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Noonan syndrome(NS)

MedGen UID:
18073
Concept ID:
C0028326
Congenital Abnormality; Disease or Syndrome
Synonyms: MAP2K1-Related Noonan Syndrome; Noonan's syndrome; NS; Pseudo-Turner syndrome
SNOMED CT: Noonan-Ehmke syndrome (205824006); Turner-like syndrome (205824006); Noonan syndrome (205824006); Turner phenotype, karyotype normal (205684007); Turner's phenotype, karyotype normal (205684007); Noonan's syndrome (205824006)
 
Genes (locations): MAP2K1 (15q22.31); PTPN11 (12q24.13)
OMIM®: 163950
Orphanet: ORPHA648

Disease characteristics

Excerpted from the GeneReview: Noonan Syndrome
Noonan syndrome (NS) is characterized by short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, characteristic facies, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one third of affected individuals have mild intellectual disability.  [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Judith E Allanson  |  Amy E Roberts   view full author information

Additional descriptions

From OMIM
Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002). Genetic Heterogeneity of Noonan Syndrome See also NS3 (609942), caused by mutation in the KRAS gene (190070); NS4 (610733), caused by mutation in the SOS1 gene (182530); NS5 (611553), caused by mutation in the RAF1 gene (164760); NS6 (613224), caused by mutation in the NRAS gene (164790); NS7 (613706), caused by mutation in the BRAF gene (164757); NS8 (615355), caused by mutation in the RIT1 gene (609591); NS9 (616559), caused by mutation in the SOS2 gene (601247); and NS10 (616564), caused by mutation in the LZTR1 gene (600574). See also NS2 (605275) for a possible autosomal recessive form of NS; Noonan syndrome-like disorder with loose anagen hair (NSLH; 607721), caused by mutation in the SHOC2 gene (602775); and Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL; 613563), caused by mutation in the CBL gene (165360). Mutations in the neurofibromin gene (NF1; 613113), which is the site of mutations causing classic neurofibromatosis type I (NF1; 162200), have been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).  http://www.omim.org/entry/163950
From GHR
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.  http://ghr.nlm.nih.gov/condition/noonan-syndrome

Professional guidelines

PubMed

Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H
Eur Heart J 2014 Oct 14;35(39):2733-79. Epub 2014 Aug 29 doi: 10.1093/eurheartj/ehu284. [Epub ahead of print] PMID: 25173338
Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA
Pediatrics 2010 Oct;126(4):746-59. Epub 2010 Sep 27 doi: 10.1542/peds.2009-3207. [Epub ahead of print] PMID: 20876176

Recent clinical studies

Etiology

Ekvall S, Wilbe M, Dahlgren J, Legius E, van Haeringen A, Westphal O, Annerén G, Bondeson ML
BMC Med Genet 2015 Oct 14;16:95. doi: 10.1186/s12881-015-0239-1. [Epub ahead of print] PMID: 26467218Free PMC Article
Poterucha JT, Johnson JN, O'Leary PW, Connolly HM, Niaz T, Maleszewski JJ, Ackerman MJ, Cetta F, Dearani JA, Eidem BW
Am J Cardiol 2015 Oct 1;116(7):1116-21. Epub 2015 Jul 16 doi: 10.1016/j.amjcard.2015.06.037. [Epub ahead of print] PMID: 26272816
van Trier DC, van Nierop J, Draaisma JM, van der Burgt I, Kunst H, Croonen EA, Admiraal RJ
Int J Pediatr Otorhinolaryngol 2015 Jun;79(6):874-8. Epub 2015 Apr 1 doi: 10.1016/j.ijporl.2015.03.021. [Epub ahead of print] PMID: 25862627
Pierpont EI, Tworog-Dube E, Roberts AE
Dev Med Child Neurol 2015 Apr;57(4):385-92. Epub 2014 Nov 3 doi: 10.1111/dmcn.12621. [Epub ahead of print] PMID: 25366258
Turner AM
J Paediatr Child Health 2014 Oct;50(10):E14-20. Epub 2011 Jul 19 doi: 10.1111/j.1440-1754.2010.01970.x. [Epub ahead of print] PMID: 21771153

Diagnosis

Hopper RK, Feinstein JA, Manning MA, Benitz W, Hudgins L
Am J Med Genet A 2015 Apr;167A(4):882-5. Epub 2015 Feb 23 doi: 10.1002/ajmg.a.37024. [Epub ahead of print] PMID: 25706034
Loddo I, Romano C, Cutrupi MC, Sciveres M, Riva S, Salpietro A, Ferraù V, Gallizzi R, Briuglia S
Eur J Med Genet 2015 Mar;58(3):188-90. Epub 2015 Jan 13 doi: 10.1016/j.ejmg.2014.12.013. [Epub ahead of print] PMID: 25595571
Nair S, Fort JA, Yachnis AT, Williams CA
Pediatr Blood Cancer 2015 Jun;62(6):1084-6. Epub 2015 Jan 13 doi: 10.1002/pbc.25382. [Epub ahead of print] PMID: 25585602
Guerin A, So J, Mireskandari K, Jougeh-Doust S, Chisholm C, Klatt R, Richer J
Am J Med Genet A 2015 Feb;167A(2):403-6. Epub 2014 Nov 25 doi: 10.1002/ajmg.a.36841. [Epub ahead of print] PMID: 25425531
Pierpont EI, Tworog-Dube E, Roberts AE
Dev Med Child Neurol 2015 Apr;57(4):385-92. Epub 2014 Nov 3 doi: 10.1111/dmcn.12621. [Epub ahead of print] PMID: 25366258

