Page 106 - Clinical variability in Noonan syndrome with emphasison ear and eye

CHAPTER 7
proteins can express in different organs and tissues makes it even more interesting (9). Noonan syndrome and other RASopathies have mutations in different core components of the RAS-MAPK pathway, but the individual patients show many of the same developmental defects, including cardiac anomalies, facial dysmorphology and skin abnormalities. Clinical trials for improving the cognitive functioning in children with a RASopathy, did not show a significant change. Also other treatments, for example MEK inhibitors, did not clearly improved the symptoms in RASopathies (9,10). This all confirms the complexity and difficulties of the RASopathies.
Mutation in SOS1 gene
In Chapter 2 we present a large Noonan syndrome family due to a SOS1 mutation. The phenotype shows a broad spectrum of characteristics, ranging from only few suggestive features to typical Noonan syndrome characteristics. The typical characteristics were mostly found in the youngest generation of the family. Our study confirms large intra-familial variability in clinical characteristics in the same genetically confirmed SOS1 mutation. This facial variability might be due to a changing phenotype with ages, which is also suggested in the literature (11). Another explanation for the variety within one family might be epigenetic mechanisms. In 2015, three family members with a SOS1 mutation with phenotypical variation were described. Research was conducted on allelic expressions and a different allelic expression of SOS1 in healthy individuals was found (12). They hypothesized that epigenetic mechanisms might be responsible for the variable clinical expression of SOS1 pathogenic alleles (12). Furthermore it is suggested that non-coding regions can be involved in the aetiology of diseases (13).
Ocular manifestations
Ocular abnormalities are described in up to 100% of the Noonan syndrome patients (14,15), but few studies have reported comprehensively about the ocular features. Complete ophthalmologic examinations for both external and inner ocular manifestations are rare. In Chapter 3 we describe the complete ophthalmologic examination we performed prospectively in 25 Noonan syndrome patients. External ocular abnormalities are an important part of the facial characteristics and include hypertelorism, ptosis, epicanthic folds and downward slanting palpebral fissures. Other frequently and remarkably found ocular manifestations include refractive errors, amblyopia, strabismus and abnormal stereopsis. Abnormalities in the anterior segment include prominent corneal nerves and posterior embryotoxon and in the posterior segment include optic nerve head excavation. Our prospective observational study shows the variety of multiple ocular manifestations in Noonan syndrome. We included
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