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Noonan syndrome (NS) is an autosomal dominant disorder of variable expressivity characterized by short stature, congenital heart defects, characteristic facial dysmorphology, unusual chest shape, developmental delay of varying degree, cryptorchidism, and coagulation defects, among other features. Heart defects include pulmonary valve stenosis (20%-50%), hypertrophic cardiomyopathy (20%-30%), atrial septal defects (6%-10%), ventricular septal defects (approximately 5%), and patent ductus arteriosus (approximately 3%). Facial features, which tend to change with age, may include hypertelorism, downward-slanting eyes, epicanthal folds, and low-set and posteriorly rotated ears. Mild mental retardation is seen in up to one third of adults.
The incidence of NS is estimated to be between 1 in 1,000 and 1 in 2,500, although subtle expression in adulthood may cause this number to be an underestimate. There is no apparent prevalence in any particular ethnic group. Several syndromes have overlapping features with NS, including cardiofaciocutaneous, Costello, and LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and deafness) syndromes.
NS is genetically heterogeneous, with 4 genes currently associated with the majority of cases: PTPN11, RAF1, SOS1, and KRAS. Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes. All of these genes are involved in a common signal transduction pathway, the Ras-mitogen-activated protein kinase (MAPK) pathway, which is important for cell growth, differentiation, senescence, and death. Molecular genetic testing identifies PTPN11 mutations in 50% of individuals with NS. Mutations in RAF1 are identified in approximately 3% to 17%, SOS1 approximately 10%, and KRAS <5% of affected individuals. NS can be sporadic and due to new mutations; however, an affected parent can be recognized in 30% to 75% of families.
Some studies have shown that there is a genotype-phenotype correlation associated with NS. An analysis of a large cohort of individuals with NS has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, while hypertrophic cardiomyopathy is commonly associated with RAF1 mutations, but rarely associated with PTPN11.
Mutations in the genes associated with NS have also been identified in individuals with a variety of other disorders that overlap phenotypically with NS. PTPN11 mutations have been associated with LEOPARD syndrome, an autosomal dominant disorder sharing several clinical features with NS, characterized by lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects. Mutations in PTPN11 have also been identified in patients who have clinical features of NS and features of cardiofaciocutaneous syndrome, a condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. RAF1 mutations have been associated with LEOPARD syndrome as well as 1 case of nonsyndromic hypertrophic cardiomyopathy.(1) KRAS has been associated with cardiofaciocutaneous and Costello syndrome, which is characterized by coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, failure to thrive, cardiac anomalies, and developmental disability.
Identification of PTPN11, RAF1, SOS1, and KRAS mutations may confirm a suspected genetic disease. Confirmation of NS or other associated phenotypes allows for proper treatment and management of the disease and preconception, prenatal, and family counseling.
Aiding in the diagnosis of Noonan syndrome and related phenotypes such as LEOPARD syndrome
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(2) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Absence of a mutation does not preclude the diagnosis of Noonan syndrome or another related disorder. Additional genes not tested by this assay known to be involved in Noonan syndrome and related phenotypes include NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL.
This method will not detect mutations that occur in the introns (except in the splicing regions) and regulatory regions of the gene and large rearrangement-type mutations.
Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of appropriate family members may be useful to determine pathogenicity of the alteration.
An interpretive report will be provided.
1. Pandit B, Sarkozy A, Pennacchio L, et al: Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007;39:1007-1012
2. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300
3. Allanson J: Noonan syndrome. Am J Med Genet Part C 2007;145C:274-279
4. Tartaglia M, Mehler E, Goldberg R, et al: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468
5. Roberts A, Araki T, Swanson K, et al: Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007;39(1):70-74
6. Schubbert S, Zenker M, Rowe S, et al: Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006;38(3):331-336
7. Nystrom A-M, Ekvall S, Berglund E, et al: Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet 2008;45:500-506
8. Tartaglia M, Gelb B, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011;25:161-179