July 18, 2009: GENDIA now offers a new "resequencing" platform for 8 genes implicated in Noonan, Leopard, Costello and Cardiofaciocutaneous syndrome.
These are clinically overlapping syndromes due to mutations in 8 genes in the RAS/MAPK pathway, including PTPN11, SOS1, RAF1, BRAF, MAP2K1, MAP2K2, HRAS and KRAS.
Noonan Syndrome (NS) is an autosomal dominant condition characterized by distinctive craniofacial features; cardiac defects; short stature; musculoskeletal, ophthalmologic, and renal anomalies; lymphatic dysplasia; bleeding diathesis; cryptorchidism in males; and a predisposition to leukemia. Developmental delay of variable degree is present in 25%-30%. Congenital heart defects occur in the majority, with pulmonary valve stenosis being the most common, followed by hypertrophic cardiomyopathy. Other frequent structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, tetralogy of Fallot, and coarctation of the aorta. Noonan syndrome is caused by mutations in PTPN11, SOS1, KRAS and RAF1.
Leopard Syndrome (LS) (Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, Deafness) is an autosomal dominant condition with variable expression. It shows significant overlap with Noonan syndrome (NS), in which pigmentary findings such as nevi (25%), café au lait patches (10%), and lentigines (3%) are reported. PTPN11 and RAF1 are the only genes known to be associated with LS. Molecular testing of these two genes identifies mutations in about 93% of affected individuals.
Cardiofaciocutaneous Syndrome (CFC) is an autosomal dominant condition characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema oophorogenes, eczema, pigmented moles, palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent. Nails may be dystrophic or fast growing. Cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasias have not been reported. The four genes known so far to be associated with CFC syndrome are BRAF, MAP2K1, MAP2K2, and KRAS.
Costello Syndrome (CS) is an autosomal dominant condition sharing features with both NS and CFC. Germline mutations occurring exclusively in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome.
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