Noonan syndrome represents one of the most common dysmorphic disorders with an incidence between 1 in 1000 to 1 in 2500 live births. The most characteristic features of this syndrome are craniofacial dysmorphy, short stature, cardiovascular defects, bone and skeletal defects, as well as delayed puberty and cryptorchidism in males.
Noonan syndrome has a genetic background with the autosomal dominant pattern of inheritance. It belongs to the group of the RAS-opathies, which means that this condition arises as a result of mutations in the genes encoding proteins of RAS/MAPK signaling pathway responsible for cell proliferation and differentiation. Therefore the molecular analysis of RAS/MAPK genes is recommended as a useful tool in clinical differentiation of the disease.
Genes implicated in the disorder
The RAS-mitogen activated protein kinase (RAS-MAPK) signaling pathway is responsible for the signal transduction from the outer cell membrane to the nucleus. Proteins that interact with each other and lead to their phosphorylation and activation are crucial constituents. The pathway is activated by specific growth factors (such as the epidermal growth factor, insulin-like growth factor or the fibroblast growth factor), hormones and cytokines.
All the genes that have a role in Noonan syndrome encode proteins integral to this pathway, and mutations causing the disease usually enhance signal flow through this pathway. At least eight genes that are pivotal for the RAS–MAPK signaling pathway cause Noonan syndrome or closely related conditions (PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, BRAF and CBL).
Missense, gain-of-function mutations in the PTPN11 gene, which encodes the Src homology 2 (SH2) that contains protein tyrosine phsophatase SHP-2, account for approximately 50% of all cases of Noonan syndrome. The phosphotyrosine phosphatase domains of SHP2 are involved in switching the protein between inactive and active conformations, and mutations usually perturb established equilibrium, resulting in a constitutive or prolonged activation of the protein.
The most habitual mutation of PTPN11 that results in this syndrome is the transition from adenosine to guanine at nucleotide 922. It accounts for 25% of all PTPN11 mutations and leads to a substitution of asparagine with aspartic acid. Cardiovascular anomalies and hematologic abnormalities are predominantly found in patients with Noonan syndrome that carry this mutation.
Mutations in SOS1, which is a RAS-specific guanine nucleotide exchange factor that catalyzes the release of GDP from RAS, occurs in approximately 10% of the patients. SOS1-associated Noonan syndrome typically has a higher prevalence of ectodermal abnormalities, but stature if often not so short and there is less intellectual disability and atrial septal defects when compared to PTPN11-associated Noonan syndrome.
A mutation in the RAF1 gene (a member of a small family of serine-threonine kinases) accounts for between 5-10% of cases. Defects in the KRAS proto-oncogene account for approximately 2% of cases and generally confer milder gain-of-function effects. Other aforementioned genes are very rarely implicated in the disease, and it is estimated that no specific genetic mutation can be found in 20% of all cases of Noonan syndrome.
Pattern of inheritance
Noonan syndrome is an autosomal dominant single-gene disorder, which means that an affected individual has a 50% chance to transmit the abnormal gene to each of his or her children. Between 14 and 75% of the affected offspring will have an affected parent, with a predominance of maternal transmission. There is also evidence for a rare autosomal recessive form of disease.
This syndrome can occur on a sporadic basis as well, with de novo PTPN11 mutations of paternal origin. These mutations can be found in 59% of the familial cases and in 37% of the sporadic cases. Noonan syndrome in patients with such mutations is more often associated with pulmonary stenosis or atrial septal defect, bleeding diathesis and juvenile myelomonocytic leukemia.
Due to the discreet expression of phenotypic features in adults with Noonan syndrome, only adequate DNA analysis can eventually verify the diagnosis when this disorder is suspected clinically. Hence both a meticulous analysis of pedigree data and a thorough evaluation of the phenotype of both parents are indicated, with simultaneous molecular testing of all the family members to confirm or exclude the presence of mutation in the relatives.