Noonan Syndrome

Noonan syndrome is a genetic condition that affects many areas of the body that occurs in between 1 in 1000 to 1 in 2500 individuals.

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.


Heart Abnormalities

About 80 per cent of children with Noonan syndrome have heart abnormalities. The most common include:

  • pulmonary valve stenosis (50-80%): the pulmonary valve allows blood with reduced oxygen content (deoxygenated) to leave the heart and go to the lungs. Pulmonary valve stenosis occurs when the pulmonary valve is narrower than normal
  • hypertrophic cardiomyopathy (20-30%): thickening of the heart muscles
  • atrial septal defect – an abnormal hole between the two upper chambers of the heart (atria)
  • ventricular septal defect – an abnormal hole between the two lower chambers of the heart (ventricles).

Characteristic facial features

The severity of the Noonan syndrome ‘look’ varies from one child to the next and can change with age. Characteristics may include:

  • heavy or hooded eyelids that may interfere with vision (ptosis)
  • downward sloping eyes with an extra fold of skin at each inner corner (epicanthic eye folds)
  • widely spaced eyes (hypertelorism) with a flattened bridge of the nose
  • brilliant blue or blue-green eyes
  • strongly arched (diamond-shaped) eyebrows
  • low-set ears, tilted back so that the lobes point forward more than usual
  • low hairline at the neck
  • coarse and curly hair
  • short neck with extra skin folds or ‘webbing’ at the back of the neck – this makes the neck look wider when viewed from behind.



Musculoskeletal system abnormalities

Some possible abnormalities of the musculoskeletal system include:

  • short stature – although birth weight is usually average, children with Noonan syndrome are frequently shorter than expected for their age. As adults, people with Noonan syndrome are often short – men average 165 cm (5’ 5") and women 152 cm (5’) in height
  • low muscle tone, motor delay in infants and impaired coordination
  • An unusually shaped chest often with a sunken sternum (pectus excavatum) or raised sternum (pectus carinatum)
  • curvature of the spine (scoliosis)
  • joint hypermobility syndrome

Intellectual Difficulties

It was once commonly believed that all children with Noonan syndrome were intellectually disabled. This is actually true for only about one third of affected children. Intelligence quotient (IQ) scores generally range from 50 to 119 (100 being average). Delays in language development are the most common problem experienced by children with Noonan syndrome, with one in four affected.


Some people with Noonan syndrome develop cancer, particularly those involving the blood-forming cells (leukemia). It has been estimated that children with Noonan syndrome have an eightfold increased risk of developing leukemia or other cancers over age-matched peers.

Eye conditions

A common sign of Noonan syndrome is abnormalities of the eyes and eyelids. Differences in the shape and size of the eyes are hallmark features. Often the iris is pale blue or green.

Common problems with the eye muscles are:

  • strabismus (48-63%)
  • refractive problems (61%) such as astigmatism,
  • nearsightedness (myopia), farsightedness (hypermetropia),
  • Nystagmus (10%) - rapid movement of the eyeballs
  • Nerve abnormalities (20%).


Blood clotting issues such as low platelet counts, Von Willebrand Disease and platelet dysfunction are more common in Noonan Syndrome than the general population.

Most people with Noonan syndrome have a history of abnormal bruising or bleeding. Sometimes the bleeding condition isn't discovered until a person has surgery and experiences excessive bleeding (hemorrhage).

For these reasons it’s imperative people with Noonan Syndrome consult a haemotologist before having surgery or any invasive medical procedures.

Lymphatic conditions

Noonan syndrome can cause problems with the lymphatic system, which drains excess fluid from the body and helps fight infection. These problems can show up before or after birth and can be focused in a particular area of the body or may be widespread. The most common problem is excess fluid (lymphedema) on the back of the hands or top of the feet.

Genital, kidney, liver & spleen conditions

Noonan syndrome can adversely affect the function of the genitals, kidneys and spleen.

Puberty may be delayed in both boys and girls, but most females develop normal fertility. Males often have reduced fertility, possibly due to testicular dysfunction, deficient sperm production or undescended testicles (cryptochordism) which occurs in 80% of males with Noonan Syndrome.

