Noonan Syndrome

Updated: Apr 22, 2022
  • Author: Margaret M McGovern, MD, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Practice Essentials

Noonan syndrome is a genetic disorder that prevents normal development of various parts of the body. 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, 2, 3, 4, 5]

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.

Signs and symptoms of Noonan syndrome

Symptoms of Noonan syndrome vary in severity but may include the following:

  • Characteristic facial features affecting the eyes, ears, nose, mouth, head shape, and skin
  • Congenital heart defects - Valve disorders, hypertrophic cardiomyopathy, ventricular septal defect
  • Growth insufficiencies, short stature in adulthood
  • Musculoskeletal issues
  • Learning disabilities
  • Eye and eyelid abnormalities
  • Hearing deficits
  • Bleeding issues
  • Lymphatic issues
  • Genital and renal issues
  • Skin issues

Diagnosis of Noonan syndrome

Diagnosis is usually based on characteristic signs. Molecular genetic testing, however, can aid in confirmation.

Treatment of Noonan syndrome

Treatment is focused on the symptoms of Noonan syndrome and may include cardiac therapy, growth hormone therapy, physical and speech therapy, ophthalmologic treatment, management of bleeding disorders, treatment of lymphatic problems, and urologic therapy (in males).



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 KRASNRASBRAFMAP2K1, MRAS, RASA2, RIT1, RRAS2, SOS2, and LZATR1 also have been identified. Several other genes that have been linked to a Noonan syndrome–like phenotype have been recognized as well but have been found in a very small number of persons. [3]



Frequency of Noonan syndrome

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. [6] 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. [7] 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.

A study by Cessans et al comparing growth patterns in patients with Noonan syndrome based on genotype found that at birth, patients with PTPN11 mutations tended to be shorter and thinner than were those with mutations in SOS1, KRAS, or Noonan syndrome with multiple lentigines–associated PTPN11 (NSML-PTPN11). Additionally, at age 2 years, growth retardation was more severe and frequent in patients with PTPN11 mutations than in those with mutations in SOS1 or NSML-PTPN11. At age 10 years, although patients with Noonan syndrome had lower body mass indexes in general, no growth differences were found between the different genotypes. [8]

A study by Croonen et al indicated that feeding problems contribute to growth impairment during the first year of life in children with Noonan syndrome. Although PTPN11 mutation, greater gestational age, and cardiac surgery also had a negative effect on weight gain and length in the study, the investigators found that at age 1 year, children with feeding problems weighed, on average, 290 g less than children without feeding problems and were, on average, 0.8 cm shorter. [9]

A study by Draaisma et al indicated that in children with Noonan syndrome, feeding problems frequently arise in infancy—particularly in patients in whom the syndrome developed from mutations in genes other than PTPN11 and SOS1—but typically resolve between age 1-2 years. The report found that out of a cohort of 108 patients with Noonan syndrome, 71 (65.7%) had feeding problems, including 40 who required tube feeding. Of the 71 patients, 52 (73.2%) developed feeding problems before age 1 year. [10]


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.