Noonan syndrome

Alternate names

Male Turner Syndrome; Noonan-Ehmke syndrome; Ullrich-Noonan syndrome; Female Pseudo-Turner Syndrome; Pseudo-Ullrich-Turner syndrome

Definition

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.

Other conditions in this group include:

• neurofibromatosis type 1
• LEOPARD syndrome, also called Noonan syndrome with multiple lentigines
• Costello syndrome
• cardiofaciocutaneous syndrome
• Legius syndrome
• capillary malformation–arteriovenous malformation syndrome

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Epidemiology

Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 people.

Cause

• 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).

Gene mutations

• 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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

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.

Signs and symptoms

Some of the signs and symptoms seen in people with Noonan syndrome (NS) are listed below. Please note that the list below does not include all possible symptoms of NS and that not all people with NS will have all of these the signs and symptoms. In general, the signs and symptoms of NS are more obvious early in life and become less obvious as individuals get older.

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)
• A syndrome named Noonan-like/multiple giant cell lesion syndrome used to be considered a separate condition from Noonan syndrome. It is now known that multiple giant cell lesions are one of the possible symptoms that can occur in people with Noonan syndrome.

Diagnosis

• NS is diagnosed on clinical grounds by observation of key features.
• Affected individuals have normal chromosome studies. Molecular genetic testing identifies a pathogenic variant in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 and RIT1 each in 5%, and KRAS in fewer than 5%.
• Other reported genes – in which pathogenic variants have been found to cause Noonan syndrome in fewer than 1% of cases – include BRAF, LZTR1, MAP2K1, and NRAS.
• Several additional genes associated with a Noonan-syndrome-like phenotype in fewer than ten individuals have been identified.

Treatment

• 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.
• Developmental disabilities are addressed by early intervention programs. 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.

Prognosis

• There is a wide range in the nature and severity of signs and symptoms that may be present in people with Noonan syndrome, so the long-term outlook (prognosis) and life expectancy may differ among affected people.
• 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.
• Some affected people have ongoing health problems due to congenital heart defects, lymphatic vessel dysplasia, urinary tract malformations, blood disorders, or other associated health issues.
• 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.

Summary

• Noonan syndrome belongs to a group of related conditions called the RASopathies.
• These conditions have some overlapping features and are all caused by genetic changes that disrupt the body's RAS pathway, affecting growth and development.

Noonan syndrome Resources
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NIH genetic and rare disease info

• NIH info on Noonan syndrome

Noonan syndrome is a rare disease.