Page 57 - Clinical variability in Noonan syndrome with emphasison ear and eye

OCULAR MANIFESTATIONS OF NOONAN SYNDROME: A PROSPECTIVE STUDY OF 25 PATIENTS
mutation was reported (29). SHP-2 plays an important role in the Ras/MAPK pathway and is postulated to play a role in the neural crest cell differentiation (29,30). Disruption in this signaling pathway is linked to craniofacial abnormalities and more specific to the development of the anterior segment of the eye (29). Some ocular abnormalities attributed to NS are only described in case reports (31-36), but were not found in our or other cohort studies (18,19,25,26). These ocular abnormalities, including keratoconus (31), colobomas (32,33), spontaneous corneal rupture (34), pupillary block glaucoma caused by anterior dislocation of the lens (35), and acute angle closure induced by pharmacologic mydriasis (36), are probably less common manifestations of NS.
The high prevalence of ocular abnormalities in NS, including amblyogenic factors such as ptosis, strabismus and astigmatism, makes it necessary to perform ocular examinations in the first years of life. Our study shows that patients with NS due to PTPN mutations generally have a good visual prognosis. We speculate that severe visual impairment in NS might be associated with a BRAF mutation, based on our single BRAF mutation patient with poor vision since infancy due to optic nerve hypoplasia. In similar visually impaired NS patients of Lee et al (18), no DNA studies were performed. More recently, hypoplastic or dysplastic optic nerves were found in a significant proportion (9 out of 20) of individuals with BRAF mutation in cardio-facio-cutaneous syndrome (37).
We found that some more extreme variants of the ocular manifestations of NS were associated with different mutations, e.g., most severe ptosis with PTPN11, lowest visual acuity with BRAF, highest number of corneal nerves with SOS1, highest hypertelorism index with KRAS. However, the number of patients is too low to draw conclusions about a possible ocular phenotype-genotype correlation. All patients in the present study showed at least three (range, 3-13; mean, 7) ocular features of NS, including at least one external ocular feature in more than 95 percent of the cases.
In conclusion, NS is a clinical diagnosis with multiple genetic bases, associated with an extensive variety of congenital ocular abnormalities. Ocular features of NS are characterized by one or more developmental anomalies of the eyelids (hypertelorism, epicanthic folds, ptosis, high upper eyelid crease, lower eyelid retraction, incomplete eyelid closure, and abnormal slanting palpebral fissures), associated with other ocular abnormalities in childhood (amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, and posterior embryotoxon).
55
3