Kidney problems are generally mild and occur in a fairly small number of people with the syndrome (<10%).

An enlarged liver and spleen (called hepatosplenomegaly) occurs in approximately 25-50% of people with Noonan Syndrome.


Noonan syndrome can adversely affect the function of the gastrointestinal system in many ways.

Failure to thrive is common from infancy to puberty in 75% of cases.

Swallowing difficulties, poor gut motility and gastroparesis (delayed gastric emptying) are also common issues experienced. Some children with Noonan Syndrome will require a feeding tube to procure adequate nutrition.

Coeliac Disease (an autoimmune condition in which the immune system reacts to Gluten) is 10 times more common in people with Noonan Syndrome than the general population.

Skin conditions

Various problems that affect the color and texture of the skin are common. People with Noonan syndrome often have curly, coarse hair or sparse hair.

Hearing Loss

Hearing loss due to otitis media is a frequent complication (15-40%). Sensorineural hearing loss is less common; involving low range frequencies in 10% and high range frequencies in 25% of people with Noonan Syndrome.


Diagnosis of Noonan Syndrome can be made clinically and confirmed via genetic testing.


Clinical Findings

Noonan syndrome (NS) should be suspected in individuals with the following key features:

  • Characteristic facial features such as:
    low-set, posteriorly rotated ears with fleshy helices;
  • vivid blue or blue-green irises;
  • eyes that are often wide-spaced, downslanted, and with epicanthal folds and fullness or droopiness of the upper eyelids (ptosis).


  • Short stature
  • Congenital heart defect, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy
  • Developmental delay of variable degree
  • Broad or webbed neck
  • Unusual chest shape with superior pectus carinatum, inferior pectus excavatum
  • Widely set nipples
  • Cryptorchidism in males
  • Coagulation defects
  • Lymphatic dysplasias of the lungs, intestines, and/or lower extremities.

Diagnostic criteria developed by van der Burgt in 1997 is below:


Scoring system for Noonan syndrome (NS)
Feature A = Major B = Minor
1 Facial Typical face dysmorphology Suggestive face dysmorphology
2 Cardiac Pulmonary valve stenosis, HOCM and/or ECG typical of NS Other defect
3 Height <P3* <P10*
4 Chest wall Pectus carinatum/excavatum Broad thorax
5 Family history First degree relative with definite NS First degree relative with suggestive NS
6 Other Mental retardation, cryptorchidism and lymphatic dysplasia One of mental retardation, cryptorchidism, lymphatic dysplasia

HOCM: hypertrophic obstructive cardiomyopathy;

*P3 and P10 refer to percentile lines for height according to age, with the normal range of variation defined as P3-P97 inclusive

Definitive NS: 1 "A" plus one other major sign or two minor signs; 1 "B" plus two major signs or three minor signs


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Genetic Testing

Molecular testing approaches can include use of a multi-gene panel, serial single-gene testing, and more comprehensive genomic testing.

Multi Gene Panel

A multi-gene panel is the test of choice for an individual suspected of having Noonan syndrome. Because of significant overlap with cardiofaciocutaneous (CFC) syndrome and Costello syndrome, most available panels include the genes for these diagnoses, too.

Serial Single Gene Testing

Serial single-gene testing can be considered if panel testing is not feasible. Approximately 50% of individuals with NS have a pathogenic missense variant in PTPN11; therefore, single-gene testing starting with PTPN11 would be the next best first test.

Comprehensive Genomic Testing

More comprehensive genomic testing (if available) including whole-exome sequencing (WES) or whole-genome sequencing (WGS) may be considered if use of a multi-gene panel and/or serial single-gene testing fails to confirm a diagnosis in an individual with features of NS.


There are currently ten genes in the RAS-MAPK signalling pathway that cause Noonan Syndrome or other closely related rasopathies; PTPN11 (50%), SOS1 (13%), KRAS (<5%), NRAS, RAF1 (5%), BRAF (<2%), RIT1 (5%), MAP2K1 (<2%), SHOC2 & CBL.



Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (de novo) in the affected individual. Approximately 50% of affected individuals have an affected parent. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.