Page 75 - Clinical variability in Noonan syndrome with emphasison ear and eye

EXTERNAL EAR ANOMALIES AND HEARING IMPAIRMENT IN NOONAN SYNDROME
Introduction
Noonan Syndrome (NS) was first described by Noonan and Ehmke in 1963 (1). A broad spectrum of features is seen and multiple abnormalities are characterizing NS. Common features include congenital heart anomalies, short stature and facial dysmorphism consisting of hypertelorism, short neck, low set ears and downslanting palpebral fissures. Other characteristics comprise chest deformity, cryptorchidism, learning difficulties and hearing impairment (HI) (2). NS is an autosomal dominant disorder with an estimated incidence between 1:1000 and 1:2500 live births (2).
In the literature there are several studies describing NS patients with HI. HI is not mentioned as one of the clinical criteria for the diagnosis of NS (3). However, it has been linked to NS since 1976 when it was described by Cremers (4). External ear anomalies are described as well, mainly as part of facial dysmorphism (2,5). Sharland et al. described HI in 40% of the 146 NS patients (6). Qiu et al. also studied data of HI in Noonan patients and they found sensorineural hearing impairment (SNHI) in 50% of the 40 ears without describing further information of the inclusion of NS patients (7).
In 2001 the first gene responsible for NS was discovered and mapped on chromosome 12q24.1 (8). An activating missense mutation in the PTPN11 gene accounts for approximately 50% of the Noonan patients. PTPN11 influences the RAS-MAPK pathway. Also other genes of this pathway are involved in NS. KRAS was described in 2006 (9), SOS1 in 2007 (10) and also other genes such as BRAF (11), RAF1 (12) and SHOC2 (13) are involved in NS.
In this study, we present data on hearing impairment, external ear anomalies, and molecular findings of 97 NS patients. We will compare our results with those in the literature and we will give an overview of the genotype-phenotype correlations for HI. To the best of our knowledge, this is the first time a large cohort of NS with these symptoms is presented with genotype-phenotype correlations.
Methods and patients
We collected retrospective data from 97 NS patients, 49 of them were males and 48 females. All these patients were seen in our medical center at the human genetic department and NS was clinically diagnosed by using the validated criteria of van der
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