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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 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 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-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 less than 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.
The PTPN11 gene comprises 15 exons and encodes the Src homology-2 domain-containing phosphatase (SHP-2), a widely expressed extra-cellular 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.
Aiding in the diagnosis of PTPN11-associated Noonan syndrome and LEOPARD syndrome
An interpretive report will be provided.
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.
PTPN11 testing for a specific familial variant (PT1K / PTPN11 Gene, Known Mutation, Blood) is available for individuals who are at risk for a PTPN11 variant that has been previously identified in the family.
Absence of a mutation does not preclude the diagnosis of Noonan syndrome or another PTPN11-related disorder unless a specific mutation has already been identified in an affected family member.
This method will not detect mutations that occur deep 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.
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