Page 67 - Clinical variability in Noonan syndrome with emphasison ear and eye

OCULAR FINDINGS IN NOONAN SYNDROME: A RETROSPECTIVE STUDY OF 105 PATIENTS
strabismus. In the prospective study, we had 1 visually impaired patient (20). This patient had NS due to a BRAF mutation. In this cohort, we show visually impaired patients with a RAF1, SHOC2, or KRAS mutation. It is remarkable that in 5 patients with NS (with loose anagen hair) due to a SHOC2 mutation, 2 patients are visually impaired. In the 4 patients with a KRAS mutation, also 2 patients are visually impaired. The cohort is too small for genotype-phenotype correlations but it shows that visual impairment is found in patients with NS due to a SHOC2, KRAS, and RAF1 mutation. In the 50 PTPN11- positive patients, no visual impairment is found. In 2 patients with NS due to a PTPN11mutation, keratoconus is found and the patient with iris coloboma also has a PTPN11 mutation. Keratoconus in NS is described in literature in two case reports (2,7), iris coloboma is described two times (3,6) and cataract is also described in a few patients with NS (5,8).
The most frequent external features, are in accordance with the NS cohorts described in literature (1,8,10,12,20), including hypertelorism, ptosis, strabismus, downslanting palpebral fissures, and epicanthic folds. The external features are important for the clinical diagnosis of NS regarding facial characteristics. These external features/ periorbital findings are mostly diagnosed by pediatricians and clinical geneticists.
Although it is strongly recommended to do a comprehensive ocular examination in all NS patients, still 9 patients never went to an ophthalmologist. In 3 other patients with ocular anomalies and reduced vision, there was a delay of many years before they were referred to an ophthalmologist. In the international NS guidelines (9,13,15), referral for an ophthalmological examination after diagnosing NS is recommended for all patients. Examination by an orthoptist and ophthalmologist is also recommended for patients with a suspicion of NS. Repeat the ophthalmological examination in children every 2 years or as advised by the ophthalmologist based on the pathology and the expertise of the ophthalmologist and orthoptist. The high prevalence of ophthalmological anomalies in NS including amblyogenic factors (ptosis, strabismus, astigmatism) makes an early ophthalmological examination necessary (20). For a successful treatment of amblyopia, it should be diagnosed in time. Some ocular abnormalities in NS patients can occur or increase later in life, for example the keratoconus as described above. The guidelines are published in 2010 and 2013, and that might be an explanation why older NS patients were not referred to an ophthalmological clinic after diagnosing Noonan syndrome. Another reason might be that other symptoms, sometimes life threatening, require more attention early in life (including cardiac abnormalities and feeding difficulties) and therefore vision and other ocular abnormalities do not have priority.
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