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Noonan syndrome

Reviewed March 2011

What is Noonan syndrome?

Noonan syndrome is a condition that affects many areas of the body. It is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms.

People with Noonan syndrome have distinctive facial features such as a deep groove in the area between the nose and mouth (philtrum), widely spaced eyes that are usually pale blue or blue-green in color, and low-set ears that are rotated backward. Affected individuals may have a high arch in the roof of the mouth (high-arched palate), poor alignment of the teeth, and a small lower jaw (micrognathia). Many children with Noonan syndrome have a short neck and both children and adults may have excess neck skin (also called webbing) and a low hairline at the back of the neck.

Approximately 50 to 70 percent of individuals with Noonan syndrome have short stature. At birth, they are usually of normal length and weight, but growth slows over time. Abnormal levels of growth hormone may contribute to the slow growth.

Individuals with Noonan syndrome often have either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some affected people may also have an abnormal side-to-side curvature of the spine (scoliosis).

Most people with Noonan syndrome have a heart defect. The most common heart defect is a narrowing of the valve that controls blood flow from the heart to the lungs (pulmonary valve stenosis). Some affected individuals have hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood.

A variety of bleeding disorders have been associated with Noonan syndrome. Some people may have excessive bruising, nosebleeds, or prolonged bleeding following injury or surgery. Women with a bleeding disorder typically have excessive bleeding during menstruation (menorrhagia) or childbirth.

Adolescent males with Noonan syndrome typically experience delayed puberty. Affected individuals go through puberty starting at age 13 or 14 and have a reduced pubertal growth spurt. Most males with Noonan syndrome have undescended testicles (cryptorchidism), which may be related to delayed puberty or to infertility (inability to father a child) later in life. Females with Noonan syndrome typically have normal puberty and fertility.

Noonan syndrome can cause a variety of other signs and symptoms. Most children diagnosed with Noonan syndrome have normal intelligence, but a small percentage has special educational needs, and some have intellectual disability. Some affected individuals have vision or hearing problems. Infants with Noonan syndrome may be born with puffy hands and feet caused by a buildup of fluid (lymphedema), which can go away on its own. Affected infants may also have feeding problems, which typically get better by age 1 or 2. Older individuals can also develop lymphedema, usually in the ankles and lower legs.

How common is Noonan syndrome?

Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 people.

What genes are related to Noonan syndrome?

Mutations in the PTPN11, SOS1, RAF1, KRAS, NRAS and BRAF genes cause Noonan syndrome.

Most cases of Noonan syndrome result from mutations in one of three genes, PTPN11, SOS1, or RAF1. PTPN11 gene mutations account for approximately 50 percent of all cases of Noonan syndrome. SOS1 gene mutations account for 10 to 15 percent and RAF1 gene mutations account for 5 to 10 percent of Noonan syndrome cases. About 2 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. It is not known how many cases are caused by mutations in the BRAF or NRAS genes, but it is likely a very small proportion. The cause of Noonan syndrome in the remaining 20 percent of people with this disorder is unknown.

The PTPN11, SOS1, RAF1, KRAS, NRAS and BRAF genes all provide instructions for making proteins that are important in signaling pathways needed for the proper formation of several types of tissue during development. These proteins also play roles in cell division, cell movement, and cell differentiation (the process by which cells mature to carry out specific functions). Mutations in any of the genes listed above cause the resulting protein to be continuously active, rather than switching on and off in response to cell signals. This constant activation disrupts the regulation of systems that control cell growth and division, leading to the characteristic features of Noonan syndrome.

Related Gene(s)

Changes in these genes are associated with Noonan syndrome.

  • BRAF
  • KRAS
  • NRAS
  • PTPN11
  • RAF1
  • SOS1

How do people inherit Noonan syndrome?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of Noonan syndrome?

These resources address the diagnosis or management of Noonan syndrome and may include treatment providers.

