Gain‐of‐function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genetics 39: 75–79.

Tidyman WE and Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Current Opinion in Genetics & Development 19: 230–236.

Wan PT, Garnett MJ, Roe SM et al. (2004) Mechanism of activation of the RAF‐ERK signaling pathway by oncogenic mutations of B‐RAF. Cell 116: 855–867.

Yang FC, Ingram DA, Chen S et al. (2008) Nf1‐dependent tumors require a microenvironment containing Nf1+/− and c‐kit‐dependent bone marrow. Cell 135: 437–448.

Further Reading

Krab LC, Goorden SM and Elgersma Y (2008) Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends in Genetics 24: 498–510.

Poulikakos PI, Zhang C, Bollag G et al. (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild‐type BRAF. Nature 464: 427–430.

Rauen KA, Schoyer L, McCormick F et al. (2010) Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: from bedside to bench and back. American Journal of Medical Genetics Part A 152A: 4–24.

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Denayer, Ellen, and Legius, Eric(Sep 2011) Cardiofaciocutaneous (CFC) Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021470]