Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

Abstract

Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

Growth references for Japanese individuals with Noonan syndrome

“…There is increasing evidence that germline mutations in the genes involved in the Ras/mitogen-activated protein kinase signaling pathway cause NS and Noonan-related syndrome (9). While mutations in such genes were identified in ~60-70% of patients with NS phenotype (10,11), the diagnosis of NS remains clinical (2,12). Several scoring systems are currently available to aid in the diagnostic process, with the one developed by van der Burgt et al (13) in 1994 being the most widely used.…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…Noonan syndrome (NS) is an autosomal‐dominant disease characterized by distinctive facial dysmorphism, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), short stature, webbed neck, cryptorchidism, skeletal abnormalities, and hematologic disorders1, 2 Recent evidence revealed that gain‐of‐function germline mutations affecting components of the RAS‐mitogen‐activated protein kinase (MAPK) signaling pathways are involved in NS. PTPN11 mutations (40%‐50%), SOS1 mutations (10%‐20%), RAF1 (3%‐17%), and RIT1 (9%) are common, followed by KRAS , NRAS , BRAF , SHOC2 , MAP2K1 , CBL, LZTR1, SOS2, RRAS, and CDC42 1, 2, 3, 4, 5, 6, 7, 8, 9…”

“…PTPN11 mutations (40%‐50%), SOS1 mutations (10%‐20%), RAF1 (3%‐17%), and RIT1 (9%) are common, followed by KRAS , NRAS , BRAF , SHOC2 , MAP2K1 , CBL, LZTR1, SOS2, RRAS, and CDC42 1, 2, 3, 4, 5, 6, 7, 8, 9…”

Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family

“…NS is a clinically heterogeneous disorder predominantly characterized by variable developmental delay, short stature, dysmorphic facial features, skeletal abnormalities, congenital heart defects, neck abnormalities, chest deformities and predisposition to myeloproliferative disease; mild mental retardation, bleeding diathesis, lymphedema, hearing difficulty and cryptorchidism are also occasionally observed in affected individuals. 1 The diagnosis is carried out by a clinical-based scoring system, comprising major and minor criteria. 2 NS is numbered among the RASopathies, a class of developmental disorders caused by germline mutations in genes encoding components or regulators of the RAS/MAPK pathway.…”

“…4 Compared with the other RASopathies, NS is characterized by a significant locus heterogeneity caused by the involvement of the mutated version of several RAS/MAPK pathway genes: protein tyrosine phosphatase, non-receptor type 11 (PTPN11), son of sevenless 1 (SOS1) and RAF1 in~60-70% of NS cases, and more rarely NRAS, KRAS, BRAF, MEK, SHOC2, CBL, RIT1 and RRAS genes. 1,[5][6][7] Both the genetics and the allelic heterogeneity can explain only in part the variable and complex NS phenotype. Furthermore, despite the identification of several NS genes, for~30% of patients the pathogenetic mutation remains unknown and additional NS genes remain to be identified.…”