Noonan Syndrome and Related Disorders: A Review of Clinical Features and Mutations in Genes of the RAS/MAPK Pathway

Abstract

Noonan syndrome (NS) is one of the most common syndromes transmitted by a mendelian mode. In recent years, germline mutations that affect components of the RAS-MAPK (mitogen-activated protein kinase) pathway were shown to be involved in the pathogenesis of NS and four rare syndromes with clinical features overlapping with NS: Leopard syndrome, cardio-facio-cutaneous syndrome, Costello syndrome and neurofibromatosis type 1. Several hormones act through receptors that stimulate the RAS-MAPK pathway, and therefore, NS and related disorders represent a remarkable opportunity to study the implication of the RAS-MAPK pathway in different endocrine systems. Additionally, children with NS frequently are referred to the endocrinologist because of short stature, delayed puberty and/or undescended testes in males. In this paper, we review the diagnostic, clinical and molecular aspects of NS and NS-related disorders.

Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype

“…This protein participates in a wide variety of intracellular signal cascades elicited by a number of growth factors, cytokines and hormones, and is required in several developmental processes (Tartaglia et al, 2001(Tartaglia et al, , 2002. Mutations in the SOS1-, RAF1-, KRAS-, BRAF-, MAP2K1/2-, NRASand SHOC2-gene have been described to account for a small percentage of Noonan syndrome cases (Jorge et al, 2009). The above-mentioned genes, especially mutations in the RAS/MAPK pathway, are not only involved in the pathogenesis of Noonan syndrome but also in four syndromes with clinical features overlapping with Noonan syndrome; Leopard syndrome, Cardiofacio-cutaneous syndrome, Costello syndrome and Neurofibromatosis type 1 (Schubbert et al, 2007).…”

Giant Cell Lesions in Noonan Syndrome: Case Report and Review of The Literature

“…Although mental retardation and delay on acquisition of developmental milestones are considered usual for patients with NS, our patient showed normal intellect [11]. Coagulation tests of the patient presented here were within normal limits, but bleeding diathesis is well documented in NS patients and involves either platelet dysfunction or factor XI or XII deficiencies [12]. This feature should be considered in the surgical procedures of the syndromic patients.…”

“…Furthermore, giant cell lesions from both NS and cherubism are histologically and immunohistochemically indistinguishable. However, while cherubism is caused by mutations in SH3BP2 gene, NS is genetically heterogeneous and caused by mutations in PTPN11, KRAS, RAF1, MEK1 or SOS1 [12]. PTPN11 mutations are present in 29-60% of cases, and genetic testing should initially include screening of exons 3, 8 and 13, in which 75-80% of defects reside [9].…”

C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome

“…Indeed, all five samples carried heterozygous mutations in amino acid 12 (G12A, G12S; Table 1), which have previously been described as HRAS gain-of-function mutations in Costello syndrome, as well as various cancers. 8,10,12,13,15,16,37 We next prepared mRNA from fibroblasts from the five Costello syndrome cell lines, as well as two different unaffected individuals (normal 1 and 2), and determined C4ST-1 mRNA levels by qRT-PCR (Figure 1d). Although both normal samples showed high levels of C4ST-1 expression, C4ST-1 mRNA levels were severely reduced in all Costello syndrome samples, with lowest levels observed in C7669 and C563 cells (Figure 1d).…”