Noonan Syndrome

What is Noonan syndrome?

Noonan syndrome is a genetic disorder characterized by short stature, distinctive facial features, heart defects, bleeding problems and skeletal abnormalities. Most individuals with Noonan syndrome have normal intelligence, but some may have special educational needs or intellectual disability. Noonan syndrome occurs in about 1 in 2,500 births. 


Noonan syndrome is caused by alterations (also known as mutations) at specific areas within a person's genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as genes. Genes provide the necessary instructions that our cells need to perform different functions within our bodies.

Noonan syndrome is caused by mutations in one of several different genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF or MEK1. Together mutations in these genes account for 70-75 percent of Noonan syndrome cases. PTPN11 accounts for about 50 percent of cases, SOS1 for 10-15 percent, RAF1 and KRAS each account for 5 percent, and BRAF or NRAS account for only a small proportion.

Noonan syndrome is an autosomal dominant condition, which means that alterations involving only one of the two copies of a Noonan syndrome-associated gene are sufficient to cause the disorder. The cause of Noonan syndrome in the remaining 25-30 percent of people with the disorder is unknown.

The PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes produce proteins that regulate key signaling pathways within cells required for the proper formation of tissues during development. Noonan syndrome-associated mutations cause the resulting proteins to be continuously active, instead of switching “on” and “off” in response to specific external cues. This disrupts the normal pattern of signals that control cell growth and division, and leads to the characteristic features of Noonan syndrome and the increased risk for developing benign or malignant tumors.

How is Noonan syndrome inherited?

With the exception of egg and sperm cells, each cell of the body normally has two working copies of each gene. Noonan syndrome occurs when there is a mutation in one of the two copies of a Noonan syndrome-associated gene in the various cells of the body. Although a second normally functioning copy of the gene is present, it is not sufficient to correct the disrupted signaling that results due to the presence of the altered gene copy.

A person carrying a mutation in one copy of a Noonan syndrome-associated gene has a 50 percent — or one in two — chance of passing this same alteration on to each of his or her future children. Children who inherit the altered gene copy will have Noonan syndrome and be at risk of developing the various features associated with this disease.

Approximately 30-75 percent of patients inherit a mutation in one of the genes associated with Noonan syndrome from a parent who also has Noonan syndrome. In the remaining patients, there is no family history of Noonan syndrome. In these individuals, Noonan syndrome likely results from occurrence of a "new mutation" in one copy of a Noonan syndrome-associated gene. Although these individuals will be the first ones in their family to carry the genetic change, each of their future children will have a 50 percent chance of inheriting the same genetic change.


The diagnosis of Noonan syndrome is often made on clinical grounds, based on the presence of specific features, including:

  • Short stature (less than the third percentile)
  • Congenital heart defect
    • Pulmonary valve stenosis (a heart valve disorder in which blood flow from the right ventricle is obstructed at the pulmonic valve)
    • Hypertrophic cardiomyopathy (a thickening of the muscle of the heart)
    • Atrial septal defect (a hole that enables blood flow between the left and right atria of the heart)
  • Developmental delay of variable degree
  • Broad neck and/or excess neck skin (webbed neck)
  • Unusual shape of the chest with superior pectus carinatum (protruding chest), inferior pectus excavatum (sunken chest)
  • Low-set nipples
  • Cryptorchidism in males (undescended testicles)
  • Characteristic facial features
    • Low-set, posteriorly rotated, fleshy ears
    • Vivid blue or blue-green irises (colored part of the eye)
    • Eyes are often wide-spaced, with epicanthal folds (skin folds of the upper eyelid that partially cover the inner corners of the eyes) and thick or droopy eyelids
    • The facial features of Noonan syndrome may change considerably with age. The characteristic appearance is often most evident in the newborn period and childhood and more subtle in adults.

In addition to these clinical findings, coagulation (blood clotting) defects may be present in patients with Noonan syndrome. Coagulation screening tests such as prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time may show abnormalities.

There is significant variability in the number of features and/or the severity of their presentation in children with Noonan syndrome. Therefore, individuals should meet with a genetics specialist with experience in the diagnosis and management of Noonan syndrome in order to confirm the diagnosis and coordinate medical management.

Testing for Noonan syndrome

To confirm — on a molecular level — that an individual has Noonan syndrome, he or she can undergo the process of genetic testing. Genetic testing usually involves the collection of a sample of blood, from which the white blood cells are isolated and used as a source of DNA. Two copies of each of the Noonan syndrome-associated genes are analyzed using a variety of methods to look for possible changes in the normal lettering of one of the two copies of these genes. If a change in one of the two copies of a Noonan syndrome gene is identified, it can be further analyzed to determine if it is causative of Noonan syndrome or simply a normal variation in the gene.

Mutations in the PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes are identified in 70-75 percent of people with Noonan syndrome. However, it is important to remember that not all patients with Noonan syndrome carry a detectable alteration in one of these genes. There are likely to be additional, undiscovered genes that play a role in the development of Noonan syndrome for the remaining 25-30 percent of patients. Therefore, the failure to identify an alteration in one of these genes does not exclude the diagnosis of Noonan syndrome.

