Noonan Syndrome Clinical Presentation

Updated: Apr 22, 2022
  • Author: Margaret M McGovern, MD, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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The prenatal history in Noonan syndrome is typically unremarkable; however, some cases are complicated by polyhydramnios, fetal edema, increased nuchal fold translucency, cystic hygroma, or congenital heart disease (particularly pulmonary valvular dysplasia).

A careful family history should be obtained, paying particular attention to the presence of congenital heart disease, mental retardation, short stature, or unusual facies among the parents or siblings of an affected child.

A child with mild expression of the facial phenotype may present only with developmental delay and history of congenital heart disease. A history of abnormal bleeding is present in as many as 50% of patients.

A study by Niemczyk et al suggested that incontinence affects a significant proportion of children with Noonan syndrome. The study, of 19 children and 10 adults with Noonan syndrome, found that among the younger children (aged 4-12 years), the incidence of daytime urinary incontinence, nocturnal enuresis, and fecal incontinence was 36.4%, 27.3%, and 11.1%. However, only one adolescent and one adult experienced incontinence, indicating that the condition tends not to persist into adulthood. [11]



Growth parameters associated with Noonan syndrome

Size at birth is usually within the reference range in Noonan syndrome. Short stature is present in as many as 80% of patients. Average adult height for is 5 feet 5 inches in males and 5 feet in females.

Facial features

These include the following:

  • Triangular-shaped face

  • Hypertelorism

  • Down-slanting palpebral fissures

  • Ptosis

  • Strabismus (48%)

  • Amblyopia (33%)

  • Refractive errors (61%)

  • Low-set ears with thickened helices: In a study of 97 patients with Noonan syndrome, van Trier et al found that 75 of them (77%) had external ear anomalies, including 69 patients whose ears were low set, 28 whose ears were posteriorly rotated, 14 whose ears protruded, and 18 who had thickened helices [12]

  • High nasal bridge

  • Short, webbed neck

A subgroup of patients have Noonan-like/multiple giant cell lesion syndrome (NS/MGCLS), which is characterized by benign, tumorlike lesions, usually occurring in the jaws. This condition was once thought to be separate from Noonan syndrome but is now considered to be a variant of it. NS/MGCLS is associated with PTPN11 and SOS1 gene mutations. [13]

A study by Allanson et al, however, indicated that facial phenotype by itself is not sufficient to predict the presence of specific Noonan syndrome mutations. In an examination of facial photos of 81 persons with Noonan syndrome, the investigators determined that even though mutations in PTPN11 are associated with the cardinal physical characteristics of the disorder, some individuals with these mutations have facial features that are atypical for the syndrome. On the other hand, although a correlation can be seen between KRAS mutations and an intellectual and physical phenotype that is somewhat atypical for Noonan syndrome, some patients with these mutations have the characteristic facial features of the disorder. [14]

Ocular features

A prospective study by van Trier et al reported that in addition to hypertelorism and eyelid abnormalities, ocular anomalies in patients with Noonan syndrome also include amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, abnormal stereopsis, and posterior embryotoxon. At least three ocular abnormalities were found in each of the study’s 25 patients, with more than 95% of these individuals having at least one external ocular feature. [15]

Auditory features

The incidence of progressive high-frequency sensorineural hearing loss may be as high as 50%. A study by Tokgoz-Yilmaz et al indicated that children with Noonan syndrome have higher hearing thresholds and lower transient evoked otoacoustic emissions amplitudes than do children without the syndrome. However, hearing sensitivity was found to be within normal limits, as were middle ear pressures and auditory brainstem response values. [16]

Chest/back features

These include pectus carinatum and/or excavatum. Scoliosis is another feature.

Cardiovascular findings

Cardiac defects occur in up to 80% of patients. The characteristic lesion is dysplastic/stenotic pulmonic valve, but virtually all types of congenital heart defects have been described in patients with Noonan syndrome. Hypertrophic cardiomyopathy (obstructive or nonobstructive type) is present in up to 30% of patients and can present at birth or in infancy or childhood. Other cardiac defects frequently include atrial and ventricular septal defects, branch pulmonary artery stenosis, tetralogy of Fallot, and coarctation of the aorta. [1]

Abdominal features

Hepatosplenomegaly unrelated to cardiac status is present in approximately 25% of patients.

Genitourinary features

Renal anomalies are present in 10% of patients but are not clinically significant. However, more than half of male patients have undescended testes.

Skeletal features

Joint laxity is present in more than half of patients. Talipes equinovarus, radioulnar synostosis, cervical spine fusion, and joint contractures are less common findings. [17]

Skin findings

These include the following:

  • Lymphedema (See the images below)

    Lymphedema of the feet in an infant is shown. The Lymphedema of the feet in an infant is shown. The toes have the characteristic sausagelike appearance.
    Generalized lymphedema is seen here in an infant. Generalized lymphedema is seen here in an infant. The loose skin folds around the neck will form a webbed neck later in life.
  • Prominent pads of fingers and toes (67%)

  • Follicular keratosis of the face and extensor surfaces (14%)

  • Multiple lentigines (3%)

Neurologic findings associated with Noonan syndrome

These include the following:

  • Hypotonia

  • Seizure disorder (13%)

  • Unexplained peripheral neuropathy (infrequent)



Sporadic and autosomal dominant cases have been identified. Female patients with Noonan syndrome have normal pubertal development and fertility, while fertility in males with undescended testes may be decreased. For this reason, the mother is more frequently the transmitting parent in familial cases.

Causative gene mutations in Noonan syndrome include the following [18, 19, 20, 21, 22, 23] :

  • PTPN11 mutations: Account for approximately 50% of clinically recognized cases

  • SOS1 mutations: Account for approximately 13% of cases

  • RAF1 mutations: Account for 5-17% of cases

  • RIT1 mutations: Account for 5% of cases

  • KRAS, NRAS, BRAFMAP2K1, MRAS, RASA2, RRAS2, SOS2, and LZATR1 mutations

Cases due to SOS1 mutations are generally associated with better cognitive function than those associated with PTPN11 mutations. [24]

Correlations have been demonstrated between patient phenotype in Noonan syndrome and mutations in specific genes. A study by Lee et al found that patients with Noonan syndrome who had SOS1 mutations tended to have normal stature, while RAF1 mutations appeared to be associated with hypertrophic cardiomyopathy and developmental delay. [25]

A study by Meier et al found that in individuals with childhood-onset cardiomyopathy associated with Noonan syndrome, cell cycle pathways in left ventricular myocardial tissue demonstrated significant upregulation, including genes in charge of mitotic processes. Importantly, the expression of FGF10 was found to be greatly elevated; according to the investigators, evidence suggests that left ventricular cardiomyocyte production in Noonan syndrome–associated cardiomyopathy is being driven by increased expression of this gene. [26]