Noonan Syndrome

Updated: Feb 19, 2017
  • Author: Margaret M McGovern, MD, PhD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Noonan syndrome was first recognized as a unique entity in 1963 when Noonan and Ehmke described a series of patients with unusual facies and multiple malformations, including congenital heart disease. These patients were previously thought to have a form of Turner syndrome, with which Noonan syndrome shares numerous clinical features. The observation that patients with Noonan syndrome have normal karyotypes was important in allowing the distinction to be made between the Turner and Noonan syndromes.

The cardinal features of Noonan syndrome include unusual facies (ie, hypertelorism, down-slanting eyes, webbed neck), congenital heart disease, short stature, and chest deformity. Approximately 25% of individuals with Noonan syndrome have mental retardation. Bleeding diathesis is present in as many as half of all patients with Noonan syndrome. Skeletal, neurologic, genitourinary, lymphatic, eye, and skin findings may be present to varying degrees. [1]



The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. Approximately 50% of patients have gene mutations in PTPN11, with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. Mutations in KRAS, NRAS, BRAF, and MAP2K1 also have been identified, but in smaller numbers of patients.




United States

The incidence of Noonan syndrome is estimated to be 1 case per 1000 to 1 case per 2500 live births.


The incidence of Noonan syndrome appears to be consistent worldwide.


The primary source of morbidity and mortality in patients with Noonan syndrome depends on the presence and type of congenital heart disease.

Noonan syndrome is also characterized by a slight increase in the risk for certain cancers. In a literature review spanning 1937-2010, Kratz et al found the most commonly reported cancers in Noonan syndrome, as diagnosed in a total of 1051 patients, to be neuroblastoma (8 cases), acute lymphoblastic leukemia (8 cases), low-grade glioma (6 cases), and rhabdomyosarcoma (6 cases); like Noonan syndrome, all of these cancers are associated with RAS signaling pathway mutations. [2] Juvenile myelomonocytic leukemia and myeloproliferative disorder have also been associated with Noonan syndrome.

A study by Jongmans et al also demonstrated an elevated cancer risk in patients with Noonan syndrome. [3] Twelve of 297 patients with a PTPN11 mutation developed a malignancy—a 3.5-fold increased risk compared with that of healthy individuals. Hematologic malignancies occurred most frequently, while 2 malignancies not previously observed in Noonan syndrome were found: a malignant mastocytosis and malignant epithelioid angiosarcoma.


Noonan syndrome is panethnic.


Noonan syndrome occurs in either a sporadic or autosomal dominant fashion. In either case, males and females are equally affected.


The disorder is present from birth, but age impacts the facial phenotype. Infants with Noonan syndrome can be difficult to recognize by facial appearance alone. The phenotype becomes more striking in early childhood, but with advancing age, it may again become quite subtle. Careful examination of an affected child's parents may in fact reveal that they are mildly affected.