Noonan syndrome is an autosomal dominant inherited disorder with a frequency of 1:1,000 – 2,500 live births. The variable spectrum of symptoms includes facial dysmorphia (broad forehead, hypertelorism, low-set ears, eyelids that slop downwards and outwards), proportional dwarfism, pterygium colli (webbed neck), chest deformities, cryptorchidism, mental retardation, a slight tendency to bleeding disorders, and heart defects, usually in the form of pulmonary stenosis or hypertrophic cardiomyopathy. The PTPN11 gene, which codes for a cytoplasmic protein tyrosine phosphatase (SHP-2), is the gene mainly affected in Noonan syndrome. Pathogenic variants in the PTPN11 gene, which almost exclusively lead to amino acid exchanges, are the molecular cause in about 50% of all Noonan patients investigated so far.
Pathogenic variants have currently been identified in several other genes, including the RAS‑ERK-MAP kinase signal transduction in Noonan syndrome. Mutations in the SOS1 (Son of Sevenless) gene were detected in up to 15% of Noonan patients who did not have a mutation in the PTPN11 gene. Pathogenic variants in the RAF1 gene could be identified in about 8% of Noonan patients. Almost all patients with RAF1 mutations show hypertrophic cardiomyopathy. Other genes include RIT1 (approximately 5% of patients) and KRAS (approximately 3% of patients), pathogenic variants here predominantly lead to severe phenotypes.
Pathogenic variants in the genes MAP2K1, MAP2K2 and BRAF are identified less frequently in Noonan syndrome, although these genes are more frequently altered in patients with cardiofaciocutaneous (CFC) syndrome. The incidence of pathogenic BRAF variants in Noonan syndrome is estimated to be 2%. Here, the patients described show neonatal growth retardation, slight cognitive deficits and muscule hypotonia. Even rarer are variants in the NRAS and CBL genes (1%). In addition, other genes described in connection with Noonan syndrome include RASA2, PPP1CB (Noonan syndrome-like disorder with loose anagen hair) and MRAS.
Variants of these genes and the genes MAP2K2, SHOC2, HRAS and NF1 are also found in patients with Noonan syndrome-like diseases, such as CFC syndrome, LEOPARD syndrome, Noonan syndrome-like disorder with juvenile myelomonocytic leukemia (JMML), and neurofibromatosis-Noonan syndrome, among others. Pathogenic variants in the NF1 gene have also been detected in Noonan syndrome patients who do not fulfill the clinical criteria for classic neurofibromatosis (NF).
In about 25% of all patients with Noonan syndrome, no causative variant can be detected in the genes that are currently known.
Motta et al. 2019 Hum Mol Genet, ddz108, doi.org/10.1093/hmg/ ddz108 / Bouchikhi et al. 2016 Int J of Ped and Adol Med 3:133 / Chen et al. 2014, PNAS 111:11473 / Vissers et al. 2014, Eur J Hum Genet doi:10.1038/ejhg.2014.115 / Aoki et al. 2013, Am J Hum Genet, 93:173-180 / Tartaglia et al. 2011, Best Pract Res Clin Endocrinol Metab 25:161 / Tartaglia et al. 2010, Mol Syndromol 1:2 / Cirstea et al. 2010, Nat Genet 42:27 / Sarkozy et al. 2009, Hum Mutat 30:695 / Nava et al. 2007, J Med Genet 44:763 / Razzaque et al. 2007, Nat Genet 39:1013 / Roberts et al. 2007, Nat Genet 39 / Carta et al. 2006, Am J Hum Genet 79: 129 / Schubbert et al. 2006, Nature Genet 38: 331 / Noonan 1968, Am J Dis Child 116:373