Genetic test results can provide important information for patients as well as other family members. Identification of the specific genetic alteration in an individual with Noonan syndrome allows other family members to undergo testing to determine whether they also carry the same alteration. Identification of the specific gene mutation is also important if the individual with Noonan syndrome would like to become pregnant and undergo prenatal genetic testing.

Related conditions

LEOPARD syndrome

One condition related to Noonan syndrome is known as LEOPARD syndrome (Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, Deafness). LEOPARD syndrome shows clinical overlap with Noonan syndrome, but patients also have findings on the skin, such as café au lait patches and lentigines (small colored spots on the skin with clearly-defined edges) and over time some develop hearing loss. Mutations in PTPN11 and RAF1 are identified in approximately 93 percent of individuals with LEOPARD syndrome.

Cardiofaciocutaneous (CFC) syndrome

Another condition related to Noonan syndrome is cardiofaciocutaneous (CFC) syndrome. CFC syndrome is caused by gene mutations that are similar to those observed in Noonan syndrome, including alterations in the KRAS, BRAF, and MEK1 genes.

People with CFC syndrome have similar facial, skeletal, and cardiac features as people with Noonan syndrome. However, people with CFC syndrome tend to have:

  • Unique facial features (overall, a broad, long face with features that are sometimes described as “coarse”)
  • More severe feeding problems (such as gastroesophageal reflux, aspiration, vomiting, and oral aversion)
  • Follicular hyperkeratosis (a skin condition characterized by excessive development of keratin in hair follicles)
  • Sparse eyebrows and eyelashes
  • Developmental and/or cognitive delays

Tumor risks

While cancer is not a major feature of Noonan syndrome, people with Noonan syndrome are at a slightly increased risk to develop certain malignant (cancerous) conditions including:

  • Myeloproliferative disorder (a disease of the bone marrow)
  • Juvenile myelomonocytic leukemia (JMML) (a cancer of the white blood cells)
  • Neuroblastoma (a cancer of developing nerve cells)
  • Embryonal rhabdomyosarcoma (a cancer of the muscle)
  • Giant cell lesions (benign tumor-like lesions that most frequently occur in the jaws)
  • Granular cell tumors (benign tumors generally involving the skin or the mucosal surfaces)

The exact magnitude of the tumor risk in individuals with Noonan syndrome is not well described, and may vary depending on the specific gene mutation. However, the overall cancer risk for individuals with Noonan syndrome or LEOPARD syndrome appears to be relatively low. Infants with Noonan syndrome are predisposed to developing a myeloproliferative disorder (MPD), which may regress without treatment or follow an aggressive clinical course similar to juvenile myelomonocytic leukemia (JMML).

There are currently no standard cancer screening recommendations for patients with Noonan syndrome. Screening guidelines may vary between experts and may be dependent on factors such as the patient’s age and clinical history. Management of patients with Noonan syndrome should be provided by specialists with expertise in this condition. 

Reproductive options

A person with Noonan syndrome who is concerned about passing this disorder onto future children has several options regarding prenatal genetic analysis. The Noonan syndrome-associated mutation must be identified in a parent before either of these tests can be performed.

Current options regarding prenatal molecular genetic testing include:

  • Molecular prenatal genetic testing — DNA is isolated from the cells of the developing baby though one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and is analyzed for the disease-causing mutation. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
  • Preimplantation genetic diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos without the genetic alteration would be implanted.

In addition to these molecular genetic tests, high-resolution fetal ultrasound examination is also an option for pregnancies at 50 percent risk for Noonan syndrome.

Prenatal features suggestive for Noonan syndrome may include:

  • Polyhydramnios (an excess of fluid in the amniotic sac)
  • Hydronephrosis (distention of the kidney due to obstruction of the flow of urine)
  • Pleural effusion (excess fluid that accumulates around the lungs)
  • Edema (an abnormal accumulation of fluid beneath the skin)
  • Cardiac defects
  • Distended jugular lymphatic sacs
  • Cystic hygroma (a fluid-filled lesion)
  • Increased nuchal translucency (caused by buildup in fluid in the fetal neck due to a blockage of fluid in the developing fetal lymphatic system)

Based on the presence of these features, a potential clinical diagnosis of Noonan syndrome may be made. However, absence of these features does not exclude the diagnosis of Noonan syndrome.

Additionally, some of these findings may not be specific for Noonan syndrome. For example, they may be found in babies who have other syndromes or they may occur as isolated findings (and not necessarily associated with Noonan syndrome or any other genetic disorder).


Allanson JE, Roberts AE. Noonan Syndrome. 2001 Nov 15 [Updated 2011 Aug 4]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. 

DYSCERNE — Noonan Syndrome Guideline Development Group. "Management of Noonan Syndrome: A Clinical Guideline." DYSCERNE, 15 Feb. 2010. Web.

"Noonan Syndrome." Genetics Home Reference. U.S. National Library of Medicine, 29 July 2013. Web.

Romano, Alicia A., MD, Judith E. Allanson, MD, Jovanna Dahlgren, MD, Bruce D. Gelb, MD, Bryan Hall, MD, Mary Ella Pierpont, MD, Amy E. Roberts, MD, Wanda Robinson, Clifford M. Takemoto, MD, and Jacqueline A. Noonan, MD. "Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines." Pediatrics. American Academy of Pediatrics, 27 Sept. 2010. Web.

Reviewed by Kristin Zelley, MS, LCGC