There were 128 patients who gave permission for the use of their data. In 14 patients, no ophthalmological data were available and 9 of 128 patients (7%) were excluded because they never visited an ophthalmologist. A total of 105 patients were included and 68 of them were younger than 18 years old. The median age of the cohort was 12 years, with a range between 1 and 60 years. Genetic examinations showed a causative mutation for NS in 78 patients.
The ocular features and gene mutations of the 105 NS patients are shown in Table 1. Seven patients were visually impaired, defined as binocular best-corrected visual acuity (BCVA) lower than 0.3, mainly attributable to binocular optic nerve abnormalities and manifest nystagmus These patients had a mutation in the RAF1 gene (1 patient), SHOC2 gene (2 patients), or KRAS gene (2 patients); in 1 patient, no mutation was identified after genetic testing and another patient had no genetic analysis. These 7 patients are shown comprehensively in Table 2. Amblyopia, defined as visual loss caused by visual deprivation (e.g., by strabismus, refractive errors, cataract, or ptosis) in childhood, was reported in 28 patients.
Refractive errors, defined as spherical equivalent of ametropia (SEA) of one diopter or more, showed myopia (25 patients), hyperopia (39 patients), and astigmatism (35 patients). High refractive errors, defined as 5 diopters or more, were found for myopia in 5 patients, for hyperopia in 2 patients, and for astigmatism in 3 patients, mainly associated with a causative PTPN11 mutation.
In 3 patients with a delay in first presentation to an ophthalmologist, ocular abnormalities were found. All 3 of them were diagnosed with Noonan syndrome early in childhood. They were referred to an ophthalmologist for the first time at the ages of 17 to 20 years. One of them was diagnosed with visual impairment due to congenital optic nerve hypoplasia and the other 2 were diagnosed with high corneal astigmatism resulting in keratoconus. In retrospect, visual complaints were noticed earlier in childhood.
External ocular features were frequently found without ophthalmological examination, mostly described by pediatricians and clinical geneticists. The findings included hypertelorism (63 patients), ptosis (55 patients), and downslanting palpebral fissures (39 patients). Other ophthalmological abnormalities included strabismus (40 patients) and nystagmus (16 patients). Anterior segment abnormalities included keratoconus (4 patients), different types and densities of cataract (3 patients), and posterior embryotoxon (2 patients). The posterior ocular segment showed abnormalities of the optic nerve head (ONH), including ONH excavation (8 patients), ONH coloboma (1 patient), ONH hypoplasia (1 patient), and ANH paleness (8 patients) diagnosed as optic nerve atrophy in 5 of them.
In 50 patients, a PTPN11 mutation was found with genetic testing. These patients were diagnosed with ocular manifestations in the different categories including refractive errors, external ocular features, ocular alignment and motility, and abnormalities in the anterior and posterior ocular segment. No visual impairment was found in the patients with a PTPN11 mutation. In the NS patients due to a SOS1 mutation, the most frequent ocular findings were hypertelorism and ptosis. We also found prominent corneal nerves. In the group with NS due to a RAF1 mutation, we found 1 patient with a unilateral exudative retinopathy (Coats disease).