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A 3-year-old boy is brought to see his pediatrician for a health maintenance visit. During the exam, the pediatrician notes that the child’s face lacks expression, has a short neck with excessive skin, a low hairline, low set ears, and a short broad nose (Figure 226-1). The child is appropriate for weight but his height is well below the third percentile. An audible systolic ejection murmur is heard. The pediatrician refers the child to a pediatric cardiologist who makes the diagnosis of pulmonic stenosis from physical exam and echocardiogram. Based on these findings, the pediatrician and cardiologist make a clinical diagnosis of Noonan syndrome, which is confirmed by genetic testing. A multidisciplinary approach to the child’s care is planned.
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Noonan syndrome is an autosomal dominant, variably expressed, multisystem disorder characterized by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS–MAPK pathway, leading to pathway dysregulation.
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First described by Jacqueline Noonan, who reported nine patients with pulmonary stenosis, short stature, chest deformities, and mild developmental delay.1,2
Estimated prevalence is 1 in 1000 to 2500.2
Although this syndrome was first described in males who had the Turner syndrome phenotype, it is now recognized in females as well.
Autosomal dominant condition with complete penetrance but variable expressivity.
Congenital heart disease present in 80 to 90 percent of patients.
After trisomy 21, Noonan syndrome is the second most common syndromic cause of congenital heart disease.
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Etiology and Pathophysiology
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Autosomal dominant inheritance.
Eight genes in the RAS–MAPK signaling pathway cause Noonan syndrome or closely related conditions (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, and CBL).
The RAS–MAPK pathway is a well-studied, widely important signal transduction pathway through which extracellular ligands—such as some growth factors, cytokines, and hormones—stimulate cell proliferation, differentiation, survival, and metabolism.
Noonan syndrome has been linked to the chromosomal band 12q24.1 and PTPN11, which encodes the protein SHP2. Because SHP2 has essential roles in signal transduction pathways that control several developmental processes, including cardiac semilunar valvulogenesis, PTPN11 was deemed an excellent candidate gene.
Studies suggest that 50 percent of ...