Other Names: Male Turner Syndrome; Noonan-Ehmke syndrome; Ullrich-Noonan syndrome
Noonan syndrome is a genetic disorder that causes abnormal development of multiple parts of the body. Features of Noonan syndrome may include a distinctive facial appearance, short stature, a broad or webbed neck, congenital heart defects, bleeding problems, problems with bone structure (skeletal malformations), and developmental delay. Individuals with Noonan syndrome often have either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some affected people may also have an abnormal side-to-side curvature of the spine (scoliosis).
Noonan syndrome is one of a group of related conditions, collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome, the RASopathies include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines.
Mutations in multiple genes can cause Noonan syndrome. Mutations in the PTPN11 gene cause about half of all cases. SOS1 gene mutations cause an additional 10 to 15 percent, and RAF1 and RIT1 genes each account for about 5 percent of cases. Mutations in other genes each account for a small number of cases. The cause of Noonan syndrome in 15 to 20 percent of people with this disorder is unknown.
The PTPN11, SOS1, RAF1, and RIT1 genes all provide instructions for making proteins that are important in the RAS/MAPK cell signaling pathway, which is needed for cell division and growth (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell movement (migration). Many of the mutations in the genes associated with Noonan syndrome cause the resulting protein to be turned on (active) longer than normal, rather than promptly switching on and off in response to cell signals. This prolonged activation alters normal RAS/MAPK signaling, which disrupts the regulation of cell growth and division, leading to the characteristic features of Noonan syndrome.
Rarely, Noonan syndrome is associated with genes that are not involved in the RAS/MAPK cell signaling pathway. Researchers are working to determine how mutations in these genes can lead to the signs and symptoms of Noonan syndrome.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Some of the signs and symptoms seen in people with Noonan syndrome (NS) are listed below. Head/Neck: Widely spaced eyes (hypertelorism) Large ears rotated back Short webbed neck Droopy eyelids (ptosis) Low hairline Multiple giant cell lesions (MGCL): painless, benign growths in the jaw that can lead to dental or orthodontic issues Heart: Pulmonary stenosis Aortic regurgitation Atrial septal defect Skeletal: Short stature Concave chest (pectus excavatum) Bending or curvature of the finger (clinodactyly) Weak bones (generalized osteopenia) Skin: Café au lait spots Hemangioma (raised red birthmark) Neurological: Delayed milestones due to low muscle tone Developmental delay Learning disabilities or intellectual impairment Bleeding disorder Undescended testicles (cryptorchidism)
Gene mutations identified in individuals with the NS phenotype are involved in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway and currently explain ∼61% of NS cases. Thus, NS frequently remains a clinical diagnosis. Because of the variability in presentation and the need for multidisciplinary care, it is essential that the condition be identified and managed comprehensively. Genetic testing can help diagnose this syndrome.
Management of Noonan syndrome generally focuses on the specific signs and symptoms present in each person. Treatments for the complications of Noonan syndrome (such as cardiovascular problems) are generally standard and do not differ from treatment in the general population. Some children with Noonan syndrome may need special help in school, including for example, an individualized educational program (IEP). Treatment for bleeding problems depends on the cause.Growth hormone (GH) therapy can increase the rate at which a child with Noonan syndrome grows in most cases. GH therapy during childhood and teen years may also increase final adult height slightly, often enough to reach the low normal range of average height. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.
- Somatropin (r-DNA) for injection (Brand name: Norditropin)Treatment of short stature in patients with Noonan syndrome.
Studies generally suggest that long-term outcome depends largely on the presence and severity of congenital heart defects. Death in affected people has been frequently associated with the presence of complex left ventricular disease. Studies have indicated that people with Noonan syndrome have a 3-fold higher mortality rate than those in the general population. However, with special care and counseling, the majority of children with Noonan syndrome grow up and function normally as adults. Signs and symptoms tend to lessen with age, and new medical problems associated with the condition are generally not expected to appear in adulthood.
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