Noonan syndrome is a common autosomal dominant multiple congenital anomaly syndrome that was initially described over 40 years ago. It belongs to the group of RASopathies, which are developmental disorders caused by germline mutations in genes encoding particular proteins of the RAS/mitogen-activated protein kinase (MAPK) pathway.

The majority of cases of Noonan syndrome stem from mutations in three genes – PTPN11, SOS1, or RAF1. PTPN11 gene mutations account for half of all cases of Noonan syndrome, SOS1 gene mutations account for 10%, whereas RAF1 gene mutations account for 5 to 10% of Noonan syndrome cases. In 20% of people the exact cause of the disorder is still unknown.

Despite the lack of stringent diagnostic criteria, the principal features of Noonan syndrome are well established. They include short stature, congenital heart defects, unusual chest shape with pectus carinatum and pectus excavatum, broad or webbed neck, variable degree of developmental delay, cryptorchidism (undescended testes) and characteristic facial features.

Epidemiology of Noonan syndrome

The incidence of Noonan syndrome is consistent and reported to be between 1 in 1000 and 1 in 2500 live births, albeit mild expression is said to occur in 1 in 100 in the general population. The characteristic variable expressivity makes it difficult to identify individuals that are slightly affected.

Familial reappearance is consistent with an autosomal dominant mode of inheritance, but de novo mutations are more common, accounting for 60% of all cases. In the absence of serious congenital heart defects, there is no reduction in the life expectancy. Higher mortality is described in patients with cardiomyopathy.

Researchers have found that among 1016 children with different congenital heart defects, 1.4% of them had Noonan syndrome. The same has been shown for 7% of children requiring surgery for pulmonary stenosis. There is no known racial predilection for this disorder, and the average age at diagnosis is 9.

Disease management

Physical and intellectual abilities tend to be normal in most adults with Noonan syndrome, although some of them necessitate multidisciplinary evaluation and regular follow-up care. Management guidelines were recently developed by American and European consortia, and optimized according to age with an emphasis on screening and testing for common health issues.

Treatment of the complications of Noonan syndrome is generally standard and does not differ from treatment in the general population. Infant stimulation programs are available for children with developmental delays. If growth hormone levels are insufficient, growth hormone therapy can represent a viable treatment option. Aspirin therapy should be avoided because it may aggravate a bleeding diathesis.

Extensive variability in the phenotypic expression of Noonan syndrome with a myriad of unresolved questions is a common issue encountered by physicians. The phenotype can vary from mild facial features and a minimal pulmonary valve stenosis in adults, to severe dysmorphisms with life-threatening heart disease in neonates. Therefore treatment should be based on the type and severity of the symptoms and complications.