Etiology

The syndrome is typically caused by gain-of-function (activating) mutations in multiple genes in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Some of the genes implicated include:

  • PTPN11: mutations of this gene are present in 50% to 60% of patients with NS.[11][12] The mutations correlate with pulmonary stenosis, short stature, easy bruising with factor VIII deficiency, pectus deformity, and typical face.[11][12][14][15] One mutation (73Ile) is found in almost half of children with NS and juvenile myelomonocytic leukemia.[2]

  • SOS1: second major gene for NS. Mutations of this gene are present in 10% to 15% of patients with NS.[3][4] Mutations in the gene correlate with more ectodermal features and a more normal growth and cognitive profile.

  • RAF1: mutations of this gene are present in approximately 5% of patients with NS.[5][6] They are strongly associated with hypertrophic cardiomyopathy.

  • KRAS: these gene mutations are rare and found in approximately 1% of cases.[7][16] They are linked with a greater likelihood and severity of cognitive impairment.[7][16][17]

  • NRAS: sequence analysis of this gene has revealed a mutation in just a small group of individuals.[8]

  • BRAF and MAP2K1: mutations in these genes are typically found in individuals with cardio-facio-cutaneous syndrome. However, about 2% of individuals described as having NS have been reported to have a mutation in 1 of these 2 genes.[9][10]

  • SHOC2: mutations of SHOC2 were identified in individuals with a Noonan phenotype with loose anagen hair.[18]

  • CBL: heterozygous mutations in CBL were identified in a small number of individuals with a Noonan phenotype with variable expressivity.[19]

  • RIT1: gain-of-function mutations in RIT1 have been reported in 9% of individuals with Noonan syndrome that did not have detectable mutations in the above listed genes.[20]

  • RASA2: loss-of-function mutation has been reported in small numbers of individuals with Noonan syndrome in one study.[21]

  • SOS2 and LZTR1: results from one cohort study suggest that approximately 3% of all patients with Noonan syndrome have mutations in these two genes.[22]

  • PPP1CB: missense mutations observed in four patients in one study show clinical overlap with individuals with SHOC2 mutations.[23]

Pathophysiology

Several hypotheses have been proposed to explain some of the manifestations of NS.[24] One implicates lymphedema, possibly secondary to hypoplasia of jugular venous and lymphatic channels or delayed connections between the two. The subsequent formation of a cystic hygroma (cystic lymphatic lesion) may result in nuchal skin redundancy and disruption of tissue migration and organ placement. This may explain many of the key physical features, which include down-slanting palpebral fissures (separation between the upper and lower eyelids); low-set, posteriorly angulated ears; prominent trapezius; pterygium colli (webbed neck); widely spaced nipples; cryptorchidism (undescended testes); and abnormal dermatoglyphs (fingerprints).[24] It has been proposed that lymphatic obstruction may reduce right-sided cardiac blood flow and cause pulmonic stenosis. Of note, certain craniofacial abnormalities such as hypertelorism (increased distance between the eyes) are not readily explained solely as a consequence of lymphatic dysfunction, and other mechanisms may contribute to the phenotype. 

Ras/MAPK signaling is involved in the development of the pulmonary, aortic, and mitral valves.[24] Therefore, increased signaling in NS may explain the development of a thickened, dysplastic valve. In addition, the protein SHP2, which is encoded by the gene PTPN11, normally down-regulates growth hormone receptor signaling; in NS, gain-of-function mutations in PTPN11 will enhance this effect, causing short stature.[25][26] It is still unclear how up-regulation of the Ras/MAPK pathway contributes to the remainder of the phenotype.

A range of autoantibodies and associated autoimmune diseases have been reported in people with Noonan syndrome or related disorders, which suggest the involvement of different genes of the Ras/MAPK pathway in immunity.[27] Conditions reported include systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, primary antiphospholipid syndrome, autoimmune hepatitis, vitiligo, and autoimmune thyroiditis.[27]

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