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CFC syndrome

 

Cardiofaciocutaneous syndrome (CFC) is a disorder that affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). People with this condition also have delayed development and intellectual disability, usually ranging from moderate to severe. CFC is considered to be an autosomal dominant condition, which means one copy of an altered gene in each cell is sufficient to cause the disorder. Cardiofaciocutaneous syndrome usually results from new gene mutations and occurs in people with no history of the disorder in their family. In a few reported cases, an affected person has inherited the condition from an affected parent.

Heart defects occur in most people with cardiofaciocutaneous syndrome. The heart problems most commonly associated with this condition is pulmonary stenosis, atrial septal defect, and hypertrophic cardiomyopathy. CFC is also characterized by distinctive facial features. These include a high forehead that narrows at the temples, a short nose, widely spaced eyes, outside corners of the eyes that point downward, droopy eyelids, a small chin, and low-set ears. Overall, the face is broad and long, and the facial features are sometimes described as "coarse."

Skin abnormalities occur in almost everyone with CFC. Many affected people have dry, rough skin; dark-colored moles; wrinkled palms and soles; and a skin condition called keratosis pilaris, which causes small bumps to form on the arms, legs, and face. People with cardiofaciocutaneous syndrome also tend to have thin, dry, curly hair and sparse or absent eyelashes and eyebrows.

Infants with cardiofaciocutaneous syndrome typically have hypotonia, feeding difficulties, and a failure to grow and gain weight at the normal rate. Additional features of this disorder in children and adults can include an unusually large head, short stature, problems with vision, and seizures.

The signs and symptoms of cardiofaciocutaneous syndrome overlap significantly with those of two other genetic conditions, Costello syndrome and Noonan syndrome. The three conditions are distinguished by their genetic cause and specific patterns of signs and symptoms; however, it can be difficult to tell these conditions apart, particularly in infancy. Unlike Costello syndrome, which significantly increases a person's cancer risk, cancer does not appear to be a major feature of cardiofaciocutaneous syndrome.

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, cell movement, and the self-destruction of cells. The SHOC2 gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. We provide testing for the mutations below that are believed to cause CFC and related disorders.

Type OMIM Gene/Protein Description
CFC1 115150 BRAF/B-Raf Mutations in the BRAF gene are most common, accounting for 75 to 80 percent of all cases.
CFC2 615278 KRAS

Fewer than 5 percent of cases are caused by mutations in the KRAS gene.

CFC3 615279 MAP2K1/MEK1 10 to 15 percent of cases result from mutations in MAP2K1.
CFC4 615280 MAP2K2/MEK2 10 to 15 percent of cases result from mutations in MAP2K2.
Noonan like syndrome with loose anagen hair 602775 SHOC2/SHOC-2 Clinical manifestations in SHOC2 positive mutation patients overlaps with those in patients with CFC or Noonan syndrome, but the loose anagen hair is distinctive to SHOC2 mutation-positive patients.

Methodology: Sequencing of entire coding region for each gene

Purpose:Confirmation of Clinical Diagnosis

Test Requisition: Sequencing Requisition

BRAF CPT Code: 81406 Cost: $1089.00

KRAS CPT Code: 81405 Cost: $528.00

MAP2K1 CPT Code: 81406 Cost: $1100.00

MAP2K2 CPT Code: 81406 Cost: $1100.00

SHOC2 CPT Code: 81405 Cost: $440.00

Panel CPT Codes: 81405x2, 81406x3 Cost: $4257.00

Turn-around-time: 5-6 weeks each test

Specimen Requirements

Shipping Information

References

1. Armour CM, Allanson JE. Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. J Med Genet. 2008 Apr;45(4):249-54.   

2. Nava C, et al Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007 Dec;44(12):763-71

3. Rauen KA, Tidyman WE, Estep AL, Sampath S, Peltier HM, Bale SJ, Lacassie Y. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. Am J Med Genet A. 2010 Apr;152A(4):807-14.

 4. Rauen KA. Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. Am J Med Genet A. 2006 Aug 1;140(15):1681-3.  

5. Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G. The cardiofaciocutaneous syndrome. J Med Genet. 2006 Nov;43(11):833-42. Epub 2006 Jul 6. Review.

6. Hoban, R., Roberts, A. E., Demmer, L., Jethva, R., Shephard, B. Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant.Am. J. Med. Genet. 158A: 1411-1413, 2012.


 

 



Contact Information
Genetics Laboratory
University of Oklahoma Health Sciences Center
1122 NE 13 Street, Suite 1400, Oklahoma City, OK 73104
Phone: (405) 271-3589 |Fax: (405) 271-7117 Email: Dr. Shibo Li

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