Page 44 - Clinical variability in Noonan syndrome with emphasison ear and eye

CHAPTER 3
Introduction
Noonan syndrome (NS), first described by Noonan and Ehmke in 1963 (1), is an autosomal dominant syndrome characterized by facial dysmorphism, short stature and congenital heart defects (2,3). Distinctive other abnormalities of NS include mild learning problems, hearing impairment, hematologic anomalies, cryptorchidism and intrinsic ophthalmic abnormalities. There is a great diversity in the phenotypes. Incidence rates vary from 1:1000 to 1:2500 live births (4,5).
The first gene discovered to be responsible for NS was PTPN11 on chromosome 12q24.1. This gene encodes the nonreceptor-type tyrosine phosphatase SHP-2, which implicates dysfunction of several signal transduction pathways and, therefore, influences various developmental processes. About 50 percent of the patients with NS have a PTPN11 mutation (6). SHP-2 is required for the function of the Ras/mitogen- activated protein kinase (Ras/MAPK) pathway and is essential in the response to growth factors, cell adhesion molecules, cytokines and hormones (7). Mutations in other coding genes of proteins that are associated with function of the Ras/MAPK pathway are also found. KRAS mutations were described in 2006 (8), and SOS1 mutations were discovered in 2007 (9). Since then, studies have described BRAF, RAF1, SHOC2, NRAS, MAP2K1, MAP2K2, SOS2 and RIT1 mutations in NS (10-16).
In clinical reports, the main facial findings of NS are hypertelorism, downslanting palpebral fissures and ptosis (4,17), but few studies with in depth ophthalmologic examinations have been performed. In 1992, a study of 58 patients showed at least one ophthalmological abnormality in 95 percent of the patients (18). In a more recent study, all 35 patients with NS showed at least one abnormality (19). Although ocular abnormalities are described in up to 100% in all Noonan patients (5,18), few studies have reported comprehensively about these features. Complete ophthalmologic examinations for both external and inner ocular abnormalities in NS are rare. The aim of our study is to determine prospectively the full spectrum of ocular manifestations in patients with NS and link the phenotypes to the genotypes.
Patients and Methods
Protocol setup
Twenty-five patients with NS from the Departments of Genetics and Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands, were referred for prospective
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