Noonan Syndrome

From EyeWiki

Disease Entity

Noonan syndrome (NS) is a genetic disorder characterized by unusual facial features, short stature, heart defects and can present with visual loss including optic nerve hypoplasia or cavitary disc anomalies (e.g., optic disc coloboma). Patients may also have strabismus or neurologic manifestations (e.g. Chiari malformation).


The prevalence of NS is unknown. However, a common estimate is between 1 in 1000 to 1 in 2500 live births.[1]

Genetics and pathogenesis

NS is a genetic disorder due to a variant in one of several genes important in the RAS-MAPK pathway. The most commonly detected pathogenic variants are in PTPN11 (about 50% of cases), SOS1 (about 13%), RAF1 (5%), and RIT1 (5%). Other genes such as KRAS, BRAF, LZTR1, and NRAS are less commonly involved.[2] This pathway plays a pivotal role in cellular differentiation and proliferation[3] and therefore has been extensively studied in the setting of cancer genetics. In NS, the underlying pathophysiological mechanism involves dysregulation of the RAS-MAPK signaling, almost always due to a gain-of-function variant in one of the associated genes. A gain-of-function mutation in any of the aforementioned genes can lead to abnormal cellular function in tissues throughout the body, resulting in a complex phenotype which involves multiple organ systems. NS is most commonly an autosomal dominant condition, with about 2/3’s of cases resulting from de novo variants; very few cases show autosomal recessive inheritance. Importantly, NS is associated with advanced paternal age similarly to many other autosomal dominant conditions. Mutations linked to NS which occur during spermatogenesis can provide a selective advantage to the affected sperm but, upon fusion with the egg, ultimately produce a fetus affected by the disorder.[1]

One study showed permanent visual impairment in NS (bilateral best-corrected visual acuity < 0.3) in patients with known mutations in RAF1 and KRAS (listed above) and SHOC2 (not listed above). That same study found no visual impairment in patients with the PTPN11 mutation. The authors reported that no definitive genotype-phenotype correlation could be established with this data because the cohort was too small (n = 105).[3]

Another prospective study of 25 patients with NS also suggests that clinical presentation could be linked to a patient’s specific mutation (i.e. presence of genotype-phenotype correlation). For example, the lowest visual acuity was found in a patient with a BRAF variant and poor vision since infancy due to optic nerve hypoplasia. However, the authors caution that a definitive genotype-phenotype correlation cannot be established until more patients are studied.[4]


Ophthalmic presentation

Key ocular findings in NS are listed below. As noted, visual impairment may be permanent.[3]

Refractive: refractive errors occur in most patients.[1] Examples include myopia, high myopia, hyperopia, high hyperopia, and astigmatism.

External: ptosis, hypertelorism, down slanting palpebral fissures with high-arched eyebrows, epicanthal folds

Anterior Segment: keratoconus, prominent corneal nerves, vivid blue or blue-green irises, posterior embryotoxon, cataract

Neuro-ophthalmologic: strabismus, nystagmus, amblyopia, binocular optic nerve head abnormalities including hypoplasia, excavation, coloboma

Other Presenting Features

As noted above, due to the wide variety of tissues which can be affected by signaling abnormalities in RAS-MAPK, the presentation of NS is highly variable. Important manifestations may include:

Constitutional: Short stature. However children are often born at normal length and ultimately approach the lower limit of normal height as adults.[2]

Cognitive/Psychiatric: Mild intellectual disability, developmental delay, and behavioral anomalies. These behavioral problems may be even more prominent than the characteristic facies, which often receive special attention in NS. However, many patients ultimately function normally as adults.

Neurological: A wide variety of symptoms is possible. Associated with Chiari malformation and hydrocephalus. Sensorineural deafness may occur (although conductive and mixed hearing loss are also possible).

Head: Relative macrocephaly and craniosynostosis may be present.

Characteristic Facies: Findings include high forehead, depressed nasal bridge, and low-set posteriorly rotated ears with fleshy helices. These facies are often most prominent in infancy and childhood and become more subtle by adulthood.[1][3][2]

Jaw: Giant cell tumors (non-malignant) of the jaw during childhood, while rare, are suggestive of NS.

Neck: Webbed or broad neck.

Thorax: Sternal deformities including pectus carinatum involving the superior sternum and pectus excavatum involving the inferior sternum.[5] Widely spaced nipples.[2]

Cardiovascular: Classic finding is pulmonic stenosis often associated with dysplasia. However many other cardiac findings have been described including hypertrophic cardiomyopathy, ASD, and VSD. Lymphatic dysplasia can also occur.[2]

Reproductive: Cryptorchidism in males. Infertility may also occur.

Hematologic: Various findings including elevations in PT/PTT, abnormal platelet count and function.[5]


NS can be diagnosed clinically. There are formal diagnostic criteria which are typically evaluated by a clinical geneticist. Molecular confirmation studies of the pertinent genes may also be pursued.


Due to the complex and highly variable presentation, NS should be managed in a multidisciplinary manner including a clinical geneticist who can help to coordinate the proper care. A comprehensive evaluation by an ophthalmologist is generally recommended at diagnosis with subsequent annual follow-ups.[1][3]


The prognosis in NS varies greatly, ranging from patients who die prenatally to those who live a normal lifespan with few medical complications. However, fortunately, despite developmental difficulties, the majority of patients can ultimately function normally as adults. The data suggests that a diagnosis of hypertrophic cardiomyopathy before age 2 is associated with the highest risk of cardiac death. However further studies are needed to determine overall long-term prognosis.[1]

In terms of ocular prognosis, it appears that the severity of visual findings varies with an individual’s genetic variant. However both of the studies cited above caution against establishing a definitive genotype-phenotype correlation with the data currently available. Therefore further studies are needed to establish ocular prognosis.[3][4]


  1. 1.0 1.1 1.2 1.3 1.4 1.5 Burkitt-Wright, E., & Kerr, B. (2018). NS. In E. TePas (Ed.), UpToDate. Retrieved September 6, 2019, from
  2. 2.0 2.1 2.2 2.3 2.4 Allanson, J. E., & Roberts, A. E. (2019). NS. GeneReviews. Retrieved from
  3. 3.0 3.1 3.2 3.3 3.4 3.5 van Trier, D. C., van der Burgt, I., Draaijer, R. W., Cruysberg, J. R. M., Noordam, C., & Draaisma, J. M. (2018). Ocular findings in NS: a retrospective cohort study of 105 patients. European Journal of Pediatrics, 177(8), 1293–1298.
  4. 4.0 4.1 van Trier, D. C., Vos, A. M. C., Draaijer, R. W., van der Burgt, I., Draaisma, J. M. T., & Cruysberg, J. R. M. (2016). Ocular Manifestations of NS: A Prospective Clinical and Genetic Study of 25 Patients. Ophthalmology, 123(10), 2137–2146.
  5. 5.0 5.1 Bhambhani, V., & Muenke, M. (2014). NS. American Family Physician, 89(Jan 1, 2014), 37–43. Retrieved from
  1. (2019, September 3). NS - Genetics Home Reference - NIH. Retrieved from
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