Page 89 - Clinical variability in Noonan syndrome with emphasison ear and eye

COCHLEAR IMPLANTATION IN NOONAN SYNDROME AND NOONAN SYNDROME WITH MULTIPLE LENTIGINES
Introduction
Germline mutations in the PTPN11 gene can cause Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML). These two developmental disorders have numerous shared phenotypic features. PTPN11 encodes the non-receptor protein tyrosine phosphatase (SHP-2) (1). NS and NSML are genetically related allelic disorders. Mutations that cause NS and NSML modify genes encoding proteins that play a role in the RAS-MAPK pathway, leading to pathway disorders. The RAS-MARK pathway is an important signal transduction pathway, through which extracellular ligands (growth factors, cytokines, and hormones) stimulate cell proliferation, differentiation, survival and metabolism (2).
NS is an autosomal dominant congenital disorder with an estimated incidence of 1 in 1000-2500 live births (3,4) The syndrome is named after the pediatric cardiologist Dr. Jacqueline Noonan. NS is characterized by typical craniofacial dysmorphic features (broad forehead, hypertelorism, down-slanting palpebral fissures, and low set, posteriorly rotated ears), short stature, and congenital heart defects, including pulmonary stenosis, as the most frequent cardiac abnormality (5,6). The phenotype is variable. Before 2001, the diagnosis of NS was only based on phenotypic features. Genetic techniques have recently emerged, making it possible to identify the responsible mutations in most patients. Nevertheless, NS is a clinical diagnosis in approximately 25% of cases. Mutations in different genes can cause NS, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, CBL MAP2K1, A2ML1, SOS2 and RIT1 (2,7,8). In approximately 50% of the cases, NS is caused by a missense mutation in the PTPN11 gene on the chromosomal band 12Q24.1 (9-11).
NSML is a rare autosomal dominant congenital disorder with a high penetrance and markedly variable expression. Approximately 200 patients have been reported worldwide, but the real incidence of NSML has not been assessed (12). NSML was first reported by Zeisler and Becker in 1936 in a 24-year-old woman with lentigines (increasing in number), pectus carinatum, hypertelorism and prognathism (12). NSML was formerly called LEOPARD, as result of the large overlap with NS, and it is currently called NS with multiple lentigines (13). In 1969, the acronym LEOPARD (lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness), which comprised the major features, was conceived by Dr. R. Gorlin and Dr. M. Blaw (14). The diagnosis of NSML is made on clinical grounds based on the major features. NSML is allelic with NS and is caused by different missense mutations in the corresponding genes. PTPN11, BRAF and RAF1 are known to be associated with NSML (15).
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