  • Gene Review: Noonan Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1124/)
  • Genetic Testing Registry: Noonan's syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0028326)
  • Genetic Testing Registry: Noonan syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0041409)
  • Genetic Testing Registry: Noonan syndrome 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1854469)
  • Genetic Testing Registry: Noonan syndrome 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1860991)
  • Genetic Testing Registry: Noonan syndrome 4 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1853120)
  • Genetic Testing Registry: Noonan syndrome 5 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1969057)
  • Genetic Testing Registry: Noonan syndrome 6 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2750732)
  • Genetic Testing Registry: Noonan syndrome 7 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C3150970)
  • MedlinePlus Encyclopedia: Noonan Syndrome (http://www.nlm.nih.gov/medlineplus/ency/article/001656.htm)

You might also find information on the diagnosis or management of Noonan syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/noonan-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/noonan-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Noonan syndrome?

You may find the following resources about Noonan syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Noonan syndrome?

  • familial Turner syndrome
  • Female Pseudo-Turner Syndrome
  • Male Turner Syndrome
  • Noonan-Ehmke syndrome
  • pseudo-Ullrich-Turner syndrome
  • Turner-like syndrome
  • Turner's phenotype, karyotype normal
  • Turner syndrome in female with X chromosome
  • Ullrich-Noonan syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Noonan syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Noonan syndrome?

adolescent ; atypical ; autosomal ; autosomal dominant ; cardiomyopathy ; cell ; cell division ; chromosome ; cryptorchidism ; differentiation ; disability ; familial ; fertility ; gene ; growth hormone ; hormone ; hypertrophic ; infertility ; inherited ; injury ; karyotype ; lower jaw ; lymphedema ; menstruation ; micrognathia ; mutation ; palate ; pectus excavatum ; phenotype ; philtrum ; protein ; puberty ; pulmonary ; scoliosis ; short stature ; stature ; stenosis ; surgery ; syndrome ; testicles ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Allanson JE. Noonan syndrome. Am J Med Genet C Semin Med Genet. 2007 Aug 15;145C(3):274-9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17639592?dopt=Abstract)
  • Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1. (http://www.ncbi.nlm.nih.gov/pubmed/17603483?dopt=Abstract)
  • Rohrer T. Noonan syndrome: introduction and basic clinical features. Horm Res. 2009 Dec;72 Suppl 2:3-7. doi: 10.1159/000243772. Epub 2009 Dec 22. (http://www.ncbi.nlm.nih.gov/pubmed/20029230?dopt=Abstract)
  • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010 Oct;126(4):746-59. doi: 10.1542/peds.2009-3207. Epub 2010 Sep 27. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20876176?dopt=Abstract)
  • Schubbert S, Zenker M, Rowe SL, Böll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar;38(3):331-6. Epub 2006 Feb 12. Erratum in: Nat Genet. 2006 May;38(5):598. (http://www.ncbi.nlm.nih.gov/pubmed/16474405?dopt=Abstract)
  • Shaw AC, Kalidas K, Crosby AH, Jeffery S, Patton MA. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32. Epub 2006 Sep 21. (http://www.ncbi.nlm.nih.gov/pubmed/16990350?dopt=Abstract)
  • Sznajer Y, Keren B, Baumann C, Pereira S, Alberti C, Elion J, Cavé H, Verloes A. The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. Pediatrics. 2007 Jun;119(6):e1325-31. Epub 2007 May 21. (http://www.ncbi.nlm.nih.gov/pubmed/17515436?dopt=Abstract)
  • Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan;39(1):75-9. Epub 2006 Dec 13. Erratum in: Nat Genet. 2007 Feb;39(2):276. (http://www.ncbi.nlm.nih.gov/pubmed/17143282?dopt=Abstract)
  • van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007 Jan 14;2:4. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17222357?dopt=Abstract)
  • Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, Doerr HG, Gaspar H, Hofbeck M, Gillessen-Kaesbach G, Koch A, Meinecke P, Mundlos S, Nowka A, Rauch A, Reif S, von Schnakenburg C, Seidel H, Wehner LE, Zweier C, Bauhuber S, Matejas V, Kratz CP, Thomas C, Kutsche K. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007 Oct;44(10):651-6. Epub 2007 Jun 23. (http://www.ncbi.nlm.nih.gov/pubmed/17586837?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: March 2011
Published: July 21, 2014