Page 63 - Clinical variability in Noonan syndrome with emphasison ear and eye

OCULAR FINDINGS IN NOONAN SYNDROME: A RETROSPECTIVE STUDY OF 105 PATIENTS
Introduction
Noonan syndrome (NS) is an autosomal dominant disorder with a great variety in phenotype. Characteristics described with high frequency include short stature, congenital heart defects, face dysmorphology, and mild developmental delay. Other manifestations are cryptorchidism in males, chest wall abnormalities and ophthalmological abnormalities (19). NS belongs to the Rasopathies. Different mutations in coding genes leading to dysregulation of the Ras/mitogen-activated protein kinase pathway can cause NS. The first gene discovered was PTPN11 on chromosome 12q24.1 (17). Gain-of-function mutations in PTPN11 are found in approximately 50% of the NS patients (18). At the moment, more than 14 genes responsible for NS are elucidated, most frequent PTPN11 (50%), SOS1 (10–13%), and other less frequent genes including KRAS, RAF1, and RIT1 (4,11,14,16). Facial dysmorphology is one of the major used clinical criteria for NS (19) and external ocular abnormalities (including hypertelorism, epicanthic folds, ptosis, and downslanting palpebral fissures) play an important role in facial characteristics. Besides the external ocular manifestations, other ocular manifestations occur and the results of ophthalmic examinations in NS are described briefly. The first cohort is described in 1992 with ophthalmological examinations in 58 patients (8). Few other studies report on ocular examinations (1,10,12) and the most recent study is a prospective ocular examination performed in our tertiary referral center in 25 patients that shows at least three ocular features in more than 95% of NS patients (20). In the international NS clinical management guidelines, referral to an ophthalmologist for assessment at the point of diagnosis is recommended (9,13,15). To give a more extensive overview of ophthalmological abnormalities and ocular problems in NS patients, we collected ophthalmological data in a large retrospective cohort.
Materials and methods
We collected retrospective data in a NS population at the Radboud University Medical Center in the Netherlands. All patients were clinically diagnosed, fulfilling the Van der Burgt criteria (19). In total, 201 patients were asked for informed consent and 128 responded and gave permission for the use of their data. All available ophthalmological, pediatric, and genetic data of the participating patients were collected and used. Children were defined as younger than 18 years old. Patients without available data or who never visited an ophthalmologist/pediatrician were excluded.
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