Noonan syndrome (NS) is an autosomal dominant dysmorphology syndrome characterized by short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, ocular abnormalities, and deafness. Characteristic facies include hypertelorism, downward sloping palpebral apertures, epicanthal folds, ptosis, and low-set posteriorly rotated ears. Early feeding difficulties such as poor suck or gastrointestinal dysfunction are also common. Although birth length is usually normal, final adult height approaches the lower limit of normal. Up to one-third of affected individuals have mild mental retardation. KRAS mutations have been implicated in 5% or less of cases of Noonan syndrome.
Click here for the GeneTests summary on Noonan syndrome.
Cardiofaciocutaneous (CFC) syndrome is characterized by features in three primary systems: cardiac, craniofacial, and ectodermal; however, other systems may be involved as well. Cardiac abnormalities can include pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, and rhythm disturbances. Individuals with CFC syndrome have a distinctive craniofacial appearance. Ectodermal features include skin findings, such as xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema oophorogenes, eczema, pigmented moles, palmoplantar hyperkeratosis; hair findings such as sparse, curly, fine or thick, woolly, or brittle hair, and possible absent eyelashes and eyebrows; and the nails may be dystrophic or fast growing. Cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasias have been reported in some individuals with CFC.
There are four genes known to be associated with CFC. Mutations in the BRAF gene account for ~75% of cases, MAP2K1 and MAP2K2 account for ~25% of cases, and KRAS accounts for <2% of cases. CFC syndrome is inherited in an autosomal dominant manner; however, most cases of CFC syndrome arise de novo.
Click here for the GeneTests summary on CFC syndrome.
KRAS is said to be one of the most activated oncogenes, with 17 to 25% of all human tumors harboring an activating KRAS mutation. KRAS mutations described to date in patients with Noonan syndrome/CFC are distinct from those found in malignancies.
Based on the provisional clinical opinion released by the American Society of Clinical Oncology in January, 2009, it is recommended that all patients with colorectal cancer (CRC) have tumors tested for KRAS oncogene prior to therapy. It is estimated that the incidence of the KRAS mutations in CRC is approximately 35-45%. Detection of KRAS mutations in CRC is beneficial in identifying patients who will benefit from treatment which in turn will improve the clinical outcome and help in determining the best therapy strategy. If a KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.
For patients with suspected KRAS-related conditions, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
Please note that this test is for the KRAS (12p12.1) gene only.
(1) Allegra, C. et al. American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy. 2009. J Clin Oncol 27:2091-2096.
(2) Zenker, M. et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. 2007. J Med Genet 44:131-135.
This test is indicated for:
- Confirmation of a clinical diagnosis of a KRAS-related condition in an individual in whom sequence analysis was negative.
- Individuals at-risk for a KRAS-related condition due to family history in whom sequence analysis was negative.
- Testing of colorectal cancer tissue for therapeutic decisions in an individual in whom sequence analysis was negative.
Please note that a "backbone" of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off-target copy number variants causative of disease may be identified that may or may not be related to the patient's phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
- Sequence analysis of the KRAS gene is available and is required before deletion/duplication analysis.
- Sequencing and deletion/duplication analysis of the PTPN11 gene for Noonan syndrome is also available.
- Sequencing and deletion/duplication analysis of the BRAF and MAP2K2 genes for CFC syndrome is also available.
- Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
- Prenatal testing is available to adults who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.