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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 underestimated. There is no apparent prevalence in any particular ethnic group.
Several syndromes have overlapping features with NS, including cardiofaciocutaneous (CFC), Costello,
Williams, Aarskog, and multiple lentigines (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
Noonan syndrome and related phenotypes. All of these genes are involved in a common signal
transduction pathway, the Ras-MAPK pathway, which is important for cell growth, differentiation,
senescence, and death. Molecular genetic testing identifies PTPN11 mutations in 50% of individuals.
Mutations in RAF1 are identified in approximately 3% to 17%, SOS1 approximately 10%, and KRAS
less than 5% of affected individuals. NS can be sporadic and due to new mutations; however, an
affected parent can be recognized in up to 30% to 75% of families. The PTPN11 gene comprises 15
exons and encodes the Src homology-2 domain-containing phosphatase (SHP-2), a widely expressed
extracellular protein. SHP-2 is a key molecule in the cellular response to growth factors, hormones,
cytokines, and cell adhesion molecules. It is required in several intracellular signal transduction
pathways that control diverse developmental processes. Most reported mutations in PTPN11 are
missense mutations, although small deletions as well as whole gene duplications have been reported to
cause NS. Most mutations associated with NS destabilize the catalytically inactive conformation of the
protein, causing a gain of function of SHP-2. 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 (HCM) is commonly associated with RAF1 mutations but
rarely associated with PTPN11. Mutations in PTPN11 have also been identified in individuals with a
variety of other disorders that overlap phenotypically with NS. PTPN11 has been associated with
LEOPARD syndrome, an autosomal dominant disorder sharing several clinical features with NS and
characterized by multiple lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects. Two
mutations, p.Tyr279Cys and p.Thr468Met, represent the most common PTPN11 mutations found in
LEOPARD syndrome, although other mutations have been described. Mutations in PTPN11 have also
been identified in patients who have clinical features of NS along with features of CFC syndrome, a
condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and
severe psychomotor developmental delay. Genetic testing for PTPN11 mutations can allow for the
confirmation of 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.
Useful For: Genetic testing of individuals at risk for a known PTPN11
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Tartaglia M, Mehler E, Goldberg R, et al: Mutations in PTPN11, encoding
the protein tyrosine phophatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468 2. Tartaglia
M, Kalidas K, Shaw A, et al: PTPN11 mutations in Noonan syndrome: molecular spectrum,
genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002;70:1555-1563 3.
Musante L, Kehl H, Majewski F, et al: Spectrum of mutations in PTPN11 and genotype-phenotype
correlation in 96 patients with Noonan syndrome and 5 patients with cardio-facio-cutaneous syndrome.
Eur J Hum Genet 2002;11:201-206 4. Kontaridis M, Swanson K, David F, et al: PTPN11 (Shp2)
mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem
2006;281(10):6785-6792 5. Cohen MM, Gorlin RJ: Noonan-like/multiple giant cell lesion syndrome. Am
J Med Genet 1991;40:159 6. Lee JS, Tartaglia M, Gelb BD, et al: Phenotypic and genotypic
characterization of Noonan-like/multiple giant cell lesion syndrome. J Med Genet 2005;42(2):e11 7.
Tartaglia M, Gelb B, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin
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