Therapy

Asahi Y, Fujii R, Usui N, Kagamiuchi H, Omichi S, Kotani J
Anesth Prog 2015 Summer;62(2):71-3. doi: 10.2344/0003-3006-62.1.71. PMID: 26061577Free PMC Article
Araz C, Kaval E, Torgay A, Moray G, Haberal M
Exp Clin Transplant 2015 Apr;13 Suppl 1:273-5. PMID: 25894171
Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S
Horm Res Paediatr 2015;83(3):167-76. Epub 2015 Feb 21 doi: 10.1159/000371635. [Epub ahead of print] PMID: 25721697
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. [Epub ahead of print] PMID: 25503994
Lee YS, Ehninger D, Zhou M, Oh JY, Kang M, Kwak C, Ryu HH, Butz D, Araki T, Cai Y, Balaji J, Sano Y, Nam CI, Kim HK, Kaang BK, Burger C, Neel BG, Silva AJ
Nat Neurosci 2014 Dec;17(12):1736-43. Epub 2014 Nov 10 doi: 10.1038/nn.3863. [Epub ahead of print] PMID: 25383899Free PMC Article

Prognosis

Poterucha JT, Johnson JN, O'Leary PW, Connolly HM, Niaz T, Maleszewski JJ, Ackerman MJ, Cetta F, Dearani JA, Eidem BW
Am J Cardiol 2015 Oct 1;116(7):1116-21. Epub 2015 Jul 16 doi: 10.1016/j.amjcard.2015.06.037. [Epub ahead of print] PMID: 26272816
Hopper RK, Feinstein JA, Manning MA, Benitz W, Hudgins L
Am J Med Genet A 2015 Apr;167A(4):882-5. Epub 2015 Feb 23 doi: 10.1002/ajmg.a.37024. [Epub ahead of print] PMID: 25706034
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. [Epub ahead of print] PMID: 25503994
Mathur D, Somashekar S, Navarrete C, Rodriguez MM
Fetal Pediatr Pathol 2014 Aug;33(4):253-7. Epub 2014 Apr 22 doi: 10.3109/15513815.2014.904026. [Epub ahead of print] PMID: 24754368Free PMC Article
Turner AM
J Paediatr Child Health 2014 Oct;50(10):E14-20. Epub 2011 Jul 19 doi: 10.1111/j.1440-1754.2010.01970.x. [Epub ahead of print] PMID: 21771153

Clinical prediction guides

Ekvall S, Wilbe M, Dahlgren J, Legius E, van Haeringen A, Westphal O, Annerén G, Bondeson ML
BMC Med Genet 2015 Oct 14;16:95. doi: 10.1186/s12881-015-0239-1. [Epub ahead of print] PMID: 26467218Free PMC Article
Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S
Horm Res Paediatr 2015;83(3):167-76. Epub 2015 Feb 21 doi: 10.1159/000371635. [Epub ahead of print] PMID: 25721697
Noonan JA, Kappelgaard AM
Horm Res Paediatr 2015;83(3):157-66. Epub 2014 Dec 10 doi: 10.1159/000369012. [Epub ahead of print] PMID: 25503994
Strullu M, Caye A, Lachenaud J, Cassinat B, Gazal S, Fenneteau O, Pouvreau N, Pereira S, Baumann C, Contet A, Sirvent N, Méchinaud F, Guellec I, Adjaoud D, Paillard C, Alberti C, Zenker M, Chomienne C, Bertrand Y, Baruchel A, Verloes A, Cavé H
J Med Genet 2014 Oct;51(10):689-97. Epub 2014 Aug 5 doi: 10.1136/jmedgenet-2014-102611. [Epub ahead of print] PMID: 25097206
Artoni A, Selicorni A, Passamonti SM, Lecchi A, Bucciarelli P, Cerutti M, Cianci P, Gianniello F, Martinelli I
Pediatrics 2014 May;133(5):e1299-304. doi: 10.1542/peds.2013-3251. PMID: 24753526

Recent systematic reviews

Giacomozzi C, Deodati A, Shaikh MG, Ahmed SF, Cianfarani S
Horm Res Paediatr 2015;83(3):167-76. Epub 2015 Feb 21 doi: 10.1159/000371635. [Epub ahead of print] PMID: 25721697
Bader-Meunier B, Cavé H, Jeremiah N, Magerus A, Lanzarotti N, Rieux-Laucat F, Cormier-Daire V
Semin Arthritis Rheum 2013 Oct;43(2):217-9. Epub 2013 Jun 17 doi: 10.1016/j.semarthrit.2013.04.009. [Epub ahead of print] PMID: 23786871
Benca J, Hogan K
Anesth Analg 2009 Oct;109(4):1049-53. doi: 10.1213/ane.0b013e3181adca28. PMID: 19762731
van Driel MA, Cuelenaere K, Kemmeren PP, Leunissen JA, Brunner HG
Eur J Hum Genet 2003 Jan;11(1):57-63. doi: 10.1038/sj.ejhg.5200918. PMID: 12529706
Lee CK, Chang BS, Hong YM, Yang SW, Lee CS, Seo JB
J Bone Joint Surg Am 2001 Oct;83-A(10):1495-502. PMID: 11679599

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