FaCD Online Syndrome Fact Sheet

Last updated: 19 Apr 2011

Name: Cardiofaciocutaneous syndrome

Synonym: CFC, CFCS

Mode of Inheritance: sporadic (de novo)

Genes

BRAF, mapped to 9q34
KRAS, mapped to 12p12.1
MEK1/MAP2K1, mapped to 15q21
MEK2/MAP2K2, mapped to 7q32

Tumor features

hemangioma

Tumor features (possible)

hepatoblastoma
leukemia, acute lymphoblastic (ALL)
non-Hodgkin lymphoma
rhabdomyosarcoma

Non-tumor features

growth deficieny
heart, congenital defect
high forehead
hyperkeratosis
nasal bridge, depressed
palpebral fissures, downward slanting
woolly, sparse and friable hair

Comment

Hallmarks of CFCS are a typical facies, congenital heart defects (predominantly pulmonary stenosis and ASD), growth failure and ectodermal anomalies. There is clinical and molecular overlap with Noonan syndrome and Costello syndrome.These disorders share disruption of the RAS/MAPK signalling pathway.[1-5]. It has been suggested that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations[5]

Van den Berg and Hennekam[6] reported a 5-year-old girl with CFC and unknown mutation status, who was diagnosed with ALL. Makita et al[7] reported another case in a patient with a BRAF mutation. Bisogno et al[8] described a 20 months old boy with CFC, unknown mutation status, and an embryonal rhabdomyosarcoma. A hepatoblastoma in a MEK1 mutation CFC patient was reported by Al-Rahawan[9]. A 2-month-old child with NHL, CFC and a BRAF mutation was reported by Ohtake et al[10]. A recent review of te literature listed 4 cases of ALL, 2 of NHL, and 1 hepatoblastoma and 1 embryonal rhabdomyosarcoma each[11]. Hemangiomas are not uncommon in CFC[12].

References

[1] Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G. The cardiofaciocutaneous syndrome. Journal of medical genetics 2006; 43(11):833-42.
[2] Narumi Y, Aoki Y, Niihori T, Neri G, Cavé H, Verloes A, Nava C, Kavamura MI, Okamoto N, Kurosawa K, Hennekam RC, Wilson LC, Gillessen-Kaesbach G, Wieczorek D, Lapunzina P, Ohashi H, Makita Y, Kondo I, Tsuchiya S, Ito E, Sameshima K, Kato K, Kure S, Matsubara Y. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. American journal of medical genetics. Part A 2007; 143(8):799-807.
[3] Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, Aoki Y, Matsubara Y, Arveiler B, Lacombe D, Pasmant E, Parfait B, Baumann C, Héron D, Sigaudy S, Toutain A, Rio M, Goldenberg A, Leheup B, Verloes A, Cavé H. 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 2007; 44(12):763-71.
[4] Schulz AL, Albrecht B, Arici C, van der Burgt I, Buske A, Gillessen-Kaesbach G, Heller R, Horn D, Hübner CA, Korenke GC, König R, Kress W, Krüger G, Meinecke P, Mücke J, Plecko B, Rossier E, Schinzel A, Schulze A, Seemanova E, Seidel H, Spranger S, Tuysuz B, Uhrig S, Wieczorek D, Kutsche K, Zenker M. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. Clinical genetics 2008; 73(1):62-70.
[5] Gripp KW, Lin AE, Nicholson L, Allen W, Cramer A, Jones KL, Kutz W, Peck D, Rebolledo MA, Wheeler PG, Wilson W, Al-Rahawan MM, Stabley DL, Sol-Church K. 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 2007; 143(13):1472-80.
[6] van Den Berg H, Hennekam RC. Acute lymphoblastic leukaemia in a patient with cardiofaciocutaneous syndrome. Journal of medical genetics 1999; 36(10):799-800.
[7] Makita Y, Narumi Y, Yoshida M, Niihori T, Kure S, Fujieda K, Matsubara Y, Aoki Y. Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology 2007; 29(5):287-90.
[8] Bisogno G, Murgia A, Mammi I, Strafella MS, Carli M. Rhabdomyosarcoma in a patient with cardio-facio-cutaneous syndrome. Journal of pediatric hematology/oncology 1999 Sep-Oct; 21(5):424-7.
[9] Al-Rahawan MM, Chute DJ, Sol-Church K, Gripp KW, Stabley DL, McDaniel NL, Wilson WG, Waldron PE. Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome. American journal of medical genetics. Part A 2007; 143(13):1481-8.
[10] Ohtake A, Aoki Y, Saito Y, Niihori T, Shibuya A, Kure S, Matsubara Y. Non-Hodgkin Lymphoma in a Patient With Cardiofaciocutaneous Syndrome. J Pediatr Hematol Oncol. 2010 Jun 2. [Epub ahead of print]
[11] Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011 Apr 15.[Epub ahead of print].
[12] Tang B, Reardon W, Black GC, Kerr BA. Congenital ulcerating hemangioma in a baby with KRAS mutation and cardio-facio-cutaneous syndrome. Clinical dysmorphology 2007; 16(3):203-6.